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As the most invasive and lethal subtype of breast cancer (BC), triple-negative breast carcinoma (TNBC) is of increasing interest. However, the androgen receptor (AR) still has an unclear role in TNBC. The current study is aimed at testing the diagnostic and therapeutic performance of novel biomarkers for AR-positive TNBC. The GSE76124 dataset was analyzed by combining WGCNA and other bioinformatics methods. Subsequently, function enrichment analysis was applied to identify the relationships between these differential expression genes (DEGs). Subsequently, the protein-protein interaction network was established, and the hub genes were identified by Cytoscape software. Eventually, the miRNA-hub gene modulate network was developed and the Drug-Gene Interaction Database (DGIdb) was applied to verify the potential drugs for AR-positive TNBC. In the current research, 88 DEGs in total were selected from the intersection of the purple module genes identified by WGCNA and limma package. TFF1, FOXA1, ESR1, AGR2, TFF3, AGR3, GATA3, XBP1, SPDEF, and TOX3 were selected as hub genes by the MCC method, which were all upregulated. The survival analysis suggested that TFF1 was the only one related to significant lower survival rate in TNBC. Ultimately, hsa-miR-520g-3p and hsa-miR-520h were found taking part in the regulation of TFF1, and 2 small molecules were identified as the potential targets for AR-positive TNBC treatment. As a result, our study suggested that hsa-miR-520g-3p, hsa-miR-520h, and TFF1 might have significant potential values for AR-positive TNBC diagnosis and prognosis prediction. TFF1, hsa-miR-520g-3, and hsa-miR-520h may serve as the novel therapeutic targets, and our findings offer further insights into the therapy of AR-positive TNBC.

A considerable number of surrogate-assisted evolutionary algorithms (SAEAs) have been developed to solve expensive optimization problems (EOPs) with continuous objective functions. However, in the real-world applications, we may face EOPs with discontinuous objective functions, which are also called EOPs with discontinuous responses (EOPDRs). Indeed, EOPDRs pose a great challenge to current SAEAs. In this paper, a surrogate-assisted differential evolution (DE) algorithm with region division is proposed, named ReDSADE. ReDSADE includes three main strategies: the region division strategy, the Kriging-based search, and the radial basis function (RBF)-based local search. In the region division strategy, we define a new distance measure, called the objective-decision distance. Based on this distance, the evaluated solutions are partitioned into several clusters, and several support vector machine (SVM) classifiers are trained to classify them. These SVM classifiers divide the decision space into several subregions, with the aim of making the objective function continuous in them. In the Kriging-based search, a Kriging model is established in each subregion and combined with DE to search for the optimal solution. In the RBF-based local search, DE is coupled with RBF to search around the best solution found so far, thus accelerating the convergence. By combining these three strategies, ReDSADE is able to solve EOPDRs with limited function evaluations. Three set of test problems and a real-world application are utilized to verify the effectiveness of ReDSADE. The results demonstrate that ReDSADE exhibits good convergence accuracy and convergence speed.

Background: In multiple malignant tumors, circular RNAs (circRNAs) are believed to play a crucial role. Our prior results demonstrated that circ_ZNF778_006 was significantly increased in esophageal squamous cell carcinoma(ESCC) tissues, but the roles of circ_ZNF778_006 in ESCC is still not clear. Methods:The expression of circ_ZNF778_006 was compared in different pathological grades of ESCC. And the expression levels of circ_ZNF778_006, miR-18b-5p, HIF-1α were analyzed by qRT-PCR and Western blot, respectively. Plasmid transfection techniques were applied to prepare ESCC cells with silenced or overexpressed genes (CircZNF778_006, miR-18b-5p). The CCK8 kit was used to determine cell proliferation, and the Transwell assay was used to measure the migration and invasion. The effects of circ_ZNF778_006 on tumor growth was investigated in vivo. Furthermore, luciferase reporter gene assay and RNA-binding protein immunoprecipitation(RIP) were performed to verify the targeting relationship between miR-18b-5p and circZNF778_006, miR-18b-5p and HIF-1α. Results: The expression of circ_ZNF778_006 was positively correlated with pathological grade in ESCC. Circ_ZNF778_006 significantly inhibited sensitivity to 5-fluorouracil & cisplatin. It could promote the proliferation, invasion, migration in ESCC cells and accelerated tumor growth in vivo. Furthermore, circ_ZNF778_006 could upregulate the expression of HIF-1α via sponing miR-18b-5p. Conclusion: Circ_ZNF778_006 promoted ESCC progression by upregulating HIF-1α expression via sponging miR-18b-5p.

