Renoprotective effect of isoliquiritigenin on cisplatin-induced acute kidney injury through inhibition of FPR2 in macrophage.

Acute kidney injury (AKI) is a serious complication in critically ill patients. Accumulating evidences indicated that macrophages play an important pro-inflammatory role in AKI and isoliquiritigenin (ISL) can inhibit macrophagic inflammation, but its role in AKI and the underlying mechanism are unknown. The present study aims to investigate the renoprotective effect of ISL on AKI and the role of Formyl peptide receptors 2 (FPR2) in this process. In this study, cisplatin-induced AKI model and lipopolysaccharide-induced macrophage inflammatory model were employed to perform the in vivo and in vitro experiments. The results showed that ISL strongly relieved kidney injury and inhibited renal inflammation in vivo and suppress macrophagic inflammatory response in vitro. Importantly, it was found that FPR2 was significantly upregulated compared to the control group in AKI and LPS-induced macrophage, whereas it was strongly suppressed by ISL. Interestingly, overexpression of FPR2 with transfection of pcDNA3.1-FPR2 effectively reversed the anti-inflammatory effect of ISL in macrophage, suggesting that FPR2 may be the potential target for ISL to prevent inflammation and improve kidney injury of AKI. Take together, these findings indicated that ISL improved cisplantin-induced kidney injury by inhibiting FPR2 involved macrophagic inflammation, which may provide a potential therapeutic option for AKI.

X-ray induces mechanical and heat allodynia in mouse via TRPA1 and TRPV1 activation.

Radiotherapy-related pain is a common adverse reaction with a high incidence among cancer patients undergoing radiotherapy and remarkably reduces the quality of life. However, the mechanisms of ionizing radiation-induced pain are largely unknown. In this study, mice were treated with 20 Gy X-ray to establish ionizing radiation-induced pain model. X-ray evoked a prolonged mechanical, heat, and cold allodynia in mice. Transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 were significantly upregulated in lumbar dorsal root ganglion. The mechanical and heat allodynia could be transiently reverted by intrathecal injection of transient receptor potential vanilloid 1 antagonist capsazepine and transient receptor potential ankyrin 1 antagonist HC-030031. Additionally, the phosphorylated extracellular regulated protein kinases (ERK) and Jun NH2-terminal Kinase (JNK) in pain neural pathway were induced by X-ray treatment. Our findings indicated that activation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 is essential for the development of X-ray-induced allodynia. Furthermore, our findings suggest that targeting on transient receptor potential vanilloid 1 and transient receptor potential ankyrin 1 may be promising prevention strategies for X-ray-induced allodynia in clinical practice.

Aesthetic and Functional Evaluation of Large Full-Thickness Vermilion and Lower Lip Defects Reconstruction.

BACKGROUND: It is hardly to reconstruct a huge defect of lower lip by using of partial flap which brings no mouth closing functional problem. In this study, we would like to introduce our experience in large full-thickness vermilion and lower lip/chin defects reconstruction, and also focus on the evaluation of the surgery effects. METHODS: The large lower lip and chin (include vermilion) reconstruction were performed in Sichuan Provincial People's Hospital (2012-2015). The surgery experience was introduced in this study first. In the following section, after a statement of these basic problems, various situations involving are investigated, such as the surgical effects of aesthetic and function that were evaluated through a visual analogue scale (VAS) by doctors and patients separately. The VAS score assessments of 2 kinds of surgery were collected and compared. RESULTS: A total of 7 patients use the tongue flap alone. Four patients use the combination of the free forearm flap and the anterior ventral tongue flap (COMBO flap). The VAS score of doctors group was significantly lower than the patients group (P < 0.05), and the aesthetic appearance was excellent (>90 points). Language features were not affected (>90 points). Slight mouth opening problems exist on these patients who were used COMBO flaps (>80 points; <90 points). The drooling and drumming gas problems were not observed. These 11 patients had no recurrence within 12 months after the operation. CONCLUSION: The 1:1 ratio between upper and lower lip is crucial to the design of anterior ventral tongue flap which brings with an excellent 3-dimensional morphologic and anatomic structure outcome. The bite block might become an essential operation step for vermilion reconstruction by using of tongue flap. And the COMBO flap may enhance the facial aesthetics and oral function for the reconstruction.

Preliminary Analysis of Parkinson-like Motor Coordination Abnormityin Brain-specific hS100B Transgenic Mice.

