Pyrotinib is effective in both trastuzumab-sensitive and primary resistant HER2-positive breast tumors

Objective: Primary resistance to trastuzumab frequently occurs in human epidermal growth factor receptor 2(HER2)-positive(+) breast cancer patients and remains a clinical challenge. Pyrotinib is a novel tyrosine kinase inhibitor that has shown efficacy in the treatment of HER2+ breast cancer. However, the efficacy of pyrotinib in HER2+ breast cancer with primary trastuzumab resistance is unknown.Methods: HER2+ breast cancer cells sensitive or primarily resistant to trastuzumab were treated with trastuzumab, pyrotinib, or the combination. Cell proliferation, migration, invasion, and HER2 downstream signal pathways were analyzed. The effects of pyrotinib plus trastuzumab and pertuzumab plus trastuzumab were compared in breast cancer cells in vitro and a xenograft mouse model with primary resistance to trastuzumab.Results: Pyrotinib had a therapeutic effect on trastuzumab-sensitive HER2+ breast cancer cells by inhibiting phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT) and rat sarcoma virus(RAS)/rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)/extracellular-signal regulated kinase(ERK)pathways. In primary trastuzumab-resistant cells, pyrotinib inhibited cell growth, migration, invasion, and HER2 downstream pathways, whereas trastuzumab had no effects. The combination with trastuzumab did not show increased effects compared with pyrotinib alone. Compared with pertuzumab plus trastuzumab, pyrotinib plus trastuzumab was more effective in inhibiting cell proliferation and HER2 downstream pathways in breast cancer cells and tumor growth in a trastuzumab-resistant HER2+ breast cancer xenograft model.Conclusions: Pyrotinib-containing treatments exhibited anti-cancer effects in HER2+ breast cancer cells sensitive and with primary resistance to trastuzumab. Notably, pyrotinib plus trastuzumab was more effective than trastuzumab plus pertuzumab in inhibiting tumor growth and HER2 downstream pathways in HER2+ breast cancer with primary resistance to trastuzumab. These findings support clinical testing of the therapeutic efficacy of dual anti-HER2 treatment combining an intracellular small molecule with an extracellular antibody.

Research Progress of High Entropy Ceramic Materials

High-entropy materials(HEMs)have better mechanical,thermal,and electrical properties than traditional materials due to their special"high entropy effect".They can also adjust the performance of high entropy ceramics by adjusting the proportion of raw materials,and have broad application prospects in many fields.This article provides a review of the high entropy effect,preparation methods,and main applications of high entropy ceramic materials,especially exploring relevant research on high entropy perovskite ceramics.It is expected to provide reference for the promotion of scientific research and the development of further large-scale applications of high-entropy ceramic materials.

Distinct taxonomic and ecological functions of microbiome in sediments of different depth in Bohai Sea and Yellow Sea

Microorganisms in sediments are critical to marine ecosystems.The microbial communities in marine sediments of the Bohai Sea(BS)and Yellow Sea(YS),the eastern Chinese marginal seas,were uncovered in employing the metagenomic approach.In addition,the taxonomic and functional compositions of microbes were compared among various sediment core depths.Results showing the compositions,diversities,and functions of the microbial communities showed no significant variations with sea areas,and significant seasonal variations was observed in station 3500-7 only on functions of the microbial communities.Moreover,the compositions,diversities,and functions of the microbial communities changed noticeably in different sediment depths in close correlation with physical and chemical properties of sediments.However,the large fraction of the variation in functional communities remained unexplained.From bioinformatic analysis of the metagenomic data,the carbon-metabolismrelated genes such as glycosyl transferase(GT),glycoside hydrolase(GH),and carbohydrate esterase(CE)genes were rich in the microbial community,especially in the top sediment depth.Additionally,in this N-polluted habitat,nitrification and anaerobic ammonia oxidation(anammox)were dominant in the top sediment depth,whereas dissimilatory nitrate reduction to ammonium(DNRA)and denitrification were dominant in the middle and bottom depth,respectively.Further identification of possible biogeochemical links suggested that Gammaproteobacteria,Alphaproteobacteria,Nitrospirae,Nitrospinae,Chloroflexi,and Methanomicrobia might promote effective circulation of carbon and nitrogen cycling.This study expanded our knowledge about the structure and functional potential of microbial communities associated with different sediment depth,and provided further comprehensive information on element cycles in marine environments.

