Background::Somatic copy number variations (SCNVs) in the CDKN2A gene are among the most frequent events in the dysplasia-carcinoma sequence of esophageal squamous cell carcinoma. However, whether CDKN2A SCNVs are useful biomarkers for the risk stratification and management of patients with esophageal squamous cell dysplasia (ESCdys) is unknown. This study aimed to investigate the characteristics and prognostic value of CDKN2A SCNVs in patients with mild or moderate (m/M) ESCdys. Methods::This study conducted a prospective multicenter study of 205 patients with a baseline diagnosis of m/M ESCdys in five high-risk regions of China (Ci County, Hebei Province; Yanting, Sichuan Province; Linzhou, Henan Province; Yangzhong, Jiangsu Province; and Feicheng, Shandong Province) from 2005 to 2019. Genomic DNA was extracted from paraffin biopsy samples and paired peripheral white blood cells from patients, and a quantitative polymerase chain reaction assay, P16-Light, was used to detect CDKN2A copy number. The cumulative regression and progression rates of ESCdys were evaluated using competing risk models. Results::A total of 205 patients with baseline m/M ESCdys were enrolled. The proportion of ESCdys regression was significantly lower in the CDKN2A deletion cohort than in the diploid and amplification cohorts (18.8% [13/69] vs. 35.0% [28/80] vs. 51.8% [29/56], P <0.001). In the univariable competing risk analysis, the cumulative regression rate was statistically significantly lower ( P = 0.008), while the cumulative progression rate was higher ( P = 0.017) in ESCdys patients with CDKN2A deletion than in those without CDKN2A deletion. CDKN2A deletion was also an independent predictor of prognosis in ESCdys ( P = 0.004) in the multivariable analysis. Conclusion::The results indicated that CDKN2A SCNVs are associated with the prognosis of ESCdys and may serve as potential biomarkers for risk stratification.

Glioblastoma multiforme (GBM), a highly malignant and heterogeneous brain tumor, contains various types of tumor and non-tumor cells. Whether GBM cells can trans-differentiate into non-neural cell types, including mural cells or endothelial cells (ECs), to support tumor growth and invasion remains controversial. Here we generated two genetic GBM models de novo in immunocompetent mouse brains, mimicking essential pathological and molecular features of human GBMs. Lineage-tracing and transplantation studies demonstrated that, although blood vessels in GBM brains underwent drastic remodeling, evidence of trans-differentiation of GBM cells into vascular cells was barely detected. Intriguingly, GBM cells could promiscuously express markers for mural cells during gliomagenesis. Furthermore, single-cell RNA sequencing showed that patterns of copy number variations (CNVs) of mural cells and ECs were distinct from those of GBM cells, indicating discrete origins of GBM cells and vascular components. Importantly, single-cell CNV analysis of human GBM specimens also suggested that GBM cells and vascular cells are likely separate lineages. Rather than expansion owing to trans-differentiation, vascular cell expanded by proliferation during tumorigenesis. Therefore, cross-lineage trans-differentiation of GBM cells is very unlikely to occur during gliomagenesis. Our findings advance understanding of cell lineage dynamics during gliomagenesis, and have implications for targeted treatment of GBMs.
Mice ; Animals ; Humans ; Glioblastoma/pathology* ; Endothelial Cells/pathology* ; DNA Copy Number Variations ; Brain/metabolism* ; Brain Neoplasms/pathology*

Pregnane X receptor (PXR) is a ligand-activated nuclear receptor that transcriptionally upregulates drug-metabolizing enzymes [e.g., cytochrome P450 3A4 (CYP3A4)] and transporters. Although the regulation of PXR target genes is well-characterized, less is known about the regulation of PXR protein level. By screening an RNAi library, we identified the F-box-only protein 44 (FBXO44) as a novel E3 ligase for PXR. PXR abundance increases upon knockdown of FBXO44, and, inversely, decreases upon overexpression of FBXO44. Further analysis revealed that FBXO44 interacts with PXR, leading to its ubiquitination and proteasomal degradation, and we determined that the F-box associated domain of FBXO44 and the ligand binding domain of PXR are required for the functional interaction. In summary, FBXO44 regulates PXR protein abundance, which has downstream consequences for CYP3A4 levels and drug-drug interactions. The results of this study provide new insight into the molecular mechanisms that regulate PXR protein level and activity and suggest the importance of considering how modulating E3 ubiquitin ligase activities will affect PXR-mediated drug metabolism.