IntroductionOverfishing and climate change have combined to cause fishery stocks to decline and fish community composition to change, further threatening the predation and nutritional health of marine mammals.MethodsIn this study, we collected potential prey fishes catched by fishermen in six habitats of Indo-Pacific humpback dolphins and analyzed their proximate composition (moisture, water, fat and protein), the fatty acid composition and the amino acid composition to evaluate the possible health effect on humpback dolphins.ResultsThe results showed that the nutritional composition varied significantly with species and locations. Fishes in the families Sciaenidae and Engraulidae displayed richer fatty acid composition, while those in the family Clupeidae had the highest value of amino acid quality index. In Zhuhai, home to the largest Indo-Pacific humpback dolphin population, pelagic/neritic prey fishes possessed lower energy density, PUFA content, PUFA/SFA ratio, DHA content, and EAA content compared to demersal fish, suggesting nutritional stress when there is a dietary switch from demersal to pelagic/neritic fishes in Zhuhai population.DiscussionOur study provided a framework, with energy density and fatty acid composition as its most important indicator, for assessment of the marine top predators based on the nutritional composition of their prey fishes and revealed the potential threats. Data here is expected to facilitate the development of scientific programs for successful conservation of not only the Indo-Pacific humpback dolphins, but also other marine top predators, possibly through reconstructing their prey fish’s quantity and quality.

The changing landscape of mutations in the SARS-CoV-2 Spike protein is linked to the emergence of variants, immune-escape and reduced efficacy of the existing repertoire of anti-viral antibodies. A major factor that contributes to the functional activity of the neutralizing antibodies are the intrinsic quaternary changes that occur as a result of antibody-Spike trimer interactions. In this study, we reveal the conformational dynamics and allosteric perturbations linked to binding of human monoclonal antibodies and the viral Spike protein. We identify epitope hotspots of known and novel antibodies, and associated changes in Spike dynamics that define weak, moderate and strong neutralizing antibodies. We show the impact of mutations in Wuhan, Delta, and Omicron variants of concern (VoCs) and differences observed in the antibody-induced conformational changes and illustrate how these render certain antibodies ineffective. Our comparative analyses of the antibody-footprints on Spike variants reveal how antibodies with similar binding affinities may induce destabilizing and stabilizing allosteric effects. These differences have important implications for neutralization efficacy and for developing new antibodies targeting emerging variants. Our results provide mechanistic insights into the functional modes and synergistic behavior of human antibodies against COVID-19, and provide a rationale to design effective antiviral strategies.

BackgroundBreast cancer (BC) is considered to be one of the primary causes of cancer deaths in women. Cuproptosis was suggested to play an important role in tumor proliferation and tumor immune microenvironment. Therefore, an investigation was conducted to identify the relationship between cuproptosis-related long non-coding RNAs (lncRNAs) and BC prognosis.MethodBased on The Cancer Genome Atlas (TCGA), nine cuproptosis-related lncRNAs were identified by Pearson’s analysis and Cox regression analysis to create a cuproptosis-related lncRNA signature. Subsequently, patients with BC were divided into high-risk and low-risk groups. The Kaplan–Meier curves and a time-dependent receiver operating characteristic (ROC) analysis were employed to elucidate the predictive capability of the signature. After that, the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted by Gene Set Enrichment Analysis (GSEA), and the lncRNA–mRNA co-expression network was established by Cytoscape software. Furthermore, the ESTIMATE score was calculated, and the immune cell type component analysis was conducted. Eventually, immunotherapy response analysis was applied to identify the predictive power of cuproptosis-related lncRNAs to tumor immunotherapy response, including immune checkpoint gene expression levels, tumor mutational burden (TMB), and microsatellite instability (MSI).ResultsPatients with BC in the low-risk groups showed better clinical outcomes. The KEGG pathways in the high-risk groups were mainly enriched in immune response and immune cell activation. Furthermore, the ESTIMATE scores were higher in the low-risk groups, and their immune cell infiltrations were dramatically different from those of the high-risk groups. The low-risk groups were shown to have higher infiltration levels of CD8+ T cells and TMB-high status, resulting in better response to immunotherapies.ConclusionThe findings of this study revealed that the nine-cuproptosis-related lncRNA risk score was an independent prognostic factor for BC. This signature was a potential predictor for BC immunotherapy response. What we found will provide novel insight into immunotherapeutic treatment strategies in BC.