Submarine groundwater discharge and seasonal hypoxia off the Changjiang River Estuary

Hypoxia is a common phenomenon in the sea adjacent to the Changjiang River Estuary(CJE),one of the global major estuaries.Submarine groundwater discharge(SGD)is a widely recognized pathway for terrestrial materials entering the sea,and has been found to be significant off the CJE.We used a^(222)Rn mass balance model to estimate the SGD fluxes off the CJE and showed that it is linked to seasonal dissolved oxygen(DO)variations.Average SGD fluxes were estimated to be(0.012±0.010)m^(3)/(m^(2)·d)in winter,(0.034±0.015)m^(3)/(m^(2)·d)in summer,and(0.020±0.010)m^(3)/(m^(2)·d)in autumn.We found a significant negative correlation between DO concentrations and SGD rates with groundwater discharge being highest in the summer flood season.In addition,distribution patterns of SGD and hypoxia zones in summer are spatially overlapped,indicating that SGD is an important contributor to summer hypoxia in this region.

Tim-3 promotes cell aggressiveness and paclitaxel resistance through NF-κB/STAT3 signalling pathway in breast cancer cells

Objective:Although T-cell immunoglobulin and mucin-domain containing molecule-3(Tim-3)has been recognized as a promising target for cancer immunotherapy,its exact role in breast cancer has not been fully elucidated.Methods:Tim-3 gene expression in breast cancer and its prognostic significance were analyzed.Associated mechanisms were then explored in vitro by establishing Tim-3-overexpressing breast cancer cells.Results:In a pooled analysis of The Cancer Genome Atlas(TCGA)database,Tim-3 gene expression levels were significantly higher(P<0.001)in breast cancer tissue,compared with normal tissues.Tim-3 was a prognosis indicator in breast cancer patients[relapse-free survival(RFS),P=0.004;overall survival(OS),P=0.099].Tim-3 overexpression in Tim-3 low breast cancer cells promoted aggressiveness of breast cancer cells,as evidenced by enhanced proliferation,migration,invasion,tight junction deterioration and tumor-associated tubal formation.Tim-3 also enhanced cellular resistance to paclitaxel.Furthermore,Tim-3 exerted its function by activating the NF-κB/STAT3 signalling pathway and by regulating gene expression[cyclin D1(CCND1),C-Myc,matrix metalloproteinase-1(MMP1),TWIST,vascular endothelial growth factor(VEGF)upregulation,concomitant with Ecadherin downregulation).Lastly,Tim-3 downregulated tight junction-associated molecules zona occludens(ZO)-2,ZO-1 and occludin,which may further facilitate tumor progression.Conclusions:Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.

Physical-biogeochemical interactions and potential effects on phytoplankton and Ulva prolifera in the coastal waters off Qingdao(Yellow Sea, China)

In recent years, the spectacular massive green tide of Ulva prolifera has become a recurrent phenomenon appearing every summer in the coastal waters off Qingdao(Yellow Sea, China), attracting the attention of scientists and local government. Based on multidisciplinary data collected during summer and winter, this study focuses on the hydrological characteristics and regional biogeochemical processes in coastal waters off Qingdao.The results show that the boundary of the Yellow Sea Cold Water Mass(YSCWM) can reach the Qingdao coastal region in summer and is locally raised to the upper layers to form coastal upwelling beyond tidal mixing and favorable wind. The regional summer upwelling off the Qingdao coast effectively enriches the nutrient concentrations in the upper water column and thus promotes growth of phytoplankton but reduces the dissolved oxygen(DO) concentration and pH value in the bottom. The regional summer upwelling off Qingdao coast may facilitate the growth and regional blooming of the U. prolifera that migrate to this region with the southerly wind.Additionally, the effects of the front on the aggregation of U. prolifera may be significant. In winter, the Yellow Sea Warm Current(YSWC) extends and spreads along the offshore region off the Subei Shoal towards the Qingdao coastal sea. This tongue-shaped warm water meets the cold coastal water off Qingdao, which leads to the formation of a physical front. As a consequence, remarkable fronts of nutrient and chlorophyll a(Chl a) also form between the shoreward warm water and the cold coastal water. This study increases the understanding of the interactions between the regional physical, chemical, and biological processes off the Qingdao coast.