Objective To investigate the role of S100B in the development of Parkinson's disease (PD) and explore the possibility of brain-specific S100B transgenic mice as PD animal model. Methods The hS100B transgenic mice were established. The mice were divided into S100B transgenic group (TG),S100B knockout group (KG),and the non-transgenic control group (CG). Motor coordination ability of mice was measured by the rota-rod and pole-climbing test. The expressions of S100B,dopamine D1 receptor,dopamine D2 receptor,G protein-coupled receptor kinase (GRK)2,GRK5,and tyrosine hydroxylase in brain tissue were detected by reverse transcription-polymerase chain reaction and Western blot. The levels of tyrosine,levodopa,dopamine,and homovanillic acid in brain tissue were measured by high-performance liquid chromatography coupled with fluorescence detection. Results Compared with CG,the S100B protein expression in brain tissue significantly increased in TG (P<0.05);the motor coordination ability of mice showed progressive decline (P<0.05);the mRNA and protein expressions of dopamine D2 receptor and GRK2 significantly decreased (P<0.05);the levels of levodopa,dopamine,and homovanillic acid were significantly elevated (P<0.05);the expression of tyrosine hydroxylase was also down-regulated,although there was no significant difference (P>0.05). Compared with CG,there was no obvious change of the above indicators in KG (all P>0.05). Conclusion S100B plays an important role in the motor coordination abnormity of PD. The brain-specific S100B transgenic mice can be used in research on the role of S100B gene in the development of PD.

[Discrete potentials guided ablation for idiopathic outflow tract ventricular arrhythmias].

OBJECTIVE: Discrete potentials (DPs) have been recorded and targeted as the site of ablation of the outflow tract arrhythmias. The aim of the present study was to investigate the significance of DPs with respect to mapping and ablation for idiopathic outflow tract premature ventricular contractions (PVCs) or ventricular tachycardias (VTs). METHODS: Seventeen out of 24 consecutive patients with idiopathic right or left ventricular outflow tract PVCs/VTs who underwent radiofrequency catheter ablation between September 2012 and December 2013 in our department were included. Intracardiac electrograms during the mapping and ablation were analyzed. RESULTS: During sinus rhythm, sharp high-frequency DPs that displayed double or multiple components were recorded following or buried in the local ventricular electrograms in all of the 17 patients, peak amplitude was (0.51 ± 0.21) mV. The same potential was recorded prior to the local ventricular potential of the PVCs/VTs. Spontaneous reversal of the relationship of the DPs to the local ventricular electrogram was noted during the arrhythmias. The DPs were related to a region of low voltage showed by intracardiac high-density contact mapping. At the sites with DPs, unipolar and bipolar ventricular voltage of sinus beats were lower compared with the adjacent regions without DPs (unipolar: (6.1 ± 1.8) mV vs. (8.3 ± 2.3) mV, P < 0.05; bipolar: (0.62 ± 0.45) mV vs. (1.03 ± 0.60) mV, P < 0.05). The targeted DPs were still present in 12 patients after successful elimination of the ectopies. Discrete potentials were not present in seven controls. CONCLUSIONS: Discrete potentials and related low-voltage regions were common in idiopathic outflow tract ventricular arrhythmias. Discrete potential- and substrate-guided ablation strategy could help to reduce the recurrence of idiopathic outflow tract arrhythmias.

Hybridization chain reaction engineered DNA nanopolylinker for amplified electrochemical sensing of biomarkers.

A DNA nanopolylinker was designed as a three dimensional nanoprobe with high loading of signal molecules for amplifying the biosensing signal. The nanoprobe was prepared by hybridization chain reaction engineering dsDNA polymerization on initiator DNA modified Au nanoparticle with two kinds of small molecule, for example, FITC-labeled DNA hairpins. The core-shell conjugate that was formed contained approximately 320 FITC molecules for further binding of signal molecules. With a sandwich-type immunoreaction and a biotin-streptavidin affinity reaction, the biotinylated core-shell nanoprobe was immobilized on the immunosensor surface, and the FITC molecules then bound enzyme labeled anti-FITC antibody to catalyze a silver deposition process, leading to a novel cascade signal amplification strategy. By combining the proposed strategy with stripping analysis of the deposited silver, an ultrasensitive immunoassay method for biomarker detection was developed. Under optimal conditions, this method showed a linear detection range over 5 orders of magnitude for carcinoembryonic antigen with a detection limit of 1.2 fg mL(-1) (about 18 molecules in 5.0 µL sample). The preparation of DNA nanopolylinker was simple and economic, and it could be used as a universal and multifarious probe for different bioanalytical techniques and showed the promising potential of the signal amplification strategy in the future design of biosensing methodology.