In recent years, China has been promoting the process of carbon neutral by establishing carbon exchanges (CEs) and implementing relevant carbon emission reward and punishment policies. This study proposes a partnership of the CE, solar power plant (SPP) and coal-fired thermal power plant (TPP). Based on the tripartite evolutionary game model and current policies of China, the evolutionary processes are simulated and discussed. The results reveal that stable states can be achieved under different partnership modes. Effect evaluation results of typical parameters on the three participants show that on the premise of ensuring the participations of CE and SPP, properly reducing the prices of carbon emission share sold to the TPP will strengthen the participation willingness of TPP. The relatively reasonable selling price ranges of carbon emission share of the CE and SPP sold to the TPP are 6.0 ∼ 6.2 $/t and 5.3 ∼ 5.5 $/t, respectively. Higher zero carbon emission reward and higher carbon tax can strengthen the participation willingness of TPP and make the TPP achieve the carbon neutral. This study can provide a reference for the government and related industries to promote the carbon neutral development as well as the coordinated development of solar power and coal-fired thermal power.

An unprecedented number of COVID-19 vaccination campaign are under way worldwide. The spike protein of SARS-CoV-2, which majorly binds to the host receptor angiotensin converting enzyme 2 (ACE2) for cell entry, is used by most of the vaccine as antigen. ACE2 is highly expressed in the heart and has been reported to be protective in multiple organs. Interaction of spike with ACE2 is known to reduce ACE2 expression and affect ACE2-mediated signal transduction. However, whether a spike-encoding vaccine will aggravate myocardial damage after a heart attack via affecting ACE2 remains unclear. Here, we demonstrate that cardiac ACE2 is up-regulated and protective after myocardial ischemia/reperfusion (I/R). Infecting human cardiac cells or engineered heart tissues with a spike-based adenovirus type-5 vectored COVID-19 vaccine (AdSpike) does not affect their survival and function, whether subjected to hypoxia-reoxygenation injury or not. Furthermore, AdSpike vaccination does not aggravate heart damage in wild-type or humanized ACE2 mice after I/R injury, even at a dose that is ten-fold higher as used in human. This study represents the first systematic evaluation of the safety of a leading COVID-19 vaccine under a disease context and may provide important information to ensure maximal protection from COVID-19 in patients with or at risk of heart diseases.

Summary Background PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. Methods KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov , number NCT02853305 . Findings Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7–36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5–8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4–7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65–0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5–19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3–16·7) in the chemotherapy group (0·86, 0·72–1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1–17·9] with pembrolizumab vs 14·3 months [12·3–16·7] with chemotherapy; HR 0·92, 95% CI 0·77–1·11) and the population with CPS of at least 10 (16·1 months [13·6–19·9] with pembrolizumab vs 15·2 months [11·6–23·3] with chemotherapy; 1·01, 0·77–1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. Interpretation The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. Funding Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Critically endangered species are usually restricted to small and isolated populations. High inbreeding without gene flow among populations further aggravates their threatened condition and reduces the likelihood of their long-term survival. Chinese alligator (Alligator sinensis) is one of the most endangered crocodiles in the world and has experienced a continuous decline over the past c. 1 million years. In order to identify the genetic status of the remaining populations and aid conservation efforts, we assembled the first high-quality chromosome-level genome of Chinese alligator and explored the genomic characteristics of three extant breeding populations. Our analyses revealed the existence of at least three genetically distinct populations, comprising two breeding populations in China (Changxing and Xuancheng) and one breeding population in an American wildlife refuge. The American population does not belong to the last two populations of its native range (Xuancheng and Changxing), thus representing genetic diversity extinct in the wild and provides future opportunities for genetic rescue. Moreover, the effective population size of these three populations has been continuously declining over the past 20 ka. Consistent with this decline, the species shows extremely low genetic diversity, a large proportion of long runs of homozygous fragments, and mutational load across the genome. Finally, to provide genomic insights for future breeding management and conservation, we assessed the feasibility of mixing extant populations based on the likelihood of introducing new deleterious alleles and signatures of local adaptation. Overall, this study provides a valuable genomic resource and important genomic insights into the ecology, evolution, and conservation of critically endangered alligators.