Adipocyte-derived SFRP5 inhibits breast cancer cells migration and invasion through Wnt and epithelial-mesenchymal transition signaling pathways

Objective:Obesity is closely associated with metastasis in breast cancer patients.Secreted frizzled-related protein 5(SFRP5),one of the novel adipokines with anti-inflammatory properties,is associated with obesity.This study aims to study the role of SFRP5 in the crosstalk between obesity and breast cancer metastasis and identify the underlying mechanism.Methods:3T3-L1 pre-adipocytes were differentiated to mature adipocytes and a hypertrophic adipocyte model was induced with palmitic acid(PA).Cell motility was measured in MDA-MB-231 and MCF-7 breast cancer cells co-cultured with adipocytes conditioned medium(CM)with or without SFRP5 protein.Wnt and epithelialmesenchymal transition(EMT)signal pathways were investigated by western blot.Circulating SFRP5 level in 218 breast cancer patients and the association with clinicopathologic characteristics of breast cancer were further determined.Online databases ENCORI and PREDICT Plus were used to exam the link between SFRP5 and prognosis.Results:Reduced SFRP5 level was detected in the hypertrophic adipocyte model.Recombinant SFRP5 protein inhibited MDA-MB-231 and MCF-7 cells invasion and migration induced by PA-treated adipocyte CM,and SFRP5 inhibition by specific antibody reversed the effect of SFRP5.Furthermore,SFRP5 significantly inhibited Wnt and downstream EMT in breast cancer cells.Low circulating SFRP5 level correlated with body mass index(BMI),lymph node(LN)metastasis,TNM stage and high Ki67 expression in breast cancer patients.Increased SFRP5 level was associated with favorable predicted survival.Kaplan-Meier curves showed high SFRP5 level in tumor tissue was associated with better outcome of breast cancer patients.Conclusions:Our findings demonstrated SFRP5 is a vital adipokine that mediates the crosslink between obesity and the metastatic potential of breast cancer.Promotion of SFRP5 expression in the adipose microenvironment may represent a novel approach for preventing breast cancer metastasis.

Neuronal-like differentiation of bone marrow-derived mesenchymal stem cells induced by striatal extracts from a rat model of Parkinson's disease

A rat model of Parkinson＇s disease was established by 6-hydroxydopamine injection into the medial forebrain bundle. Bone marrow-derived mesenchymal stem cells （BMSCs） were isolated from the femur and tibia, and were co-cultured with 10% and 60% lesioned or intact striatal extracts. The results showed that when exposed to lesioned striatal extracts, BMSCs developed bipolar or multi-polar morphologies, and there was an increase in the percentage of cells that expressed glial fibrillary acidic protein （GFAP）, nestin and neuron-specific enolase （NSE）. Moreover, the percentage of NSE-positive cells increased with increasing concentrations of lesioned striatal extracts. However, intact striatal extracts only increased the percentage of GFAP-positive cells. The findings suggest that striatal extracts from Parkinson＇s disease rats induce BMSCs to differentiate into neuronal-like cells in vitro.

