Design, synthesis, and biological evaluation of quinoxalinone derivatives as potent BRD4 inhibitors.

The bromodomain-containing protein 4 (BRD4) has gained growing interest as an effective drug target for the treatment of hepatocellular carcinoma (HCC). Herein, we designed and synthesized a series of quinoxalinone derivatives as BRD4 inhibitors via scaffold hopping. The representative compound X9 showed potent BRD4 inhibitory activity (with IC50 = 82.3 nM), and preferable antiproliferative activity against HepG2 cells (with IC50 = 1.13 ± 0.07 µM), as well as less toxicity against GES-1 cells (with IC50 = 57.24 ± 5.46 µM). Furthermore, compound X9 dose-dependently inhibited colony formation and blocked the migration of HepG2 cells by down-regulating the expression of Snail and MMP-9 while up-regulating the E-cadherin and Occludin. Besides, compound X9 efficiently down-regulated the expression of c-Myc in HepG2 cells, induced apoptosis, and arrested at G0/G1 phase. In total, quinoxalinone was a potential core as BRD4 inhibitor and compound X9 might be effective for liver cancer therapy.

Semaphorin 3A inhibits tumor progression via the downregulation of Lin28B in ovarian cancer.

Semaphorin 3A (Sema3A) has recently been proven to play an essential role in tumorigenesis. Here, the role of Sema3A in ovarian cancer is explored. The prognostic value of Sema3A was evaluated using the Kaplan-Meier plotter database, and stable expression cells were established by the delivery of lentivirus harboring SEMA3A cDNA or shRNA into OVCA433 and SKOV3 cells, respectively. Then CCK-8 assay, colony-formation assay, wound-healing assay, and Transwell assay were utilized to verify the effect of Sema3A on tumorigenesis. Co-cultures of ovarian cancer cells (OVCA433 and SKOV3) with a conditional medium collected from the established cells were further utilized to confirm the function of Sema3A. Then, the RNA-seq assay was adopted to explore the underlying mechanism. The results demonstrated that low expression of Sema3A was predictive of poor overall survival in patients with ovarian cancer. Functional experiments revealed that Sema3A inhibited proliferation, migration, and invasion in ovarian cancer cells. Secreted Sema3A in a conditioned culture medium also exhibited an anti-tumor effect in ovarian cancer cells. RNA-seq assay suggested that focal adhesion and Lin28B were involved in regulating Sema3A. Rescue assays further verified that Lin28B/ROCK1 axis was vital in the regulation of Sema3A and Lin28B significantly upregulated ROCK1 through let-7g microRNA. The presented data indicate that Sema3A inhibits proliferation and metastasis via the downregulation of Lin28B/ROCK1 in ovarian cancer.

Valence and coordination form transition of tungsten ions in molten alkali chlorides.

This study examined the possibility of deep significance for the reduction of low-valence tungsten to inhibit disproportionation reactions in various molten alkali chlorides. Electrolysis and electrochemical tests of tungsten carbide were carried out in molten LiCl, LiCl-KCl, NaCl-KCl, NaCl-CsCl, and KCl-CsCl. One finding was that the reduction valence of tungsten ions decreased as the radius of the solvent alkali ion increased. This phenomenon may be viewed from the dissolution of tungsten carbide and the existence and deposition of tungsten ions. The mechanism of tungsten ion reduction and the stable configuration of tungsten ion groups were confirmed via a detailed study of the computational calculation. The increase in the radius of the solvent alkali ion was conducive to the dissolution of tungsten from tungsten carbide in the form of low valence state. Other results also indicated that W(II) ion groups first deposited on the cathode. They had the advantages of smaller coordination numbers and faster diffusion combined. Morphological and composition analysis results of the products are also presented.

Design, synthesis and biological evaluation of coumarin derivatives as potential BRD4 inhibitors.