Background. Breast cancer is a big threat to the women across the world with substantial morbidity and mortality. The pressing matter of our study is to establish a prognostic gene model for breast cancer based on mRNAsi for predicting patient’s prognostic survival. Methods. From The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we downloaded the expression profiles of genes in breast cancer. On the basis of one-class logistic regression (OCLR) machine learning algorithm, mRNAsi of samples was calculated. Kaplan-Meier (K-M) and Kruskal-Wallis (K-W) tests were utilized for the assessment of the connection between mRNAsi and clinicopathological variables of the samples. As for the analysis on the correlation between mRNAsi and immune infiltration, ESTIMATE combined with Spearman test was employed. The weighted gene coexpression network analysis (WGCNA) network was established by utilizing the differentially expressed genes in breast cancer, and the target module with the most significant correlation with mRNAsi was screened. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted to figure out the biological functions of the target module. As for the construction of the prognostic model, univariate, least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analyses were performed on genes in the module. The single sample gene set enrichment analysis (ssGSEA) and tumor mutational burden were employed for the analysis on immune infiltration and gene mutations in the high- and low-risk groups. As for the analysis on whether this model had the prognostic value, the nomogram and calibration curves of risk scores and clinical characteristics were drawn. Results. Nine mRNAsi-related genes (CFB, MAL2, PSME2, MRPL13, HMGB3, DCTPP1, SHCBP1, SLC35A2, and EVA1B) comprised the prognostic model. According to the results of ssGSEA and gene mutation analysis, differences were shown in immune cell infiltration and gene mutation frequency between the high- and low-risk groups. Conclusion. Nine mRNAsi-related genes screened in our research can be considered as the biomarkers to predict breast cancer patients’ prognoses, and this model has a potential relationship with individual somatic gene mutations and immune regulation. This study can offer new insight into the development of diagnostic and clinical treatment strategies for breast cancer.

Background: Breast cancer (BC) is one of the most frequent malignancies among women worldwide. Accumulating evidence indicates that long non-coding RNA (lncRNA) may affect BC progression. Exosomes, a class of small membrane vesicles, have been reported to promote tumor progression through transporting proteins, mRNAs, lncRNAs and so on. However, the interaction between exosome-related lncRNAs and the microenvironment of malignancies is unclear. Hence, we proceeded to investigate the relationship between exosome-related lncRNAs and BC microenvironment. Method: 121 exosome-associated genes were extracted from ExoBCD database. Then, the Pearson analysis was used to screened out the exosome-related lncRNAs. After that, 15 exosome-related differentially expressed lncRNAs were identified by the correlation with BC prognosis. According to the sum of the expression of these 15 lncRNAs, extracted from The Cancer Genome Atlas (TCGA), and the regression coefficients, an exosome-related lncRNAs signature was developed by using Cox regression analysis. With the median risk score of the training set, the patients in training and validation sets were separated to low-risk group and high-risk group. Subsequently, the lncRNA–mRNA co-expression network was constructed. The distinct enrichment pathways were compared among the different risk groups by using the R package clusterProfiler. The ESTIMATE method and ssGESA database were adopted to study the ESTIMATE Score and immune cell infiltration. Eventually, the expression of immune checkpoint associated genes, microsatellite instable (MSI) and the immunophenoscore (IPS) were further analyzed between different risk groups. Results: Different risk groups exhibited different prognosis, with lower survival rate in the high-risk group. The differentially expressed genes (DEGs) between the different risk groups were enriched in biological processes pathways as well as immune responses. BC patients in high-risk group were identified with lower scores of ESTIMATE scores. Subsequently, we noticed that the infiltrating levels of aDCs, B cells, CD8+ T cells, iDCs, DCs, Neutrophils, macrophages, NK cells, pDCs, Tfh, T helper cells, TIL and Tregs were obvious elevated with the decreased risk score in training and validation cohorts. And some immune signatures were significantly activated with the decreased risk score in both cohorts. Eventually, the exosome-associated lncRNAs risk model was demonstrated to accurately predict immunotherapy response in patients with BC. Conclusion: The results of our study suggest that exosome-related lncRNAs risk model has close relationship with prognosis and immune cells infiltration in BC patients. These findings could make a great contribution to improving BC immunotherapy.