Species-specific detection and quantification of scyphomedusae in Jiaozhou Bay,China,using a quantitative real-time PCR assay

Over the past decades,jellyfish occurred increasingly and abundantly in coastal areas worldwide.Usually,biomass of jellyfish,especially when they bloom,can be determined by visual counting.However,tiny individuals of jellyfish(e.g.,planulae,polyps,and ephyrae)are difficult to detect in the field.In this study,species-specific quantitative real-time PCR assays(qPCR)(SYBR Green I)targeting the mitochondrial 16S rDNA(mt-16S rDNA)of jellyfish were developed and were used to estimate the distribution and seasonal fluctuations of four jellyfish species(Nemopilema nomurai,Cyanea nozakii,Rhopilema esculentum,and Aurelia coerulea)in Jiaozhou Bay(JZB),China in 2013.The mt-16S rDNA of A.coerulea and N.nomurai was detected in most of the survey months and it peaked in July(1.03×10^(4) copies/L)and September(1.08×10^(6) copies/L),respectively.The mt-16S rDNA of C.nozakii occurred from August to October only with monthly mean values of 7.18-46.17 copies/L and was mainly located from the middle part to the outer part of the bay.The mt-16S rDNA of R.esculentum was the least abundant among the four species and was detected in only one sample(B2 station in March),with a value of 88.49 copies/L.The Spearman correlation test revealed that phytoplankton biomass was significantly and positively correlated with the mt-16S rDNA abundance of A.coerulea(R=0.37,P<0.01)and negatively with the mt-16S rDNA of N.nomurai(R=-0.36,P<0.01).The qPCR assay will enable the identification and quantification of jellyfish species in their whole life history and can be used as an approach in combination of the traditional jellyfish survey.

Characterization of microbial communities in sediments of the South Yellow Sea

Illumina sequencing and quantitative PCR(qPCR)based on the 16 S ribosomal RNA(rRNA)gene were conducted to characterize the vertical distribution of bacterial and archaeal communities in the sediments of two sites from the South Yellow Sea.Both bacterial and archaeal communities showed a clear stratified distribution with sediment depth.The microbial communities in the upper layers were distinct from those in the deeper layers;the relative abundances of sequences of Thaumarchaeota,Gammaproteobacteria,and Actinobacteria were higher in the upper than in the deeper sediments,whereas the sequences of Bathyarchaeia,Lokiarchaeota,Euryarchaeota,Chloroflexi,and Deltaproteobacteria were relatively more abundant in the deeper sediments.Sediment depth and total organic carbon(TOC)can significantly influence both the bacterial and archaeal communities.Furthermore,bacterial and archaeal groups potentially involved in nitrogen,sulfur,and methane metabolism were detected in both sites.In our study,both ammonia-oxidizing bacteria(Nitrospira)and ammonia-oxidizing archaea(Candidatus Nitrosopumilus)were responsible for ammonia oxidization.Additionally,sulfur-reducing bacteria SEEP-SRB1 forming consortia with anaerobic methane-oxidizing archaea ANME-2 a-2 b were capable of anaerobic methane oxidation(AOM)in the 3400-02 sediment samples.

Spatiotemporal variability of physical-biogeochemical processes and intrinsic correlations in the semi-enclosed South Yellow Sea

Investigating the spatiotemporal variability of biogeochemical processes and ecological responses under multiple physical controls in shelf seas is of great importance for obtaining an in-depth understanding of marine ecosystem.Based on a compiled data set of historical observations and remote sensing data,the spatiotemporal variability and heterogeneity of physical-biogeochemical processes in the semi-enclosed South Yellow Sea(SYS)are investigated,and the intrinsic connectivity among different subregions and the associated mechanisms are examined.The results show that the seasonal alternation between southward transport in cold seasons and upwelling-induced vertical delivery in warm seasons is the primary physical control of the biogeochemical processes and primary production off Shidao and in the area adjacent to the Haizhou Bay.The northeastward expansion of coastal waters in the Subei Shoal constitutes an important physical driver for the offshore transport of Ulva prolifera in summer.Stratification significantly affects the biogeochemical processes in the Yellow Sea Cold Water Mass(YSCWM)-dominated area during warm seasons,and nutrients can accumulate in bottom waters from spring to autumn,making the Yellow Sea Cold Water Mass(YSCWM)be an important nutrient pool.Upwelling around the YSCWM boundary in the stratified season leads to consistency among the high chlorophyll a(Chl a)area,high primary productivity region and low-temperature upwelling zone.During cold seasons,the interactions of the southward cold waters in the western nearshore area and the northward warm waters in the central region lead to an“S”-shaped front in the SYS.In summer,upwelling can extract nutrients from the YSCWM;thus,the biogeochemical-ecological processes inside the cold-water mass and in the frontal zone are well connected via upwelling,and three typical physical-biogeochemical coupling regions are generated,namely,the Shidao coast,the area beyond the Haizhou Bay and the area off the Subei Shoal.This work refines and integrates studies on regional oceanography in the SYS and provides a comprehensive and systematic framework of physical-biogeochemical-ecological processes.

