HTB50-2 Inhibits Growth and Migration of Triple-negative Breast Cancer via FOSL2/FOXC1 Signaling Axis and Subsequent Ferroptosis.

BACKGROUND: The manipulation of ferroptosis in cancer cells is a possible therapeutic technique that has been investigated for use in the treatment of cancer. Consequently, ferroptosis-inducing medications have recently received increased interest in cancer therapy. In this research, we assessed the anticancer efficacy of 14ß-hydroxy- 3ß-(ß-D-Glucopyranosyloxy)-5α-bufa-20,22-dienolide (HTB50-2), a natural product derived from the plant Helleborus thibetanus Franch, in Triple-Negative Breast Cancer (TNBC). Moreover, we also studied its potential mechanisms. METHODS: The biological effects of HTB50-2 in a series of breast cancer cell lines were analyzed using sulforhodamine B (SRB) and other methods. The migration ability was analyzed using three methods: wound healing assay, transwell assay, and Western blot. Meanwhile, the potential therapeutic value of HTB50-2 was evaluated in BALB/c mice by orthotopic transplantation. Transcriptome sequencing was conducted to explore the FOS-like antigen 2 (FOSL2) gene, and its role in ferroptosis was verified by Western blot and immunohistochemistry. The association of FOSL2 and ferroptosis-related genes was analyzed using NetworkAnalyst databases, and a TF-Gene interaction network was constructed. RESULTS: Ferroptosis was found to be induced in TNBC cells by HTB50-2. Furthermore, HTB50-2 inhibited tumor development by inducing ferroptosis in TNBC in vivo. Mechanistically, we demonstrated that a transcription factor FOSL2 mediated ferroptosis by HTB50-2. Additionally, it was found that Forkhead box C1 (FOXC1) was regulated by FOSL2 and correlated with ferroptosis. CONCLUSION: Our data suggest that HTB50-2 exerts its anti-cancer properties by ferroptosis via FOSL2/FOXC1 signaling pathway. Hence, HTB50-2 has an important application potential in the treatment of TNBC.

[Effect of Hei Xiaoyaosan regulating p38MAPK/Beclin-1/Bcl-2 pathway on autophagy level in Alzheimer's disease model rats].

To explore the effect of Hei Xiaoyaosan on autophagy levels in Alzheimer's disease(AD). A total of 100 4-month-old Wistar male rats were randomly selected as a blank group, and 10 rats were taken as a sham operation group and injected with 1 µL of normal saline on both sides of the hippocampus. The other rats were injected with Aß_(1-42) solution in the hippocampus to replicate the AD model. Fifty successfully modeled rats were selected and randomly divided into the model group, Aricatio group(0.5 mg·kg~(-1)), and high, medium, and low dose groups of Hei Xiaoyaosan(15.30, 7.65, and 3.82 g·kg~(-1)), with 10 rats in each group. The rats were administered by continuous gavage for 42 days. Morris water maze was used to detect the learning and memory ability of rats, and Hoechst staining was used to observe the pathological changes of nerve cells in the hippocampal CA1 region. The mRNA expression of p38MAPK, Beclin-1, and Bcl-2 was detected by RT-qPCR.Western blot was used to detect the expressions of p38MAPK, Beclin-1, Bcl-2, APP, and related proteins. The level of Aß_(1-42) in the hippocampus was detected by ELISA, and the expression level of LC3Ⅱ in the hippocampus was detected by immunohistochemistry. The experimental results showed that compared with the blank group, the learning and memory ability of rats in the model group decreased(P<0.01). The nuclei in the CA1 region of the hippocampus showed blue bright spots and were closely arranged. The mRNA expression of p38MAPK was up-regulated, and the mRNA expressions of Beclin-1 and Bcl-2 were down-regulated(P<0.01). The expressions of p38MAPK, p-p38MAPK, and APP were increased, while those of Beclin-1, Bcl-2, and p-Bcl-2 were decreased(P<0.01). The expression of Aß_(1-42) was increased(P<0.01). The relative expression of LC3Ⅱ decreased(P<0.01). Compared with the model group, the learning and memory ability of rats in each administration group was improved(P<0.05 or P<0.01). The nuclei in the CA1 region of the hippocampus gradually became clear, showing light blue. The mRNA expression of p38MAPK was down-regulated(P<0.01), and that of Beclin-1 and Bcl-2 was increased(P<0.05 or P<0.01). The expressions of p38MAPK, p-p38MAPK, and APP were down-regulated, while those of Beclin-1, Bcl-2, and p-Bcl-2 were up-regulated(P<0.05 or P<0.01). The expression of Aß_(1-42) was decreased(P<0.01). The relative expression of LC3Ⅱ was increased(P<0.01). It can be concluded that Hei Xiaoyaosan can improve the cognitive ability of AD model rats, and its potential mechanism may be related to regulating the p38MAPK/Beclin-1/Bcl-2 signaling pathway, increasing the level of autophagy, and reducing the accumulation of Aß_(1-42).

Microdeletion on Xq27.1 in a Chinese VACTERL-Like Family with Kidney and Anal Anomalies.

