Anaplastic thyroid carcinoma(ATC)is the most aggressive malignancy with poor prognosis.The pathogenesis of ATC is complex,and there is no effective treatment at present.In recent years,with the deep understanding of the genetic(such as BRAF V600E,TP53,TERT,PIK3CA mutations,etc.)and epigenetic(such as histone methylation,histone deacetylation,microRNA regulatory pathways,etc.)changes driving ATC,molecular targeted therapy has brought new hope to ATC patients.This article reviews the molecular mechanisms of ATC and the latest achievements in targeted therapy and other therapies.

Objective:To investigate the expression of HBB in anaplastic thyroid cancer(ATC)cells and its regulatory effect on proliferation,invasion,migration and apoptosis of ATC cells and its potential mechanism.Methods:The expression of HBB in thyroid cancer and paracancerous tissues was analyzed through TIMER database.The correlation between the expression of HBB and the overall survival time of thyroid cancer patients was analyzed through KM-plotter database.The expression of HBB mRNA in ATC cells was detected by RT-qPCR.The HBB knockout or overexpression plasmid was transfected into ATC cells.The expression of HBB protein was detected by Western blot.The proliferation activity was detected by CCK-8 assay.The migration and invasion ability was detected by Transwell assay.The apoptosis was detected by flow cytometry.The expression of β-catenin was detected by Western blot.Results:The expression of HBB was low in thyroid cancer,and the overall survival time of patients with high expression of HBB was high.The expression of HBB protein was down-regulated in ATC cells.Knockout of HBB increased the ability of proliferation,migration and invasion of ATC cells and the expression of β-catenin protein,and inhibited apoptosis.However,overexpression of HBB decreased the ability of proliferation,migration and invasion of ATC cells and the expression of β-catenin protein,and promoted apoptosis.Conclusions:High HBB expression is associated with higher overall survival in patients with thyroid cancer.It may inhibit the proliferation,migration and invasion of ATC cells and promote apoptosis through Wnt/β-catenin signal pathway.

Objective:This study introduces a novel approach utilizing a self-made drug delivery cannula implanted into the cerebellomedullary cistern(CMC)of rats to allow repeated administrations in conscious subjects.Methods:A self-made medication cannula is inserted through a drilled hole at the midpoint of the occipital crest of the rat's skull,de-scending along the inner wall of the occipital bone until reaching the CMC,and securing it in place with skull screws and self-curing resin.Lipopolysaccharide(LPS)is injected into the CMC to induce neuroinflammation,and the feasibility of this method is assessed using X-ray imaging,behavioral testing,and immunofluorescence staining.Results:The place-ment of the brain cannula was confirmed using X-ray film and pontamine sky blue staining.Rats in the LPS group exhib-ited a lower facial mechanical pain threshold compared to the Control group(P＜0.001),along with reduced residence time in the open field center(P＜0.01).Immunofluorescence staining revealed LPS-induced activation of caudal spinal trigeminal nucleus(SpVc)microglia.Conclusion:This method proves to be suitable for multiple administrations to the cerebellomedullary cistern of conscious rats,enabling the study of the SpVc's role in pain modulation.

Delayed wound healing in diabetes is a global challenge, and the development of related drugs is a clinical problem to be solved. In this study, purpurolide C (PC), a small-molecule secondary metabolite of the endophytic fungus Penicillium purpurogenum, was found to promote diabetic wound healing. To investigate the key regulation targets of PC, in vitro RNA-seq, molecular docking calculations, TLR4-MD2 dimerization SDS-PAGE detection, and surface plasmon resonance (SPR) were performed, indicating that PC inhibited inflammatory macrophage activation by inhibiting both TLR4-MD2 dimerization and MYD88 phosphorylation. Tlr4 knockout in vivo attenuated the promotion effect of PC on wound healing. Furthermore, a delivery system consisting of macrophage liposome and GelMA-based microneedle patches combined with PC (PC@MLIP MN) was developed, which overcame the poor water solubility and weak skin permeability of PC, so that successfully punctured the skin and delivered PC to local tissues, and accurately regulated macrophage polarization in diabetic wound management. Overall, PC is an anti-inflammatory small molecule compound with a well-defined structure and dual-target regulation, and the PC@MLIP MN is a promising novel biomaterial for the management of diabetic wound.