Degradation potential and diversity of oil-degrading bacteria isolated from the sediments of the Jiaozhou Bay, China

A great deal of oil contaminated the shoreline by the Qingdao oil pipeline explosion in 2013. The four oildegrading consortia were enriched from sediment samples with crude oil as sole carbon and energy sources. The biodiversity and community analysis showed that the Luteibacter, Parvibaculum and a genus belonging to Alcanivoracaceae were found predominant bacteria in the four consortia, which belonged to Proteobacteria. Nine strains exhibiting distinct 16S rRNA gene sequences were isolated from the consortia. These strains were identified to eight genera based on 16S rRNA gene sequences. Five of the nine strains degraded more than 30% of the crude oil in two weeks by gravimetric method. From the analysis of GC-MS, most of the isolated strains tended to degrade n-alkanes rather than PAHs. Five strains showed high degrading ability of the total n-alkanes. Only Strain D2 showed great PAHs degrading ability and the degrading rates ranged from 34.9% to 77.5%. The sequencing analysis of the oil-degrading consortia confirmed that the genus of Alcanivorax was one of the dominant bacteria in Consortia A and E and Strain E4 might be one of the dominant bacteria. The strains obtained in this study demonstrated the potential for oil bioremediation in oil-contaminated beach ecosystems.

Using LA-ICP-MS to analysis elemental composition of statoliths of Scyphozoan jellyfish

Scyphozoan jellyfish outbreak events are drawing increasing attentions during the past decade.Elemental compositions of statoliths are helpful to understand jellyfish life history and blooming mechanisms,but very rare endeavor has been focused on the Scyphozoan class.In this work,we explored the feasibility of element analysis of Aurelia aurita(a representative Scyphozoan jellyfish outbreak species in China)which may be used as proxies of environment parameters during jellyfish living and moving.Statolith crystals of Aurelia aurita were found to be a gathering of hexahedron type trigonal needle with size of 10-50μm long,and 5-10μm in diameter.By using laser ablation inductively coupled plasma mass spectrometry(LA-ICP-MS)downhole profiling method,elements such as Ca,Sr,Mg,Na and P were found to be above the limit of detection and limit of quantification.The epidermis of statocyst could significantly impact the element analyses,so the real statolith element signal section needs to be selected based on elements and Ca profiles together with care.By laser ablated a signal spot repeatedly,the analytical uncertainty was about 3%-4%for Sr/Ca content ratio and Mg/Ca content ratio,but above 10%for other element/Ca content ratios(n=3).Based on the analysis of statolith from temperature-control cultured jellyfish,Sr/Ca content ratios among different statoliths of the same jellyfish were about 6%(n=14),demonstrating biological processes/vital effects causing small variations compared with analytical uncertainties.Therefore,Sr/Ca content ratios may be used as a potential proxy to reveal the living environment variations the Scyphozoan jellyfish has experienced,such as temperature history,which is helpful to understand jellyfish bloom mechanisms.

Sand barrier morphological evolution based on time series remote sensing images:a case study of Anhaiao,Pingtan

The morphological evolution of the sand barrier in the Anhaiao coastal zone of Pingtan from 1996 to 2018 was studied.Tidal correction was used to refine the location of the coastline.A standard deviation ellipse method was applied to further analyze the movement of the barrier head with the axis and rotation angle.A natural neighbor interpolation(NNI)method was carried out to calculate the terrain of the intertidal area,and the erosion and deposition characteristics were illustrated based on the terrain.The results showed that the northern part of the sand barrier facing the lagoon area was deposited over the whole studied period,while erosion has always occurred in the southern part of the sand barrier facing the open sea.The erosion and deposition were slightly different on both sides of the barrier head due to hydrodynamic turbulence.The middle sand barrier moved 102.60 m away from its original location in 1996,and the end of the barrier moved 65.45 m.The head of the sand barrier continued moving 379 m to the northwest.Consequently,the preliminary morphological evolution of the sand barrier corresponding to the distance and direction of movement was detected.