Paper-based colorimetric glucose sensor using Prussian blue nanoparticles as mimic peroxidase.

A novel paper-based colorimetric glucose sensor was proposed employing Prussian blue nanoparticles (PB NPs) as mimic peroxidase. The sensor was manufactured by spraying solution containing PB NPs, glucose oxidase and chromogenic agents into a paper, then coating the filter layer and spreading layer on the top. The layer-by-layer structure enabled the sensor detect glucose in whole blood, as well as elimination of the coffee-ring effect which ensure the performance. As a powerful alternative to natural peroxidase, PB NPs showed the mimic enzymatic activity well preserved in dry environment. The manufacture process of the sensor is easy to be industrialized. Under optimal conditions, the sensor exhibited a linear range from 2.5 mM to 25 mM for glucose in blood with satisfactory reproducibility (the coefficient of variant <4%), great storage stability (1 month at 45 °C) and excellent linearity compared with those commercial kits (R > 0.99). Coupled with a handhold device, the PB NPs-based test strip realized the goal of personal operation, user-friendly control, automatic readouts, and data storage, and able to link the Cloud, showing unique potential in clinical application, especially in community-level medical scenarios.

Mitigating Cd and bacterial wilt stress in tomato plants through trico-synthesized silicon nanoparticles and Trichoderma metabolites.

There has been a growing apprehension in recent years about the harmful effects of environmental pollutants on agricultural output, encompassing both living organisms and non-living factors that cause stress. In this study, the soil application of bulk silicon (Si), silicon nanoparticles (SiNPs) and Trichoderma metabolites (TM) were investigated alone or in combination for the management of an important abiotic stress i.e. Cd toxicity and biotic stress i.e. bacterial wilt (BW) in tomato plants. SiNPs were synthesized by Trichoderma and confirmed through XRD, FTIR, and Ranman spectrum analysis. Results showed that Si, SiNPs and TM were all effective treatments. The combine treatment of SiNPs and TM followed by SiNPs alone were superior over other treatments in mitigating Cd toxicity and reducing BW disease on tomato plants. The soil application of these treatments reduced the Cd toxicity by enhancing Cd-tolerance index, decreasing bioavailability of soil Cd, reducing Cd contents and translocation in plants, improving gaseous exchange, photosynthesis, and increasing the antioxidant enzyme activities and their transcriptions. These treatments significantly suppressed BW pathogen leading to the significant decrease in disease index and severity on plants. In vitro evaluation and scanning electron microscopic (SEM) analysis revealed that SiNPs and TM significantly disrupted the cellular morphology of BW pathogen Ralstonia solanacearum. Findings of this study proposes the possible use of SiNPs and TM in mitigating the Cd and BW stress in tomato plants and possibly in other crops.

Landscape of team-based care to manage hypertension: results from two surveys in low/middle-income countries.

OBJECTIVES: Team-based care is essential for improving hypertension outcomes in low-resource settings. We assessed perceptions of country representatives and healthcare workers (HCWs) on team-based hypertension care in low/middle-income countries. DESIGN: Two cross-sectional surveys. SETTING: The first survey (Country Profile Survey) was conducted in 17 countries and eight in-country regions: Algeria, Bangladesh, Burundi, Chile, China (Beijing, Henan, Shandong), Cuba, Ethiopia, India (Kerala, Madhya Pradesh, Maharashtra, Punjab, Telangana), Nepal, Nigeria, Philippines, Saint Lucia, Sri Lanka, Thailand, Turkey, Uganda and Vietnam. The second survey (HCW Survey) was conducted in four countries: Bangladesh, China, Ethiopia and Nigeria. PARTICIPANTS: Using convenience sampling, participants for the Country Profile Survey were representatives from 17 countries and eight in-country regions, and the HCW Survey was administered to HCWs in Bangladesh, China, Ethiopia and Nigeria. OUTCOME MEASURES: Country-level use of team-based hypertension care framework, comprising administrative, basic and advanced clinical tasks. Current practices of different HCW cadres, perspectives on team-based management of hypertension, barriers and facilitators. RESULTS: In the Country Profile Survey, all (23/23, 100%) countries/regions surveyed integrated team-based care for basic clinical hypertension management tasks, less for advanced tasks (7/23, 30%). In the HCW Survey, 854 HCWs participated, 47% of whom worked in rural settings. Most HCWs in the sample acknowledged the value of team-based hypertension care. Although there were slight variations by country in the study sample, overall, barriers to team-based hypertension care were identified as inadequate training (83%); regulatory issues (76%); resistance by patients (56%), physicians (42%) and nurses (40%). Facilitators identified were use of treatment algorithms (94%), telehealth/m-health technology (92%) and adequate compensation for HCWs (80%). CONCLUSIONS: Our findings revealed key lessons for health systems and governments regarding team-based care implementation. Specifically, policies to facilitate additional training, optimise HCWs' roles within care teams, use of hypertension treatment protocols and telehealth/m-health technology will be essential to promote team-based care.