OBJECTIVES: This study aimed to explore the functions and potential regulatory targets of local macrophages in nonalcoholic fatty liver combined with Porphyromonas gingivalis (P. gingivalis)infection. METHODS: Single-cell RNA sequencing was used to analyze the phenotypes and functional changes in various cells in the liver tissue of nonalcoholic steatohepatitis (NASH) mice fed with P. gingivalis. Real-time polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay, and immunofluorescence staining were applied to observe the inflammation and expression levels of macrophage antigen presenting functional markers in the NASH liver. Oil red staining was performed to observe the accumulation of local adipose tissue in the NASH liver. Results were verified through RT-PCRand RNA sequencing using P. gingivalis-lipopolysaccharide treated mouse peritoneal macrophages. RESULTS: In comparison with healthy livers with Kupffer cells, the NASH liver combined with P. gingivalis infection-related macrophages showed significant heterogeneity. C1qb, C1qc, Mafb, Apoe, and Cd14 were highly expressed, but Cd209a, H2-Aa, H2-Ab1, and H2-DMb1, which are related to the antigen presentation function, were weakly expressed. Further in vivo and in vitro investigations indicated that the activation and infiltration of these macrophages may be due to local P. gingivalis-lipopolysaccharide accumulation. CONCLUSIONS P. gingivalis-lipopolysaccharide induces a local macrophage immunotolerance phenotype in nonalcoholic fatty liver, which may be the key mechanism of periodontitis pathogen infection that promotes NASH inflammation and pathogenesis. This study further clarifies the dysfunction and regulatory mechanisms of macrophages in the pathogenesis of P. gingivalis-infected NASH, thereby providing potential therapeutic targets for its clinical treatment.
Mice ; Animals ; Non-alcoholic Fatty Liver Disease/pathology* ; Kupffer Cells/pathology* ; Porphyromonas gingivalis ; Lipopolysaccharides/metabolism* ; Inflammation/pathology* ; Macrophages/metabolism* ; Mice, Inbred C57BL

Objective:To explore the feasibility and accuracy of three-dimensional (3D) modeling methods based on ultrasound imaging data for normal and abnormal fetal cardiac structures, and to construct a methodology system for 3D printing of fetal heart based on ultrasound.Methods:A total of 93 fetuses examined in Tangdu Hospital of Air Force Military Medical University from January to December 2019 were selected. Fetal echocardiography was obtained using spatio-temporal image correlation (STIC). Ninety-three hearts were 3D modeled by blood flow modeling, blood pool modeling and cavity modeling, and printed by stereolithography technique. The data measured on the 3D digital models and 3D printed solid models were compared with the corresponding fetal echocardiographic images respectively in order to evaluate the accuracy of the modeling methods.Results:The fetal cardiac blood flow models based on Doppler flow image data showed the malformation and trend of small blood vessels. The fetal cardiac structure models printed based on blood pool modeling displayed the malformation of heart and large blood vessels. Models printed based on cavity modeling method accurately displayed valve and structural defects.For 83 normal fetal hearts, the long diameters of left and right ventricles measured on echocardiography [(15.3±1.9)mm, (13.2±1.9)mm] were compared with those measured on digital models [(15.1±1.9)mm, (12.9±1.9)mm] and 3D printed models[(15.1±1.9)mm, (13.0±1.9)mm], respectively, and there were no significant differences between any two groups of them ( P>0.05). Bland-Altman showed good consistency for all measurements within and between operators. Conclusions:The three modeling methods, including blood flow modeling, blood pool modeling and cavity modeling, have their own advantages in displaying different types of fetal heart malformations. Appropriate modeling methods should be selected for 3D modeling and printing to make up for the limitations of single modeling method. The consistency between measurements on 3D models and those on echocardiography is high, and the repeatability between operators is good.

Objective:To explore the occurrence time and risk factors of deep vein thrombosis (DVT) in patients with acute cerebral infarction, so as to guide clinical prevention and treatment.Methods:1 129 patients with acute cerebral infarction treated in Beijing Tiantan Hospital from May 2014 to May 2016 were selected as the research objects. According to whether DVT occurred, the patients were divided into DVT group ( n=22) and non DVT group ( n=1 107); The information was analyzed retrospectively and the occurrence time of DVT was counted. The independent risk factors of acute cerebral infarction complicated with DVT were analyzed by univariate and multivariate logistic regression. Results:The time of DVT in patients with acute cerebral infarction was 10.5 (4-14) days. Univariate analysis showed that there were significant differences in age, gender, atrial fibrillation, smoking, drinking, chronic obstructive pulmonary disease, peripheral artery disease, renal failure, anticoagulants, BMI, white blood cell, blood glucose at admission and length of stay between the DVT group and the non DVT group ( P<0.05). Multiple factors further confirmed that renal failure [odds ratio ( OR)=57.421; 95% confidence interval ( CI), 5.792-569.314)] and length of hospital stay ( OR=1.148; 95% CI: 1.071-1.232) were independent risk factors for DVT. Conclusions:The median time of DVT in patients with acute cerebral infarction was 10.5 days. Renal failure and hospital stay were independent influencing factors of DVT in patients with acute cerebral infarction. This is helpful to determine the best prevention and treatment duration of DVT in patients with acute cerebral infarction, make rational use of medical resources and formulate personalized prevention and treatment strategies.