Implementation of Mooring Automatic Positioning System for Deepwater Semi-Submersible Platform Based on Dual-Stage Actuator

The automatic positioning control of mooring system for deepwater semi-submersible platform has become a key issue in the research and development field of deep-sea resources. The Dual- Stage Actuator (DSA) proposed in this paper can replace the single actuator to achieve the high speed and high precision positioning by cooperative control. The relative model and control algorithm of motion trajectory (CAMT) are designed and validated, which proves that the method proposed in this paper is effective.

Predictive Control and Implementation of Mooring Automatic Positioning System for Deepwater Semi-Submersible Platform

The automatic positioning control of mooring system for deepwater semi-submersible platform has become a key issue in the research and development field of deep-sea resources. The Dual-Stage Actuator (DSA) proposed in this paper can replace the single actuator to achieve the high speed and high precision positioning by cooperative control. The relative model and control algorithm of motion trajectory (CAMT) are designed and validated, which proves that the method proposed in this paper is effective.

Association of a complete breast cancer pathologic response with axillary lymph node metastasis via neoadjuvant chemotherapy:Results from the CSBrS-012 study

To the Editor:In the last decade,neoadjuvant chemotherapy(NAC)has become a well-accepted treatment option for breast cancer,although few detailed description of NAC in China has yet been reported.[1]A previous study found that among patients with clinically node-negative(cN0)breast cancer,97.7%(432/442)with breast pathologic complete response(bpCR)had ypN0(absence of metastases in the axillary lymph nodes);and 71.6%(882/1232)without bpCR achieved ypN0(P<0.001).As for human epidermal growth factor receptor 2(HER2)positive or triple-negative breast cancer(TNBC)that achieved bpCR.

An Improved Training Algorithm Based on Ensemble Penalized Cox Regression for Predicting Absolute Cancer Risk

Introduction:Biases in cancer incidence characteristics have led to significant imbalances in databases constructed by prospective cohort studies.Since they use imbalanced databases,many traditional algorithms for training cancer risk prediction models perform poorly.Methods:To improve prediction performance,we introduced a Bagging ensemble framework to an absolute risk model based on ensemble penalized Cox regression(EPCR).We then tested whether the EPCR model outperformed other traditional regression models by varying the censoring rate of the simulated data.Results:Six different simulation studies were performed with 100 replicates.To assess model performance,we calculated mean false discovery rate,false omission rate,true positive rate,true negative rate,and the areas under the receiver operating characteristic curve(AUC)values.We found that the EPCR procedure could reduce the false discovery rate(FDR)for important variables at the same true positive rate(TPR),thereby achieving more accurate variable screening.In addition,we used the EPCR procedure to build a breast cancer risk prediction model based on the Breast Cancer Cohort Study in Chinese Women database.AUCs for 3-and 5-year predictions were 0.691 and 0.642,representing improvements of 0.189 and 0.117 over the classical Gail model,respectively.Discussion:We conclude that the EPCR procedure can overcome challenges posed by imbalanced data and improve the performance of cancer risk assessment tools.

Breast Cancer Awareness and Association with Frequency of Screening Among Women—China,2020

Summary What is already known about this topic?Breast cancer awareness plays a crucial role in promoting screening attendance,enabling early detection,and improving survival rates associated with breast cancer.Nevertheless,a persistent issue is the low public awareness of breast cancer warning signs and risk factors.

Depressive Symptoms and Sleep Duration as Risk Factors for Breast Cancer—China,2020

Summary What is already known about this topic?Psychological and lifestyle factors are known to potentially play a significant role in the development of breast cancer.However,current evidence-based studies present controversial findings on the associations between depression,sleep duration,and breast cancer risk.