Jinzhuan Chen1,2 &ast;, Siyu Xie3 &ast;, Ying Chen,2,4 Ting Qiu,2,4 Jianqing Lin1,2,4 1Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 2The First Clinical Medical College of Fujian Medical University, Fuzhou, 350005, People’s Republic of China; 3Department of Anesthesiology, Fujian Provincial Hospital, Fuzhou, 350005, People’s Republic of China; 4The First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianqing Lin, Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, People’s Republic of China, Tel +86-13850143313, Email linjianqing72@fjmu.edu.cn; fjmufy@sina.comObjective: Postoperative delirium (POD) seriously affects recovery of older persons, increasing their mortality rate after surgery. We aimed to evaluate preoperative oral saline administration on postoperative delirium in older persons undergoing spinal decompression.Design: A randomised controlled trial in a large tertiary hospital.Setting and Participants: A total of 76 older persons (≧65 years old) undergoing spinal surgery from May 2020 to January 2021.Methods: Older persons (65– 83 years old) who underwent elective spinal canal decompression were randomly grouped into either the control group (n = 38) or the intervention group (n = 38). The control group was forbidden from drinking 8 hours prior to the operation while the intervention group was administered 5 mL·kg− 1 of normal saline 2 hours before anesthesia. Hemodynamic indicators, diagnostic biomarkers, preoperative mini-mental status scores, and intraoperative fluid dynamics were recorded at baseline and at various postoperative timepoints. Subjects were then scored for POD and postoperative pain.Results: S100β protein was lowered in S1 (FS1 = 12.289, P < 0.001) and S2 (FS2 = 12.440, P < 0.001) in the intervention group while mean arterial blood pressure (FT1= 42.997, P< 0.001) and heart rate (FT1= 8.974, P=0.004) were increased. The Ln c-reactive protein of the intervention group was lowered 1 day postoperatively (FS2 = 6.305, P = 0.014). The incidence of postoperative delirium in the control group was higher than in the intervention group (27.8% vs 8.3%, χ2 = 4.547, P = 0.033).Conclusion: Preoperative oral saline can reduce the incidence of postoperative delirium in older persons by minimizing perioperative hemodynamic fluctuations and central nervous system damage.Keywords: older persons, postoperative delirium, spinal canal decompression

Various works have been proposed to solve expensive multiobjective optimization problems (EMOPs) using surrogate-assisted evolutionary algorithms (SAEAs) in recent decades. However, most existing methods focus on EMOPs with less than 30 decision variables, since a large number of training samples are required to build an accurate surrogate model for high-dimensional EMOPs, which is unrealistic for expensive multiobjective optimization. To address this issue, we propose an SAEA with an adaptive dropout mechanism. Specifically, this mechanism takes advantage of the statistical differences between different solution sets in the decision space to guide the selection of some crucial decision variables. A new infill criterion is then proposed to optimize the selected decision variables with the assistance of surrogate models. Moreover, the optimized decision variables are extended to new full-length solutions, and then the new candidate solutions are evaluated using expensive functions to update the archive. The proposed algorithm is tested on different benchmark problems with up to 200 decision variables compared to some state-of-the-art SAEAs. The experimental results have demonstrated the promising performance and computational efficiency of the proposed algorithm in high-dimensional expensive multiobjective optimization.

The concentrated photovoltaic/thermal system (CPVT) adopting spectral beam splitting is a promising field of solar energy research. However, the thermo-electric properties of fluid-based CPVT collectors, which depend strongly on the non-uniform concentrated energy flux, remain unclear. This study aims to fill the gap and explore the thermo-electric properties of fluid-based CPVT collectors under non-uniform energy flux based on the finite volume method (FVM) with the Monte Carlo Ray-Trace (MCRT) method. The actual solar flux distribution on the receiver surface is obtained using Tracepro software. Then, the realistic non-uniform energy flux was employed in ANSYS Workbench 2022R1 software as a boundary condition to increase the accuracy of the CFD modeling of the system. The model is validated by comparing the results of the reference data. Moreover, the impact of uniform and non-uniform energy flux on the PV cell temperature is analyzed. In addition, the effects of mass flow rate on the electrical and thermal performance of the system are investigated. The results show that the PVT hybrid system has high conversion efficiency, with a total efficiency of more than 50%. Notably, the extreme non-uniformity of the solar-concentrated energy flux can result in local overheating of the PV cell, which may lead to irreversible damage.

BackgroundDysregulated non-coding RNAs exhibit critical functions in various cancers. Nonetheless, the levels and corresponding functions of cirCSNX14 in esophageal squamous cell carcinoma (ESCC) yet remain to be elucidated.MethodsInitially, the aberrant low levels of lncRNA-LET within ESCC tissues are validated via qRT-PCR observations. Moreover, the effects of lncRNA-LET upregulation on cell proliferation in vitro are determined. In addition, a series of assays determining the mechanistic views related to metabolism is conducted. Furthermore, the effects of lncRNA-LET in affecting tumor growth are investigated in vivo in a mouse model. Moreover, the interactions between lncRNA-LET and its networks are predicted and determined by RNA immunoprecipitation-assisted qRT-PCR as well as luciferase reporter assays.ResultsThe downregulation of lncRNA-LET is correlated to the poor prognosis of ESCC patients. Moreover, the upregulated expression of lncRNA-LET could have reduced the cell viability. In vivo tumor inhibition efficacy assays showed that an increase of lncRNA-LET presented excellent inhibitory effects on cancer proliferation as reflected by tumor weight and volume in mice. Finally, the mechanistic views regarding the effects of miR-106b-5p or miR-93-5p and SOCS4 on ESCC are related to the feedback of lncRNA-LET.ConclusionCollectively, this study suggested that lncRNA-LET miR-93-5p or the miR-106b-5p–SOCS4 axis may provide great potential in establishing ESCC therapy.