Ventromedial Thalamus-Projecting DCN Neurons Modulate Associative Sensorimotor Responses in Mice.

The deep cerebellar nuclei (DCN) integrate various inputs to the cerebellum and form the final cerebellar outputs critical for associative sensorimotor learning. However, the functional relevance of distinct neuronal subpopulations within the DCN remains poorly understood. Here, we examined a subpopulation of mouse DCN neurons whose axons specifically project to the ventromedial (Vm) thalamus (DCNVm neurons), and found that these neurons represent a specific subset of DCN units whose activity varies with trace eyeblink conditioning (tEBC), a classical associative sensorimotor learning task. Upon conditioning, the activity of DCNVm neurons signaled the performance of conditioned eyeblink responses (CRs). Optogenetic activation and inhibition of the DCNVm neurons in well-trained mice amplified and diminished the CRs, respectively. Chemogenetic manipulation of the DCNVm neurons had no effects on non-associative motor coordination. Furthermore, optogenetic activation of the DCNVm neurons caused rapid elevated firing activity in the cingulate cortex, a brain area critical for bridging the time gap between sensory stimuli and motor execution during tEBC. Together, our data highlights DCNVm neurons' function and delineates their kinematic parameters that modulate the strength of associative sensorimotor responses.

An immune risk score with potential implications in prognosis and immunotherapy of metastatic melanoma.

Melanoma is a highly aggressive cancer with a poor prognosis. We found that immune response played important roles in melanoma metastasis by GSEA analysis. Therefore, we constructed the immune risk score (IRS) by the LASSO-COX analysis in the sequencing metastatic samples from the TCGA database. Then, initial diagnosis patients with metastasis were selected as the test cohort. Importantly, we adopted overall survival (OS) as the survival outcome for initial diagnosis patients, while adopting the observed survival interval (OBS) as the survival outcome for sequencing samples which could avoid biologically meaningless associations. We found that the IRS had high power for predicting 2, 3 and 5-year survival in training (AUC = 0.70, 0.69 and 0.68) and test cohorts (AUC = 0.72, 0.70 and 0.65). The IRS was significantly associated with prognosis both in the metastatic samples (HR = 1.60, 95% CI = 1.16-2.19) and patients with metastasis (HR = 2.89, 95% CI = 1.69-4.53). we further used other independent melanoma cohorts from the GEO databases to confirm the reliability and validity of the IRS (P < 0.01 in all cohorts). The practical nomogram was also built using the IRS and clinical information with high c-index both in training (0.76, 95%CI = 0.72-0.80) and test cohorts (0.72, 95%CI = 0.65-0.79). Finally, IRS showed the predictive value of survival outcome and response of immunotherapy patients, and increased the predictive ability of current immune checkpoint gene markers. In conclusion, the IRS can serve as a potential biomarker for prognosis and responsiveness to immune checkpoint blockade immunotherapy in metastatic melanoma patients.

Predicting the Risk of Melanoma Metastasis Using an Immune Risk Score in the Melanoma Cohort.

Melanoma is a highly aggressive cancer, attracting increasing attention worldwide. The 5-year survival rate of patients with metastatic melanoma is low. Therefore, it is critical to identify potential effective biomarkers for diagnosis of melanoma metastasis. In the present study, the melanoma cohort and immune genes were obtained from the Cancer Genome Atlas (TCGA) database and the ImmPort database, respectively. Then, we constructed the immune risk score (IRS) using univariate and multivariate logistic analysis. The area under the curve (AUC) of IRS in sequencing samples and the initial diagnosis patients was 0.90 and 0.80, respectively. Besides, IRS could add benefits for metastasis diagnosis. For sequencing samples, IRS (OR = 16.35, 95% CI = 8.74-30.59) increased the odds for melanoma metastasis. Similar results were obtained in the initial diagnosis patients (OR = 8.93, 95% CI = 3.53-22.61). A composite nomogram was built based on IRS and clinical information with well-fitted calibration curves. We further used other independent melanoma cohorts from Gene Expression Omnibus (GEO) databases to confirm the reliability and validity of the IRS (AUC > 0.75, OR > 1.04, and P value < 0.01 in all cohorts). In conclusion, IRS is significantly associated with melanoma metastasis and can be a novel effective signature for predicting the metastasis risk.