OBJECTIV E To develop the infor mation-based pharmaceutical care pathway of anticoagulant therapy in patients with atrial fibrillation and improve the efficacy and safety of treatment for them. METHODS The“anticoagulant pharmaceutical care”module was developed on the basis of medical intelligent and decision system. Patients with atrial fibrillation were taken pharmaceutical care in the whole anticoagulant treatment by evaluating the thromboembolism and bleeding risks ，pre-reviewing antithrombotic prescriptions ，monitoring efficacy and drug interactions ，and warning adverse reactions. RESULTS A total of 1 228 patients receiving anticoagulant therapy were enrolled. It was found after analysis of their doctor ’s orders that 9.27％ of the patients adjusted the improper antithrombotic therapies ，3.99％ modulated treatments according to the effects of potential drug interactions or the risk of adverse reactions ，and 70.29％ of the wrong prescriptions were intervened successfully. After the information-based pharmaceutical care ，the anticoagulation treatment rate increased from 88.73％ to 97.40％，the rate of patients ’achievements to warfarin’s international normalized ratio in hospital increased from 38.64％ to 66.67％，and the incidence of serious bleeding events decreased from 2.94％ to 0.37％ （P＜0.05）. CONCLUSIONS The information-based pharmaceutical care path of anticoagulant therapy achieved comprehensive ，efficient and accurate management of patients with atrial fibrillation ，and improved the rationality ，effectiveness and safety of anticoagulant therapy.

OBJECTIVE To expl ore the clinical significance of folic acid metabolic gene detection in methotrexate （MTX） treatment of acute myeloid leukemia （AML）. METHODS Therapeutic drug monitoring （TDM）pharmacists participated in the treatment process of an AML patient who had neurotoxic side effects such as dizziness ，headache，and vomiting after intrathecal injection of MTX. According to the results of the test of the folic acid metabolic gene MTHFR C677T（rs1801133）（mutant homozygous）and the results of MTX blood concentration monitoring （＜0.05 μmol/L），combined with clinical manifestations ，it was recommended to stop MTX ，give intravenous drip of calcium folinate for rescue ，and consider using azacytidine for follow-up treatment. RESULTS The doctor took the advice of TDM pharmacist ，and the above symptoms were significantly relieved after the patient rescued for 2 times and successfully discharged from the hospital. CONCLUSIONS For AML patients who meet the indications and receive intrathecal injection of MTX ，drug metabolism genetics testing and MTX drug concentration monitoring can be performed before medication ，which helps doctors and pharmacists evaluate the feasibility of drug treatment options and reduce medical risks.

Based on the previous study of compound liquorice microemulsion, this paper aims to prepare the compound liquorice microemulsion gel and investigate its pharmacodynamics of chronic eczema. The type, dosage and adding method of gel matrix, and formula dosage of humectant were optimized by single factor method to obtain the formula and preparation technique of the gel. With glycyrrhizic acid, glycyrrhetin and oxymatrine used as evaluation indexes, the Franz diffusion cell method was adopted to monitor the in vitro release profile of the gel. Eczema model of delayed-type hypersensitivity in mice was chosen to detect the ear swelling rate, degree of inflammatory cell infiltration of ear pieces, and pathological changes of ear pieces, so as to investigate the therapeutic effect of the microemulsion gel. The preparation process of the compound liquorice microemulsion gel was stable. The release of glycyrrhizin and oxymatrine was most consistent with the Hixcon-Crowell kinetic model, while the release of glycyrrhizic acid was most consistent with the Ritger-Peppas kinetic model. The pharmacodynamics studies proved that compound liquorice microemulsion gel could significantly reduce the ear swelling rate in mice, with good anti-inflammatory effect as well as the ability to resist the pathological changes of chronic eczema and inhibit the infiltration of dermal inflammatory cells. Therefore, the preparation process of compound liquorice microemulsion gel is feasible, with stable drug release and a significant therapeutic effect on chronic eczema.
Administration, Cutaneous ; Animals ; Drug Liberation ; Emulsions ; Gels ; Glycyrrhiza ; Mice ; Skin Absorption