Objective    In this study, three-dimensional printed (3DP) titanium implants were used for skeletal reconstructions after wide excision of chest wall. 3DP titanium implants were expected to provide a valid option with perfect anatomic fitting and personalized design in chest wall reconstruction. Methods    There were 13 patients [mean age of 46 (24-78) years with 9 males and 4 females] who underwent adequate radical wide excision for tumors and chest wall reconstruction using 3DP titanium implants. Surgical data including patient demographic characteristics, perioperative clinical data and data from 1-year follow-up were collected and analyzed. Results    Six patients of rib tumors, six patients of sternal tumors and one patient of sternal pyogenic osteomyelitis were finally selected for the study. The chest wall defect area was 221.0±206.0 cm2. All patients were able to maintain the integrity of the chest wall after surgery, and no abnormal breathing was found, achieving personalized and anatomical repair. Thirteen patients were successfully discharged from the hospital. Two patients developed pneumonia in the perioperative period. During the follow-up period in the first year after surgery, no implant related adverse reaction was observed, including implant rupture, implant shift, rejection reaction and allergies. One patient had wound ulcer after chemotherapy. Three patients had tumor recurrence, with the recurrence rate of 25.0%. Two patients died of tumor recurrence, with a mortality rate of 16.7%. Conclusion    3DP titanium implant is a safe and effective material for chest wall reconstruction. 

Obeticholic acid (OCA), the first FXR-targeting drug, has been claimed effective in the therapy of liver fibrosis. However, recent clinical trials indicated that OCA might not be effective against liver fibrosis, possibly due to the lower dosage to reduce the incidence of the side-effect of pruritus. Here we propose a combinatory therapeutic strategy of OCA and apoptosis inhibitor for combating against liver fibrosis. CCl-injured mice, d-galactosamine/LPS (GalN/LPS)-treated mice and cycloheximide/TNF (CHX/TNF)-treated HepG2 cells were employed to assess the effects of OCA, or together with IDN-6556, an apoptosis inhibitor. OCA treatment significantly inhibited hepatic stellate cell (HSC) activation/proliferation and prevented fibrosis. Elevated bile acid (BA) levels and hepatocyte apoptosis triggered the activation and proliferation of HSCs. OCA treatment reduced BA levels but could not inhibit hepatocellular apoptosis. An enhanced anti-fibrotic effect was observed when OCA was co-administrated with IDN-6556. Our study demonstrated that OCA inhibits HSCs activation/proliferation partially by regulating BA homeostasis and thereby inhibiting activation of HSCs. The findings in this study suggest that combined use of apoptosis inhibitor and OCA at lower dosage represents a novel therapeutic strategy for liver fibrosis.

Two strains of porcine reproductive and respiratory syndrome virus (PRRSV) were isolated in 2006 and 2016 and designated as FZ06A and FZ16A, respectively. Inoculation experiments showed that FZ06A caused 100% morbidity and 60% mortality, while FZ16A caused 100% morbidity without death. By using genomic sequence and phylogenetic analyses, close relationships between a Chinese highly pathogenic PRRSV strain and the FZ06A and FZ16A strains were observed. Based on the achieved results, multiple genomic variations in Nsp2, a unique N-glycosylation site (N³³→K³³), and a K151 amino acid (AA) substitution for virulence in the GP5 of FZ16A were detected; except the 30 AA deletion in the Nsp2-coding region. Inoculation experiments were conducted and weaker virulence of FZ16A than FZ06A was observed. Based on our results, a 30 AA deletion in the Nsp2-coding region is an unreliable genomic indicator of a high virulence PRRSV strain. The Nsp2 and GP5 differences, in addition to the virulence difference between these two highly pathogenic PRRSV strains, have the potential to be used to establish a basis for further study of PRRSV virulence determinants and to provide data useful in the development of vaccines against this economically devastating disease.
Asian Continental Ancestry Group ; China ; Genomics ; Humans ; Mortality ; Phylogeny ; Porcine Reproductive and Respiratory Syndrome ; Porcine respiratory and reproductive syndrome virus ; Vaccines ; Virulence