Objective: VATER/VACTERL-like association is associated with adverse pregnancy outcomes. Genetic evidence of this disorder is sporadic. In this study, we aimed to provide genetic insights to improve the diagnosis of VACTERL. Methods: We have described a Chinese family in which four members were affected by renal defects or agenesis, anal atresia, and anovaginal fistula, which is consistent with the diagnosis of a VACTERL-like association. Pedigree and genetic analyses were conducted using genome and exome sequencing. Results: Segregation analysis revealed the presence of a recessive X-linked microdeletion in two living affected individuals, harboring a 196-380 kb microdeletion on Xq27.1, which was identified by familial exome sequencing. Genome sequencing was performed on the affected male, confirming a -196 kb microdeletion in Xq27.1, which included a 28% loss of the CDR-1 gene. Four family members were included in the co-segregation analysis, and only VACTERL-like cases with microdeletions were reported in X27.1. Conclusion: These results suggest that the 196-380 kb microdeletion in Xq27.1 could be a possible cause of the VATER/VACTERL-like association. However, further genetic and functional analyses are required to confirm or rule out genetic background as the definitive cause of the VACTERL association.

Characterization of the H2/NOx reaction process over the La0.9Ce0.1Co0.9Pd0.1O3-BaO/Al2O3 catalyst.

An excellent textual properties and performance La0.9Ce0.1Co0.9Pd0.1O3-BaO/Al2O3 catalyst was synthesized. The reaction mechanism of H2/NOx over the La0.9Ce0.1Co0.9Pd0.1O3-BaO/Al2O3 catalyst was investigated by temperature programmed reduction/ desorption/ surface reaction (TPR/D/SR) technologies and in-situ diffuse reflectance Fourier transform (DRIFT) technology. The results show that cerium or palladium species are inserted into the cells of LaCoO3, as well as they synergetic promote the redox properties of the La0.9Ce0.1Co0.9Pd0.1O3-BaO/Al2O3 catalyst. Surface activated nitrates exist over the La0.9Ce0.1Co0.9Pd0.1O3-BaO/Al2O3 catalyst, with thermal stable increasing in the order: absorbed N2O4 < monodentate nitrates < chelating bidentate nitrates < nitrates unidentate < free ionic nitrates < bulk free ionic nitrates. H2 preferentially reacted with absorbed N2O4 and monodentate nitrates at low temperatures, due to their high activity. The concentration of generated NH3 from the redox reaction of H2/NOx achieves the maximum value between 350 and 450 °C over the La0.9Ce0.1Co0.9Pd0.1O3-BaO/Al2O3 catalyst. Compared with the NOx adsorption process at 50 °C, monodentate nitrates and absorbed N2O4 disappeared due to their low thermal stability, chelating bidentate nitrates become stronger, as well as free ionic nitrates converted to bulk free ionic nitrates with higher thermal stability at 350 °C. When H2 is exposed to NOx species adsorbed on La0.9Ce0.1Co0.9Pd0.1O3-BaO/Al2O3, chelating bidentate nitrates and bulk free ionic nitrates are consumed gradually, indicating that although the bulk free ionic nitrates own high stability, it also could be consumed by involving in the H2/NOx reaction at 350 °C. The quantitative H2/NO reaction experiments confirmed the results of H2-TPSR and NSR. It is beneficial to the formation of NH3 when the H2/NO ratio is more than 2.5. Comparing traditional Pt-BaO/Al2O3 catalyst, the La0.9Ce0.1Co0.9Pd0.1O3-BaO/Al2O3 catalyst exhibit an excellent performance, including considerable NH3 production property, lower N2O selectivity, and the precious metal saving.

Cyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells.

Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, 'off-the-shelf' treatment option.

Value of drug resistance and homology of Acinetobacter baumannii in tracing the source of nosocomial infection in Jianyang, Sichuan / 中国热带医学

@#Abstract: Objective　To analyze the drug sensitivity and the carrying of carbapenem resistant gene of Acinetobacter baumannii isolated from clinical patients and clinical objects, and analyze the homology of strains to provide support for the control of nosocomial infection. Methods　A total of 38 strains of Acinetobacter baumannii isolated from patients and clinical objects surface were collected from January 2019 to August 2020. The antimicrobial susceptibility was tested by the minimum inhibitory concentration method. In addition, the resistance related genes were detected by polymerase chain reaction method, and homology analysis was performed by enterobacterial repetitive Enterobacterial Repetitive Intergenic Consensus Polymerase Chain Reaction (ERIC-PCR). Results All 34 strains of Acinetobacter baumannii isolated from Clinical patients and 4 strains isolated from clinical objects carried blaOXA-51 and imp resistance genes, neither of them carried blaVIM gene. 32 Acinetobacter baumannii carrying blaOXA-23 gene, 28 strains carrying blaTEM gene, 7 strains carrying blaOXA-58 gene. After cluster analysis, 38 Acinetobacter baumannii isolates were classified into 7 genotypes (expressed A, B, C, D, E, F, G), and cluster E and cluster G were the main clusters, containing 12 strains (12/38, 31.6%) and 18 strains (18/38, 47.4%), respectively, as the main prevalent clonal strains. Conclusions　Acinetobacter baumannii isolated from different sources have the significant differences in drug resistance and carry different resistance genes. There is no direct correlation between patients and environmental isolates of Acinetobacter baumannii belonging to different clonal strains. Also, there aren’t significant correlation between clinical patients infected with Acinetobacter baumannii.

