Value of pre-treatment biomarkers in prediction of response to neoadjuvant endocrine therapy for hormone receptor-positive postmenopausal breast cancer

Objective： To determine the predictive ability of biomarkers for responses to neoadjuvant endocrine therapy （NET） in postmenopausal breast cancer. Methods： Consecutive 160 postmenopausal women with T 1-3 N 0-1 M 0 hormone receptor （HR）-positive invasive breast cancer were treated with anastrozole for 16 weeks before surgery. New slides of tumor specimens taken before and after treatment were conducted centrally for biomarker analysis and classified using the Applied Imaging Ariol MB-8 system. The pathological response was evaluated using the Miller ＆ Payne classification. The cell cycle response was classified according to the change in the Ki67 index after treatment. Multivariable logistic regression analysis was used to calculate the combined index of the biomarkers. Receiver operating characteristic （ROC） curves were used to determine whether parameters may predict response. Results： The correlation between the pathological and cell cycle responses was low （Spearman correlation coefficient =0.241, P〈0.001; Kappa value =0.119, P=0.032）. The cell cycle response was significantly associated with pre-treatment estrogen receptor （ER） status （P=0.001）, progesterone receptor （PgR） status （P〈0.001）, human epidermal growth factor receptor 2 （Her-2） status （P=0.050） and the Ki67 index （P〈0.001）, but the pathological response was not correlated with these factors. Pre-treatment ER levels [area under the curve （AUC） =0.634, 95% confidence interval （95% CI）, 0.534-0.735, P=0.008] and combined index of pre-treatment ER and PgR levels （AUC =0.684, 95% CI, 0.591-0.776, P〈0.001） could not predict the cell cycle response, but combined index including per-treatment ER/PR/Her-2/Ki67 expression levels could （AUC =0.830, 95% CI, 0.759-0.902, P〈0.001）. Conclusions： The combined use of pre-treatment ER/PgR/Her-2/Ki67 expression levels, instead of HR expression levels, may predict the cell cycle response to NET.

Treatment Principles of Obesity with Chinese Herbal Medicine: Literature Analysis by Text Mining

Obesity represents a social health problem worldwide, associated with serious health risks and increased mortality. The prevalence of obesity is reported to be increasing in both developed and developing countries. Obesity is associated with a significant range of comorbidities and is linked with increases in mortality, thus the treatment of obesity is very important. Chinese herbal medicine (CHM) has been used for weight management both in China and in western countries for many years, the effectiveness and safety of CHMs in obesity have been proved. Yet the principles of treating obesity with CHMs are hard to manage due to the complexity of TCM theory. In this study, a novel text mining method was developed based on a comprehensive collection of literatures in order to explore the treatment principles more intuitively. Networks of TCM patterns and CHMs which are most frequently used in obesity treatment are built-up and analyzed, two major principles are explored in treating obesity: one is resolving phlegm and dampness, the other is clearing heat and reinforcing deficiency. These findings might guide the clinicians in treatment of obesity.

Targeted protein degradation in cancers:Orthodox PROTACs and beyond

Targeted protein degradation(TPD)is emerging as a strategy to overcome the limitations of traditional small-molecule inhibitors.Proteolysis-targeting chimera(PROTAC)technology can be used to target proteins by hijacking the ubiquitin-proteasome system.Conceptually,PROTAC aims to target the“undruggable”majority of proteins in the human proteome.Through constant exploration and optimization of PROTACs and the exploitation of other TPD strategies over two decades,TPD has expanded from theoretical studies to clinical strategies,with practical applications in oncological,immunological,and other diseases.In this review,we introduce the mechanisms,features,and molecular targets of orthodox PROTACs and summarize the PROTAC drugs under study as cancer therapeutics in clinical trials.We also discuss PROTAC derivatives and other TPD strategies,such as lysosome-targeting chimeras,autophagy-targeting chimeras,and molecular glue strategies.Collectively,the studies summarized herein support the full potential of TPD in the biomedical industry.

Drug discovery of sclerostin inhibitors

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA,the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis;however, it conferred high cardiovascular risk in clinical trials. Furthermore,romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

One-pot synthesis of silver colloid with body-heat for surface-enhanced Raman spectroscopy detections

In this study,a convenient method of preparing the substrate is proposed with one-pot synthesis of silver colloid under body heat,and the SERS detection uses the fresh substrate to avoid the drawback of substrates’short life of use.The synthesis of silver colloid is carried out in a 10 mL vial by using ascorbic acid as a reductant and trisodium citrate as a stabilizer.The vial is grasped with the palm of the experimenter for several minutes without shaking.The proposed method is simple,rapid,green energy and cost-effective.By adjusting the concentration of trisodium citrate,not only the particle size can be controlled from about 110 nm to 50 nm but also the homogeneity of nanoparticles can be improved.As a SERS substrate,the silver colloid has high batch reproducibility and showed good SERS activity.The relative standard deviation between different manufacturers is 5.51%when the substrate of silver colloid is used for the detection of rhodamine 6 G.Using the substrate,the lowest detection concentrations of rhodamine 6 G,crystal violet,enrofloxacin,melamine and leucomalachite green are 1.0×10-8,6.1×10-8,1.4×10-6,7.1×10-5 and 5.1×10-8 mol/L,respectively.Results demonstrate that the developed method has the advantage of convenience and high efficiency in the field preparation of reliable SERS substrate.