The gut microbiome is a unique marker for cetaceans' health status, and the microbiome composition of their skin wounds can indicate a potential infection from their habitat. Our study provides the first comparative analysis of the microbial communities from gut regions and skin wounds of an individual Indo-Pacific finless porpoise (

Ecological qualities and resources in coasts are threatened by various human activities, such as pollution and fishery. Impact evaluation of environmental stressors over a wide coastal stretch has been limited due to lack of efficient and standardizable biodiversity monitoring and assessment tools. Integrating environmental DNA (eDNA) and ecological traits, a holistic approach was developed to assess the impact of pollution and aquaculture on fish biodiversity in Chinese coastal areas. Taking the Yalujiang Estuary (YLJK) from the Yellow Sea and the Nan'ao Island Area (NAO) from the South China Sea as cases, the performance of the eDNA biomonitoring workflow was validated. First, the eDNA results of 22 sampling sites reached more than 85% of the asymptotes of species or ASVs in each area. A total of 115 fish species in both areas were detected and NAO was 1.8 times richer than YLJK using eDNA and the fish eDNA composition was consistent with the historical data. eDNA recovered distinct variations of fish sequence, taxonomic and functional diversity, and the corresponding trends following the offshore distance between the two areas. Fish sequence diversity was decreased primarily by estuarine pollution factors (chemical oxygen demand and zinc) in the YLJK. Compared with no breeding areas, lower fish sequence diversity was in breeding areas in the NAO. By integrating ecological traits, the eDNA approach offers promising opportunities for future fish biodiversity monitoring and assessment in national and global coastal environments.

BackgroundPyroptosis is a novel identified form of inflammatory cell death that is important in the development and progression of various diseases, including malignancies. However, the relationship between pyroptosis and triple-negative breast cancer (TNBC) is still unclear. Therefore, we started to investigate the potential prognostic value of pyroptosis-associated genes in TNBC.MethodsThirty-three genes associated with pyroptosis were extracted from previous publications, 30 of which were identified in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. On the basis of the 30 pyroptosis-related genes, patients with TNBC were divided into three subtypes through unsupervised cluster analysis. The prognostic value of each pyroptosis-associated gene was assessed, and six genes were selected by univariate and LASSO Cox regression analysis to establish a multigene signature. According to the median value of risk score, patients with TNBC in the training and validation cohorts were separated to high- and low-risk sets. The enrichment analysis was conducted on the differentially expressed genes (DEGs) of the two risk sets using R clusterProfiler package. Moreover, the ESTIMATE score and immune cell infiltration were calculated by the ESTIMATE and CIBERSORT methods. After that, the correlation among pyroptosis-associated risk score and the expression of immune checkpoint-associated genes as well as anti-cancer drugs sensitivities were further analyzed.ResultsIn the training and validation cohorts, patients with TNBC in the high-risk set were found in a lower survival rate than those in the low-risk set. Combined with the clinical characteristics, the pyroptosis-related risk score was identified as an independent risk factor for the prognosis of patients with TNBC. The enrichment analysis indicated that the DEGs between the two risk groups were mainly enriched by immune responses and activities. In addition, patients with TNBC in the low-risk set were found to have a higher value of ESTIMATE score and a higher rate of immune cell infiltration. Finally, the expression levels of five genes [programmed cell death protein 1 (PD-1); cytotoxic t-lymphocyte antigen-4 (CTLA4); lymphocyte activation gene 3 (LAG3); T cell immunoreceptor with Ig and ITIM domains (TIGIT)] associated with immune checkpoint inhibitors were identified to be higher in the low-risk sets. The sensitivities of some anti-cancer drugs commonly used in breast cancer were found closely related to the pyroptosis-associated risk model.ConclusionThe pyproptosis-associated risk model plays a vital role in the tumor immunity of TNBC and can be applied to be a prognostic predictor of patients with TNBC. Our discovery will provide novel insight for TNBC immunotherapies.