Clinical efficacy and influencing factors of mild therapeutic hypothermia for influenza-associated encephalopathy/encephalitis in children with different center temperatures / 中国热带医学

@#Abstract: Objective To investigate the clinical outcomes and influencing factors of mild therapeutic hypothermia for influenza-associated encephalopathy/encephalitis (IAE) in children with different center temperatures, and to provide ideas and references for new mild therapeutic hypothermia scheme. Methods　A total of 115 hospitalized children with IAE who were scheduled to receive mild therapeutic hypothermia in Zhongshan Hospital Affiliated to Xiamen University from January 2019 to February 2022 were collected as subjects. They were randomly divided into two groups, namely, the 33 ℃ group (n=60) and the 35 ℃ group (n=55). The clinical features and clinical outcomes of the two groups were analyzed. Univariate and multivariate logistic regression analysis was performed for 6-month to investigate the factors affecting neurological disability. Results　The baseline indicators after treatment, such as Glasgow Coma Scale (GCS) score, cerebrospinal fluid total protein (CSF-TP), CSF lactate dehydrogenase (CSF-LDH), lymphocyte (Lym), creatine kinase-MB (CK-MB), LDH, and neuron-specific enolase (NSE), revealed no significant differences between the two groups before treatment or after treatment (P>0.05). There was no significant difference between the two groups after treatment in the clinical outcomes including GCS score D-value, time of hospitalization, 6-month neurological disability rate and mRS score, CSF-TP D-value, CSF-LDH D-value, Lym D-value, CK-MB D-value, LDH D-value, NSE D-value, improvement rate of EEG and MRI (P>0.05). Univariate and multivariate logistic regression analyses [OR=1.185, 95%CI (1.026~1.369), P=0.021] indicated that the delay of the onset of mild therapeutic hypothermia treatment was an independent risk factor for neurological disability in children with IAE after mild therapeutic hypothermia treatment of 6 months. Conclusion　There was no significant difference in the clinical outcomes between 33 ℃ and 35 ℃ mild therapeutic hypothermia for children with IAE. Therefore, mild therapeutic hypothermia for children with IAE may not require a strict requirement. Timely receipt of mild therapeutic hypothermia is a key measrue to reduce the risk of neurological disability in children with IAE.

Percutaneous kyphoplasty assisted by three dimensional printing percutaneous guide plate for the treatment of osteoporotic vertebral compression fractures / 中国骨伤

OBJECTIVE@#To verify the safety of three dimensional printing percutaneous guide plate assisted percutaneous kyphoplasty(PKP) in the treatment of osteoporotic vertebral compression fractures(OVCFs).@*METHODS@#The clinical data of 60 patients with OVCFs treated by PKP from November 2020 to August 2021 were retrospectively analyzed. There were 24 males and 36 females, aged from 72 to 86 years old with an average of (76.5±7.9) years. Routine percutaneous kyphoplasty was performed in 30 cases (conventional group) and three dimensional printing percutaneous guide plate assisted PKP was performed in 30 cases (guide plate group). Intraoperative pedicle puncture time (puncture needle to posterior vertebral body edge) and number of fluoroscopy, total operation time, total number of fluoroscopy, amount of bone cement injection, and complication (spinal canal leakage of bone cement) were observed. The visual analogue scale (VAS) and the anterior edge compression rate of the injured vertebra were compared before operation and 3 days after operation between two groups.@*RESULTS@#All 60 patients were successfully operated without complication of spinal canal leakage of bone cement. In the guide plate group, the pedicle puncture time was(10.23±3.15) min and the number of fluoroscopy was(4.77±1.07) times, the total operation time was (33.83±4.21) min, the total number of fluoroscopy was(12.27±2.61) times;and in the conventional group, the pedicle puncture time was (22.83±3.09) min and the number of fluoroscopy was (10.93±1.62) times, the total operation time was(44.33±3.57) min, the total number of fluoroscopy was(19.20±2.67) times. There were statistically significant differences in the pedicle puncture time, intraoperative number of fluoroscopy, the total operation time, and the total number of fluoroscopy between the two groups(P<0.05). There was no significant difference in amount of bone cement injection between the two groups(P>0.05). There were no significant differences in VAS and the anterior edge compression rate of the injured vertebra at 3 days after operation between two groups(P>0.05).@*CONCLUSION@#Three dimensional printing percutaneous guide plate assisted percutaneous kyphoplasty is safe and reliable, which can reduce the number of fluoroscopy, shorten the operation time, and decrease the radiation exposure of patients and medical staff, and conforms to the concept of precise orthopaedic management.