The pathogenesis of diabetes retinopathy:progress in miRNAs / 眼科新进展

Diabetic retinopathy,a main microvascular complication of diabetes,remains the leading cause of blindness in the working-age population,but its specific pathogenesis has not been fully elucidated.microRNAs(miRNAs)are small non-coding RNAs,acting as post-transcriptional regulators of gene expression.Its aberrant expression plays a key role in modulating pathological processes associated to many diseases.Studies confirmed the role of miRNAs in the regulation of oxidative stress,inflammation,cell death and angiogenesis which influences the development of DR.This review focuses on the role of miRNAs in DR,which may provide a reference basis for diagnosis,prognosis and therapeutics.

Fangchinoline supplementation attenuates inflammatory markers in experimental rheumatoid arthritis-induced rats.

The present study evaluated the anti-inflammatory activity of fangchinoline in rheumatoid arthritis-induced rats. Rats were grouped into sham (group I), rheumatoid arthritis (group II, control), fangchinoline (2 µM, group III), and fangchinoline (4 µM, group IV) groups. The serum levels of lipid peroxidation, superoxide dismutase (SOD), glutathione peroxidase (Gpx), catalase, reduced glutathione (GSH), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), matrix metalloproteinases (MMPs), prostaglandin-E2 (PGE2), nitric oxide (NO), zinc, ceruloplasmin, uric acid, and copper were determined. Chondrocyte cell proliferation, reactive oxygen species (ROS), and cellular levels of TNF-α and IL-6 were assessed. Lipid peroxidation, GSH, SOD, catalase, and Gpx levels recovered to near normal levels by fangchinoline treatment. Fangchinoline treatment significantly reduced the TNF-α level by 17.8% and 40.8% in groups III and IV respectively, whereas IL-6 was significantly decreased by 23.2% and 45%, respectively. Fangchinoline treatment significantly decreased the MMP-3 level by 23.1% and 65.1% in groups III and IV respectively, whereas PGE2 was significantly decreased by 31.8% and 63.8%, respectively. Fangchinoline treatment decreased NO, uric acid, ceruloplasmin, and copper levels, whereas the zinc content was increased. Chondrocyte proliferation was significantly reduced to 73.3%, 51.3%, and 42.4% at 2 µM, 4 µM, and 6 µM fangchinoline treatment respectively. Intracellular ROS, TNF-α, and IL-6 levels were significantly reduced in the chondrocytes. Protein expression of TNF-α was significantly decreased by 0.27-, 0.53-, and 0.67-fold at 2 µM, 4 µM, and 6 µM fangchinoline treatment respectively. In conclusion, fangchinoline is effective as an anti-inflammatory agent in rheumatoid arthritis-induced rats.

Pharmacoeconomic evaluation of trastuzumab biosimilars versus original drug in the treatment of recurrent/metastatic HER-2 positive breast cancer / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of trastuzumab biosimilars （Hanquyou） versus original drug （Hesaiting） in the treatment of recurrent/metastatic human epidermal growth factor receptor-2 （HER-2） positive breast cancer. METHODS A partitional survival model was constructed based on the NCT03084237 trial data. The simulation period was 3 weeks， and the simulation time was 10 years. Using costs and quality-adjusted life year （QALY） as the output indicator， the cost- utility analysis method was used to evaluate the cost-effectiveness of the two schemes mentioned above. Univariate and probabilistic sensitivity analyses were performed to verify the robustness of the basic analysis. RESULTS The costs of the trastuzumab biosimilars group and original drug group were 111 516.72 yuan and 111 122.30 yuan respectively， with health utility values of 1.52 QALYs and 1.36 QALYs， and ICER of 2 465.12 yuan/QALY， which were less than 3 times China’s per capita gross domestic product （GDP） in 2023 as the threshold for willingness-to-pay （WTP） （268 200 yuan/QALY）. Univariate sensitivity analysis showed that the cost of the trastuzumab biosimilars and original drug had a great impact on the ICER. The probabilistic sensitivity analysis showed that the probability of trastuzumab biosimilars being cost-effective was 100% at WTP threshold of 14 902 yuan/QALY. CONCLUSIONS When WTP threshold is 3 times China’s GDP in 2023 （268 200 yuan/QALY）， compared with original drug， trastuzumab biosimilars have good cost-effectiveness in the treatment of recurrent/metastatic HER-2 positive breast cancer.