The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer. Coumarin is a highly privileged moiety for the development of novel anticancer drugs which has been identified in clinical trials for the treatment of various cancers. Herein, we modified BRD4i ABBV-075 with a coumarin ring and synthesized a novel series of coumarin derivatives as BRD4 inhibitors. Among them, the representative compound 27d showed excellent BRD4 inhibitory activities with an IC50 value of 99 nM in the TR-FRET assay. Compared with ABBV-075, compound 27d displayed a favorable cell proliferation inhibitory activity in solid tumors, such as MCF-7, HGC-27 and HepG-2. Further mechanism investigation illustrated that 27d-treatment resulted in G0/G1 phase arrest and promoted apoptosis of MCF-7 cells. Compound 27d also blocked colony formation in a concentration-dependent manner in McF-7 cell lines. As the downstream-protein of BRD4, the expression of c-Myc was decreased in a dose-dependent manner after the treatment of compound 27d. Moreover, compound 27d also exhibited good in vivo and in vitro metabolic stability. All the findings meaningfully make it as a promising lead compound for further drug development.

A simple modification to prevent the cross-infection by dermoscopy.

Because sterilization of imaging probes is commonly impossible, the issue of probe contamination and cross-infection becomes an issue when using dermoscopy in the clinic. We describe a simple modification to reduce cross-infection during dermoscopy.

Use of a metallic ink marking pen to assist in localization on the skin of lesions detected by reflectance confocal microscopy.

We report the use of a marking pen with metallic ink to assist body surface location in reflectance confocal microscopy (RCM). Not only is the marker waterproof, but the metallic ink appears brighter under RCM, thus assisting in identifying location.

Preventing crossinfection during reflectance confocal microscopy, using a transparent film dressing.

Contamination and crossinfection are always a significant concern when using reflectance confocal microscopy in the clinic because the glass window and metal ring at the front of the probe must contact the skin and mucosal surfaces, and sterilization of the imaging probes is usually impossible. We describe use of a transparent, single-use film dressing to solve this problem.

Dermoscopy, reflectance confocal microscopy, and fluorescence staining for the noninvasive diagnosis of crusted scabies.

A 91-year-old woman presented with a 3-month history of [extensive](javascript:;) cutaneous lesions with intense pruritus. She lived in a nursing home for a long time. Physical examination revealed a generalized erythematous and scaly rash with intense hyperkeratotic lesions on the neck, trunk, and limbs. Dermoscopy showed a sinuous burrow filled with white dot eggs and feces on the hand with a mite at the end of the burrow. Reflectance confocal microscopy (RCM) manifested a sinuous burrow and a mite. The presence of mites was confirmed with fluorescence staining. The patient was diagnosed with crusted scabies and started treatment with 10% sulfur ointment. Her lesions and pruritus were resolved after 2 weeks.

Progress on research and development in diabetes mellitus.

Diabetes mellitus is a kind of metabolic disease characterized by hyperglycemia resulting from insulin insufficiency and insulin resistance. It has become one of the major diseases threatening human health. In this paper, we analyze the current R&D status of diabetes from the aspects of papers, patents, drugs and industrial development. The results show that scientific outcomes are increasing steadily and the hot topics are diabetic complications and epidemiological research. In terms of technology development, large pharmaceutical companies, such as Janssen Pharmaceutical, Lilly pharmaceutical, Boehringer Ingelheim, are actively engaged in diagnosis, treatment and management of diabetes. By March 23 2022, 207 drugs have been launched and a large number of candidate drugs are in the pre-clinical and clinical stage. In terms of industrial development, the potential diabetes market is huge and the digital management of diabetes is developing rapidly. China has certain strength in diabetes research and development. In the future, measures should be taken to strengthen the transformation of research outcomes, and promote product development to meet China's huge needs of diabetes cares.

Current status and future perspectives of rare disease research.