BACKGROUND: Indoor environment is complex, with many factors potentially interacting with each other to affect health. However, previous studies have usually focused on effect of a single factor. Assessment of the combined effects of multiple factors can help with understanding the overall health risk. METHODS: A cross-sectional study was conducted among 2,306 school children in Guangzhou and Shenzhen. Questionnaire data on respiratory symptoms and diseases were collected along with sociodemographic and residential environmental information. A subset of children (N=987) were measured for their lung function. A random forest algorithm was applied to screen the top-ranked indoor environmental exposure variables and to form a composite index for cumulative risk of indoor pollution (CRIP). Logistic regressions were conducted to analyze the independent effect of single indoor environmental risk factors and the combined effect of CRIP on children’s respiratory health. Multiple linear regressions were used to examine the independent and combined effects of indoor environmental exposure on lung function. RESULTS: We found that home dampness and molds as well as environmental tobacco smoke (ETS) were significantly and independently associated with increased prevalence of children’s respiratory symptoms and diseases and with reduced lung function. A higher CRIP level was significantly associated with increased risk of cough with cold (OR =1.37, 95% CI: 1.05–1.79) and wheeze (OR =2.71, 95% CI: 1.16–6.34). A higher CRIP level was also associated with reduced lung function measured as FVC, FEV(1), PEF, FEF(25%), FEF(25–75%) and VC. CONCLUSIONS: In children living in the subtropical region of the Pearl River Delta, home dampness and the presence of mold as well as ETS were individual risk factors for children’s respiratory health. The composite CRIP index was associated with respiratory symptoms and lung function, suggesting the utility of this index for predicting the combined effects of multiple risk factors.

A novel solar concentrating PV and thermal (CPVT) combined system with beam splitter and compact concentrator structure is proposed in this study. The system structure and its design method are provided. The optical filter is designed and the incident light angle effect on the beam splitting performance is investigated. Solar concentrating simulations are conducted and the relevant results reveal that the CPVT combined system can provide a high solar concentration uniformity. The evaluation results of configuration and optical analyses indicate that when all the other parameters are settled, the optimal installation height of the solar receiver tube is 923.0 mm. The influence study of sun tracking accuracy on the system optical performance is launched. It is concluded that when the tracking error increases to 1.0°, the overall optical efficiency is 66.2%. The thermodynamic analysis results indicate that the PV conversion and overall energy efficiencies of the CPVT system are 30.5% and 26.6%, which are both higher than those of the normal CPV system. Moreover, the operating temperature effect investigation of solar thermal receiver tube is conducted. The results show that an optimal solar thermal receiver tube temperature (356.0 °C) exists, which can result in the maximum total output power.

While several scientific studies have linked PM2.5 to decreased lung function, there is still some degree of uncertainty regarding which particulate physicochemical properties are most harmful. We followed a panel of 57 healthy schoolchildren (857 person-days) to investigate the associations between a wide variety of PM2.5 and lung function in Heshan, China in 2016 for three periods. We monitored the daily concentrations of mass, chemical composition, size, number, surface area, and volume of particulate mixture. Associations of lung function with various particle metrics were estimated using generalized estimating equations and unconstrained distributed lag models. Random forest model was used to compare the relative importance of exposure metrics. Immediate (lag 0) associations of PM2.5 and carbonaceous aerosols with reduced FEV1 and MMEF, and accumulation-mode particles with FEV1 were found. Slightly delayed (lag 1, 2) effects on PEF were particularly prominent for Aitken-mode particles. Possible cumulative (lags 0-2) effects of PM2.5 and carbonaceous aerosols on PEF and Aitken-mode particles on FEV1, MMEF, and PEF were observed. This study provides comprehensive evidence that the physicochemical properties of particulate mixtures are associated with reduced lung function in children. Organic carbon (OC) may be an important risk factor for the decreased lung function related to PM exposure.

Purpose Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer. Methods and Materials Twenty men were enrolled in this institutuional review board–approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition. Results With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m2. The 5-year biochemical disease-free survival was 73%, despite 75% of patients having very high risk prostate cancer per the National Comprehensive Cancer Network guidelines. Four patients were unable to complete chemotherapy owing to dose-limiting toxicities (eg, rectal bleeding, diarrhea, and elevated transaminase). There was no significant minimally important difference in Expanded Prostate Index Composite patient-reported outcomes for either the urinary or bowel domains; however, there was a significant decrease in the sexual domain. Conclusions This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m2. Despite the aggressive nature of the disease, robust biochemical control was observed.