Effect of pre-pregnancy obesity on trimester-specific thyroid dysfunction / 上海预防医学

ObjectiveTo explore the risk of different levels of pre-pregnancy obesity on trimester-specific thyroid dysfunction. MethodsQuestionnaire information， blood samples， and urine samples from a 2017 pregnancy cohort study in Shanghai， China were collected. A total of 2 455 pregnant women were included in the analysis. Pre-pregnancy BMI was calculated based on the height and self-reported pre-pregnancy weight. Serum TSH， total thyroxine （TT4）， free thyroxine （FT4）， total triiodothyronine （TT3）， free triiodothyronine （FT3）， thyroid globulin antibody（TgAb）， and Thyroid peroxidase antibody （TPOAb） were measured using the electrochemiluminescence method. Urine iodine levels were measured using the acid digestion method. Levels of thyroid function indexes of pregnant women with different degrees of obesity during pre-pregnancy were compared， and trimester-specific thyroid dysfunction was evaluated according to the reference range of trimester-specific thyroid hormone established by this cohort. Multivariate logistic regressions analysis was used to assess the correlation between pre-pregnancy obesity and trimester-specific thyroid dysfunction. ResultsAs the degree of obesity increased， maternal levels of FT3 and TT3 gradually increased during pregnancy （P<0.001， P=0.001）， while FT4 levels gradually decreased （P=0.001）. Multivariate logistic regression analysis showed that compared with the normal weight group， pregnant women who were overweight or obesity before pregnancy had a significantly higher risk of hypothyroxinemia （OR=3.85， 95%CI： 2.08‒7.14， P<0.001） and high TT3 （OR=2.78， 95%CI： 1.45‒5.26， P=0.002） during pregnancy. ConclusionPre-pregnancy overweight or obesity can increase the risk of thyroid dysfunction during pregnancy.

A case-control study on gut microbiota diversity and species composition in obese/overweight children aged 2-6 years in Shanghai / 环境与职业医学

Background Multiple studies have shown a close relationship between changes in gut microbiota composition and obesity, and research results are influenced by factors such as race and geographical location, but there are few studies on children. Objective To analyze the diversity of gut microbiota related to obesity in a population of 2-6 years old, observe the distribution characteristics and species differences of gut microbiota between obese/overweight and normal weight groups, and explore the association betweenobese/overweight and gut microbiota diversity. Methods Fecal samples were collected from 74 children aged 2-6 years in Shanghai, including 18 obese/overweight individuals, 6 males and 12 females (male to female ratio of 1∶2), and 56 normal weight individuals, 18 males and 38 females (male to female ratio is nearly 1∶2). The 16S rDNA was extracted from bacteria in fecal samples, followed by PCR amplification, cDNA construction, and high-throughput sequencing. Naive Bayes algorithm was used to perform taxonomic analysis (phylum, class, order, family, genus, species) and community diversity analysis (Sobs index, Shannon index, Shannoneven index, Coverage index, PD index, and principal co-ordinates analysis) on representative sequences and abundance of amplicon sequence variants (ASV). Wilcoxon rank sum test, P-value multiple test correction, and analysis of similarities were used to test differences between the two groups to obtain information on the distribution characteristics and species differences of intestinal microbiota in children. Results Seventy-four fecal samples were sequenced, and the sequencing results were subjected to quality control and filtering. A total of 4905306 optimized sequences were obtained, resulting in 1860 ASVs. The diversity data analysis of ASVs generated 889 species annotation results at 8 taxonomic levels. The alpha diversity analysis showed that the richness (Sobs index), diversity (Shannon index), evenness (Shannoneven index), and phylogenetic diversity (PD index) of fecal community of the obese/overweight children were increased compared to those of the normal weight children, but there were no statistical differences between the two groups (P>0.05). The beta diversity analysis showed that there was little difference in the composition of microbial species between the two groups, and no significant clustering separation was observed. The results of species composition analysis at phylum, order, family, and genus levels of 74 samples showed a consistent core microbiota structure in the two groups of gut microbiota, but there were differences in microbiota composition. The differences in microbial community composition between the two groups were manifested at the taxonomic levels of order, family, and genus, among which phylum Firmicutes, order Erysipelotrichales, family Erysipelatocyclostridiaceae, genus Erysipelotrichaceae_ UCG-003 and genus Catenibacterium were significantly enriched in the obese/overweight group and contributed significantly to the phenotypic difference of obese/overweight [linear discriminant analysis (LDA)=3.72, P<0.01; LDA=3.29, P<0.05). Phylum Proteobacteria, order Enterobacterales, family Enterobacteriaceae, genus unclassified was significantly enriched in the normal weight group and contributed significantly to the phenotypic difference of normal body weight (LDA=3.93, P<0.05). Conclusion The richness and diversity of gut microbiota in obese/overweight children aged 2-6 years in Shanghai are increased, but there is no difference compared to normal weight children. There is a difference in the composition of gut microbiota between the obese/overweight group and the normal weight group.