Immunotherapy has been applied successfully to treat B-cell lymphomas in preclinical models or clinical settings. However, immunotherapy resistance is a major challenge for B-cell lymphoma treatment. To overcome this issue, combinatorial therapeutic strategies have been pursued to achieve a better efficacy for treating B-cell lymphomas. One of such strategies is to combine immunotherapy with histone deacetylase (HDAC) inhibitors. HDAC inhibitors can potentially increase tumor immunogenicity, promote anti-tumor immune responses, or reverse immunosuppressive tumor environments. Thus, the combination of HDAC inhibitors and immunotherapy has drawn much attention in current cancer treatment. However, not all HDAC inhibitors are created equal and their net effects are highly dependent on the specific inhibitors used and the HDACs they target. Hence, we suggest that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers and unique profiles of HDAC inhibitors. Here, we discuss the possible mechanisms by which B-cell lymphomas acquire immunotherapy resistance and the effects of HDAC inhibitors on tumor cells and immune cells that could help overcome immunotherapy resistance.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause acute respiratory distress syndrome, hypercoagulability, hypertension, and multiorgan dysfunction. Effective antivirals with safe clinical profile are urgently needed to improve the overall prognosis. In an analysis of a randomly collected cohort of 124 patients with COVID-19, we found that hypercoagulability as indicated by elevated concentrations of D-dimers was associated with disease severity. By virtual screening of a U.S. FDA approved drug library, we identified an anticoagulation agent dipyridamole (DIP) , which suppressed SARS-CoV-2 replication . In a proof-of-concept trial involving 31 patients with COVID-19, DIP supplementation was associated with significantly decreased concentrations of D-dimers ( < 0.05), increased lymphocyte and platelet recovery in the circulation, and markedly improved clinical outcomes in comparison to the control patients. In particular, all 8 of the DIP-treated severely ill patients showed remarkable improvement: 7 patients (87.5%) achieved clinical cure and were discharged from the hospitals while the remaining 1 patient (12.5%) was in clinical remission.

A case of fibrosing alopecia in a pattern distribution (FAPD) and its clinicopathological, dermoscopic and TrichoScan features were reported to improve the understanding of FAPD. A 23-year-old male patient presented with progressive hair loss on the forehead and top of the head for 10 years, local hair thinning and softening, and occasional scalp itching. Skin examination showed diffuse sparseness of hair from the forehead to the top of the head, frontal hairline recession, focal thinning and softening of hair, some follicular keratotic papules and perifollicular erythema on the alopecic area, with no obvious scales. TrichoScan examination revealed markedly decreased hair density and increased proportions of vellus hairs. Dermoscopy showed loss of some follicular ostia and confluent white dots. Histopathological examination of the scalp showed lichenoid lymphocytic infiltration around the infundibulum and isthmus of hair follicles, concentrically layered perifollicular fibrosis, hair follicle destruction, formation of follicular micro-scars, markedly increased variation in the diameter of residual follicles, and some vellus hairs. The patient was diagnosed with FAPD. FAPD is easily misdiagnosed as androgenetic alopecia, and early diagnosis and treatment are needed.

By removing a part of the structure, the tooth preparation provides restorative space, bonding surface, and finish line for various restorations on abutment. Preparation technique plays critical role in achieving the optimal result of tooth preparation. With successful application of microscope in endodontics for >30 years, there is a full expectation of microscopic dentistry. However, as relatively little progress has been made in the application of microscopic dentistry in prosthodontics, the following assumptions have been proposed: Is it suitable to choose the tooth preparation technique under the naked eye in the microscopic vision? Is there a more accurate preparation technology intended for the microscope? To obtain long-term stable therapeutic effects, is it much easier to achieve maximum tooth preservation and retinal protection and maintain periodontal tissue and oral function health under microscopic vision? Whether the microscopic prosthodontics is a gimmick or a breakthrough in obtaining an ideal tooth preparation should be resolved in microscopic tooth preparation. This article attempts to illustrate the concept, core elements, and indications of microscopic minimally invasive tooth preparation, physiological basis of dental pulp, periodontium and functions involved in tool preparation, position ergonomics and visual basis for dentists, comparison of tooth preparation by naked eyes and a microscope, and comparison of different designs of microscopic minimally invasive tooth preparation techniques. Furthermore, a clinical protocol for microscopic minimally invasive tooth preparation based on target restorative space guide plate has been put forward and new insights on the quantity and shape of microscopic minimally invasive tooth preparation has been provided.