Correlation between cold and hot pattern in traditional Chinese medicine and gene expression profiles in rheumatoid arthritis

Clinical manifestations of rheumatoid arthritis(RA)are diversified,and based on the manifestations,the patients with RA could be classified into different patterns under traditional Chinese medicine.These patterns decide the selection of herbal prescription,and thus they can help find a subset of rheumatoid arthritis patients for a type of therapy.In the present study,we combine genome-wide expression analysis with methods of systems biology to identify the functional gene networks for the sets of clinical symptoms that comprise the major information for pattern classification.Clinical manifestations in rheumatoid arthritis were clustered with factor analysis,and two factors(similar to cold and hot patterns in traditional Chinese medicine)were found.Microarray technology was used to reveal gene expression profiles in CD4^(+)T cells from 21 rheumatoid arthritis patients.Protein-protein interaction information for these genes from databases and literature data was searched.The highly-connected regions were detected to infer significant complexes or pathways in this protein-protein interaction network.The significant pathways and function were extracted from these subnetworks using the Biological Network Gene Ontology tool.The genes significantly related to hot and cold patterns were identified by correlations analysis.MAPK signalling pathway,Wnt signaling pathway,and insulin signaling pathway were found to be related to hot pattern.Purine metabolism was related to both hot and cold patterns.Alanine,aspartate,and tyrosine metabolism were related to cold pattern,and histindine metabolism and lysine degradation were related to hot pattern.The results suggest that cold and hot patterns in traditional Chinese medicine were related to different pathways,and the network analysis might be used for identifying the pattern classification in other diseases.

Natural products for infectious microbes and diseases:an overview of sources,compounds,and chemical diversities

As coronavirus disease 2019(COVID-19) threatens human health globally,infectious disorders have become one of the most challenging problem for the medical community.Natural products(NP) have been a prolific source of antimicrobial agents with widely divergent structures and a range of vast biological activities.A dataset comprising 618 articles,including 646 NP-based compounds from 672 species of natural sources with biological activities against 21 infectious pathogens from five categories,was assembled through manual selection of published articles.These data were used to identify 268 NP-based compounds classified into ten groups,which were used for network pharmacology analysis to capture the most promising lead-compounds such as agelasine D,dicumarol,dihydroartemisinin and pyridomycin.The distribution of maximum Tanimoto scores indicated that compounds which inhibited parasites exhibited low diversity,whereas the chemistries inhibiting bacteria,fungi,and viruses showed more structural diversity.A total of 331 species of medicinal plants with compounds exhibiting antimicrobial activities were selected to classify the family sources.The family Asteraceae possesses various compounds against C.neoformans,the family Anacardiaceae has compounds against Salmonella typhi,the family Cucurbitacea against the human immunodeficiency virus(HIV),and the family Ancistrocladaceae against Plasmodium.This review summarizes currently available data on NPbased antimicrobials against refractory infections to provide information for further discovery of drugs and synthetic strategies for anti-infectious agents.

Virtual screening of the inhibitors targeting at the viral protein 40 of Ebola virus

Background:The Ebola virus is highly pathogenic and destructive to humans and other primates.The Ebola virus encodes viral protein 40(VP40),which is highly expressed and regulates the assembly and release of viral particles in the host cell.Because VP40 plays a prominent role in the life cycle of the Ebola virus,it is considered as a key target for antiviral treatment.However,there is currently no FDA-approved drug for treating Ebola virus infection,resulting in an urgent need to develop effective antiviral inhibitors that display good safety profiles in a short duration.Methods:This study aimed to screen the effective lead candidate against Ebola infection.First,the lead molecules were filtered based on the docking score.Second,Lipinski rule of five and the other drug likeliness properties are predicted to assess the safety profile of the lead candidates.Finally,molecular dynamics simulations was performed to validate the lead compound.Results:Our results revealed that emodin-8-beta-D-glucoside from the Traditional Chinese Medicine Database(TCMD)represents an active lead candidate that targets the Ebola virus by inhibiting the activity of VP40,and displays good pharmacokinetic properties.Conclusion:This report will considerably assist in the development of the competitive and robust antiviral agents against Ebola infection.