RAS-selective lethal small molecule 3 inhibits the fibrosis of pathological scar fibroblasts / 中国组织工程研究

BACKGROUND:Abnormal extracellular matrix accumulation and excessive proliferation of fibroblasts are the main manifestations of pathological scars.Excessive proliferation of fibroblasts leads to the production of large amounts of collagen-based extracellular matrix.Therefore,to investigate the role of fibroblast fibrosis in the formation of pathological scar will provide a new idea for revealing the mechanism of pathological scar and biological therapy. OBJECTIVE:To investigate the effect of RAS-selective lethal small molecule 3(RSL3)on the fibrosis of human pathological scar fibroblasts. METHODS:Then cases of pathological scar tissue and normal skin tissue samples from the same individuals,provided by the Department of Burn Plastic Surgery,General Hospital of Ningxia Medical University,were collected.Fibroblasts of human pathological scar and human normal skin were extracted and used in the following experiments.The general condition of the pathological scar tissue and the normal skin tissue was detected by hematoxylin-eosin staining.The appearance of fibroblasts from pathological scar and normal skin were observed by inverted microscope.The fibroblasts were verified by immunofluorescence assay.The cells were treated with different concentrations of RSL3(1,3,5,7,9,11,13 μmol/L).The inhibitory concentration of RSL3 on fibroblasts was detected by cell counting kit-8.Control group(without treatment)and RSL3 intervention group(treated with 7 μmol/L RSL3 for 24 hours)were set up.The mRNA and protein expressions of glutathione peroxidase 4,type Ⅰ collagen,type Ⅲ collagen and α-smooth muscle actin were detected by Qrt-PCR and western blot,respectively.Level of malondialdehyde in cells was detected.The residual scratch area was measured by cell scratch test after 24 hours to calculate the percentage of residual scratch area. RESULTS AND CONCLUSION:The expression of glutathione peroxidase 4 in the pathological scar group was higher than that in the normal skin group(Mrna:t=3.252,P<0.01;protein:t=5.075,P<0.01).The expression of glutathione peroxidase 4 in the pathological scar fibroblast group was higher than that in the normal skin fibroblast group(Mrna:t=10.32,P<0.01;protein:t=26.22,P<0.01).Compared with the control group,the expression of glutathione peroxidase 4 was decreased(Mrna:t=2.798,P<0.05;protein:t=4.643,P<0.01),the content of malondialdehyde was increased(t=2.917,P<0.05),the expression of type Ⅰ collagen(Mrna:t=15.84,P<0.01;protein:t=4.610,P<0.01),type Ⅲ collagen(Mrna:t=28.86,P<0.01;protein:t=7.713,P<0.01)and α-smooth muscle actin(Mrna:t=2.671,P<0.05;protein:t=7.417,P<0.01)were decreased in the RSL3 intervention group.Compared with the control group,the migration ability was weakened in the RSL3 intervention group(t=14.06,P<0.01).To conclude,RSL3 can inhibit the expression of glutathione peroxidase 4 and then inhibit the ability of fibrosis and migration of pathological scar fibroblasts.

Efficacy comparison between olaparib and platinum-containing regimen for treatment of platinum-sensitive relapsed ovarian cancer patients with BRCA mutation / 肿瘤研究与临床