Rare diseases refer to diseases with low incidence. Currently, there are over 8000 rare diseases in the world. Effective prevention and treatment of rare diseases is an important part of 'healthy China'. In this paper, status and drug development of rare diseases were reported. These results indicate that research on rare diseases is growing rapidly driven by technology and policy. The hotspots include the identification of gene mutations, the development of therapies, and the key points of technology include the development of drugs for rare diseases, the development of viral vectors for gene therapy, and the diagnosis and management system for rare diseases. In terms of drug development, 880 drugs have been launched by December 28, 2020, and a large number of drugs are in the pre-clinical stage. Generally, a new technology or drug is applicable to various diseases. In the future, with policy support and the development of emerging technologies such as gene editing, more and more rare diseases will be diagnosed and intervened early, even be cured, and the quality of life of patients is expected to be improved.

Progress on familial hypercholesterolemia.

Familial hypercholesterolemia (FH) is an autosomal inherited disease characterized by a significant increase in low density lipoprotein cholesterol (LDL-C), tendon xanthoma and premature coronary artery disease (PCAD). In this paper, we analyze the current research status of FH, summarize the reported mutation gene loci in Chinese FH patients and treatment for them, and elaborate the current status of patents and drug researches. The results show that scientific outcomes of FH are increasing with a good developmental trend and the most popular topics of FH study are pathogenesis, treatment of FH, and research on juvenile FH patients. In terms of patents, large pharmaceutical companies, such as Regeneron Pharmaceuticals Inc, AstraZeneca Plc, Merck & Co Inc, are actively engaged in FH detection, diagnosis and treatment. In addition, 12 drugs have been launched in the United States, Japan, Europe and other countries or regions, bringing hope to FH patients.

Associations between the incidence and mortality rates of type 2 diabetes mellitus and long-term exposure to ambient air pollution: A 12-year cohort study in northern China.

BACKGROUND: Ambient air pollution has recently been related to type 2 diabetes mellitus (T2DM), a disease that has caused an economic and health burden worldwide. Evidence of an association between air pollution and T2DM was reported in the United States and Europe. However, few studies have focused on the association with high levels of air pollutants in a developing country. OBJECTIVES: We conducted a 12-year cohort study to assess the incidence and mortality of T2DM associated with long-term exposure to PM10, SO2, and NO2. METHODS: A retrospective cohort with participants from four cities in northern China was conducted to assess mortality and incidence of T2DM from 1998 to 2009. Incidence of T2DM was self-reported, and incident intake of an antidiabetic drug or injection of insulin simultaneously and mortality of T2DM was obtained from a family member and double checked against death certificates provided from the local center for disease control and prevention. Individual pollution exposures were the mean concentrations of pollutants estimated from the local environmental monitoring centers over the survival years. Hazard ratios (HRs) were estimated using Cox regression models after adjusting for potential confounding factors. RESULTS: A total of 39 054 participants were recruited into the mortality cohort, among which 59 subjects died from T2DM; 38 529 participants were analyzed in the incidence cohort, and 1213 developed new cases of T2DM. For each 10 µg/m3 increase in PM10, SO2, and NO2, the adjusted HRs and 95% confidence interval (CI) for diabetic incidence were 1.831 (1.778, 1.886), 1.287 (1.256, 1.318), and 1.472 (1.419, 1.528), respectively. Similar results can be observed in the analysis of diabetic mortality with HRs (95% CI) up to 2.260 (1.732, 2.950), 1.130 (1.042, 1.225), and 1.525 (1.280, 1.816), respectively. CONCLUSIONS: Our results suggested that long-term exposure to high levels of PM10, SO2, and NO2 increase risk of incident and mortality of T2DM in China.

Erythema papulatum centrifugum and new diagnostic criteria.

Erythema papulatum centrifugum (EPC), also known as erythema papulosa semicircularis recidivans (EPSR), is distinct from eczema and other well-described figurate erythemas characterised by annular erythematous lesions. We report 7 cases of EPC and propose new diagnostic criteria including the following: (i) EPC is characterised by single or multiple recurrent expanding annular or semi annular erythema with central regression, surrounded by tiny red papules; (ii) the lesions regularly relapse and resolve; (iii) the histopathologic feature shows superficial perivascular inflammation with or without mild inflammation around sweat glands in the mid dermis and (iv) patients lack other associated cutaneous or internal abnormalities.