Objective:To explore the differences in tumor-specific growth factors, cellular immune function and efficacy of olaparib and platinum-containing regimen for treatment of platinum-sensitive relapsed ovarian cancer patients with BRCA mutation.Methods:A retrospective cohort study was conducted. A total of 100 platinum-sensitive relapsed BRCA-mutant ovarian cancer patients in Baoding Second Central Hospital from September 2017 to March 2020 were retrospectively selected. The clinical data of the patients were analyzed, and they were divided into the olaparib group (treated with olaparib tablets) and the platinum-containing regimen group (treated with paclitaxel and platinum drugs for 6 cycles, followed by olaparib tablets maintenance therapy), with 50 patients in each group. The clinical efficacy, tumor specific growth factor [carbohydrate antigen (CA) 125, CA199, human epididymal protein 4 (HE4)] levels, cellular immune function-related indicators [T-cell subsets (proportions of CD3 + cells and CD4 + cells), CD4 + cells/CD8 + cells ratio (CD4 +/CD8 +)], and quality of life scores before treatment and after 2, 4 and 6 cycles of treatment of the two groups were compared, as well as the safety of the two groups. The data of three years of follow-up were obtained, Kaplan-Meier method was used to analyze the progression-free survival (PFS) of patients in the two groups, and log-rank test was used for comparison between groups. Results:The age of patients in the olaparib and platinum-containing regimen groups was (53±7) years old and (56±7) years old, respectively. The differences in compositions of patients with different age, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status score, primary tumor location, lesion size, pathological stage, pathological type, germline BRCA mutation, and previous chemotherapy response between the two groups were not statistically significant (all P > 0.05). The objective response rate (ORR) [58.0% (29/50) vs. 38.0% (19/50)] and disease control rate (DCR) [80.0% (40/50) vs. 56.0% (28/50)] of the olaparib group after treatment were higher than those of the platinum-containing regimen group, and the differences were statistically significant (both P < 0.05). Serum CA125, CA199 and HE4 levels were gradually decreased in both groups before treatment and after 2, 4 and 6 cycles of treatment (all P < 0.05); serum CA125, CA199 and HE4 levels in the olaparib group after 2, 4 and 6 cycles of treatment were lower than those in the platinum-containing regimen group, and the differences were statistically significant (all P < 0.05). The CD3 + cells ratio, CD4 + cell ratio and CD4 +/CD8 + in the olaparib group gradually increased before treatment and after 2, 4 and 6 cycles of treatment (all P < 0.05), while those in the platinum-containing regimen group all gradually decreased (all P < 0.05); the CD3 + cells ratio, CD4 + cells ratio and CD4 +/CD8 + in the olaparib group were higher than those in the platinum-containing regimen group after 2, 4 and 6 cycles of treatment, and the differences were statistically significant (all P < 0.05). The quality of life scores of both groups increased before treatment and after 2, 4 and 6 cycles of treatment (all P < 0.05), and the quality of life scores of the olaparib group were higher than those of the platinum-containing regimen group after 2, 4 and 6 cycles of treatment, and the differences were statistically significant (all P < 0.05). The incidence of nausea, fatigue and malaise, vomiting, anemia, and diarrhea at all levels in the olaparib group was lower than those in the platinum-containing regimen group (all P < 0.05). By follow-up for 3 years, there was no statistically significant difference in PFS between the olaparib group and the platinum-containing regimen group ( P > 0.05). Conclusions:The efficacy of olaparib treatment in platinum-sensitive relapsed ovarian cancer patients with BRCA mutation is superior to platinum-containing regimen, and it can increase the level of T cells, inhibit the expression of tumor-specific growth factors, improve the quality of life, and have a positive effect on improving the safety of treatment.

Toremifene, an Alternative Adjuvant Endocrine Therapy, Is Better Than Tamoxifen in Breast Cancer Patients with CYP2D6*10 Mutant Genotypes / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor (HR)–positive breast cancer patients under different genotypes. @*Materials and Methods@#CYP2D6*10 genotypes of HR-positive breast cancer patients were determined by Sanger sequencing, and all the patients were divided into tamoxifen group or toremifene group. @*Results@#A total of 268 patients with HR-positive breast cancer were studied. The median follow-up time was 72.0 months (range, 5.0 to 88.0 months). Of these, 88 (32.9%), 114 (42.5%), and 66 (24.6%) patients had C/C, C/T, and T/T genotypes, respectively. Among patients who received tamoxifen (n=176), the 5-year disease-free survival (DFS) rate in patients with C/C and C/T genotype was better than that in patients with T/T genotype, and the difference was statistically significant (p < 0.001 and p=0.030, respectively). In patients receiving toremifene, CYP2D6*10 genotype was not significantly associated with DFS (p=0.325). Regardless of genotypes, the 5-year DFS rate was higher in patients treated with toremifene than in patients with tamoxifen (91.3% vs. 80.0%, p=0.011). Compared with tamoxifen, toremifene remained an independent prognostic marker of DFS in multivariate analysis (hazard ratio, 0.422; p=0.021). For all the 180 patients with CYP2D6*10 C/T and T/T genotypes, the 5-year DFS rate was significantly higher in the toremifene group than in the tamoxifen group (90.8% vs. 70.1%, p=0.003). @*Conclusion@#Toremifene may be an alternative adjuvant endocrine therapy for patients with CYP2D6*10 mutant genotypes.