Background: Breast cancer (BC) is the most diagnosed malignancy in women around the word. Accumulating evidence suggest that transient receptor potential (TRP) channels play significant role in tumor progression and immune cell infiltration. Nevertheless, the relationship between TRP channels and tumor immune microenvironment of BC is still unclear. Hence, we conducted the study to investigate the correlation between TRP-associated lncRNAs and the prognosis of breast carcinoma. Method: 33 TRP-associated genes were selected from a review published by Amrita Samanta et al. and the TRP-related lncRNAs were identified by the Pearson analysis. Based on the sum of the expression levels of 12 lncRNAs, provided by The Cancer Genome Atlas (TCGA), a TRP-associated-lncRNA signature was established by use of Cox regression analysis. According to the median value of risk score in training set, BC patients were separated into high- and low-risk groups. Subsequently, the functional enrichment analysis was conducted in the differential expression genes (DEGs) between different risk groups. The ESTIMATE Score was calculated by ESTIMATE and the immune cell infiltration was evaluated by ssGSEA. Finally, the immune checkpoint genes expression levels, microsatellite instable (MSI) and the immunophenoscore (IPS) were further assessed.Results: The high-risk groups exhibited lower survival rates while the low-risk groups shown higher survival rates. The DEGs between different risk groups were highly enriched in immune cell activation and immunoregulation. Besides, the ESTIMATE scores of patients in low-risk groups were higher than those in high-risk groups. The infiltration levels of several immune cells were remarkably elevated in low-risk groups and various immune signatures were activated with the decreased risk score. Eventually, the TRP-associated lncRNAs signature was confirmed with highly potential ability to evaluate the immunotherapy response in breast carcinoma patients. Conclusion: The outcomes of current study indicated that the 12-TRP-associate-lncRNA risk model was an independent prognostic risk factor for BC patients. This risk model could be closely related to the tumor immune microenvironment in BC. Our findings will provide a new insight for future immunotherapy for BC treatment.

Despite their widespread use, our understanding of how malaria drugs work remains limited. This includes chloroquine (CQ), the most successful antimalarial ever deployed. Here, we used MS-CETSA and dose-response transcriptional profiling to identify possible protein targets and mechanism of action (MOA) of CQ, as well as MK-4815, a malaria drug candidate with a proposed MOA similar to CQ. Both compounds bind falcilysin (FLN) and hemoglobin digestion was the key biological pathway affected, with distinct MOA profiles between CQ-sensitive and CQ-resistant parasites. We showed that CQ and MK-4815 inhibit FLN proteolytic activity, and using X-ray crystallography, that they occupy a hydrophobic pocket situated within the large peptide substrate binding cavity of FLN. Studies using transgenic parasite line suggest the potential role of FLN in the CQ and MK-4815 MOA. Altogether, our data reveal a druggable pocket in the FLN substrate binding cavity that can be explored in future antimalarial development efforts.

One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)2 design (14-H-06) but not the CrossMAb design (14-crs-06) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.

To date, there have not been great breakthroughs in immunotherapy for HER2 positive breast cancer (HPBC). This study aimed to build a risk model that might contribute to predicting prognosis and discriminating the immune landscape in patients with HPBC. We analyzed the tumor immune profile of HPBC patients from the TCGA using the ESTIMATE algorithm. Thirty survival-related differentially expressed genes were selected according to the ImmuneScore and StromalScore. A prognostic risk model consisting of PTGDR, PNOC and CCL23 was established by LASSO analysis, and all patients were classified into the high- and low-risk score groups according to the risk scores. Subsequently, the risk model was proven to be efficient and reliable. Immune related pathways were the dominantly enriched category. ssGSEA showed stronger immune infiltration in the low-risk score group, including the infiltration of TILs, CD8 T cells, NK cells, DCs, and so on. Moreover, we found that the expression of immune checkpoint genes, including PD-L1, CTLA-4, TIGIT, TIM-3 and LAG-3, was significantly upregulated in the low-risk score group. All the results were validated with corresponding data from the GEO database. In summary, our investigation indicated that the risk model composed of PTGDR, PNOC and CCL23 has potential to predict prognosis and evaluate the tumor immune microenvironment in HPBC patients. More importantly, HPBC patients with a low-risk scores are likely to benefit from immune treatment.

Background: Exosomes are nanosized vesicles, play a vital role in breast cancer (BC) occurrence, development, invasion, metastasis, and drug resistance. Nevertheless, studies about exosome-related genes in breast cancer are limited. Besides, the interaction between the exosomes and tumor immune microenvironment (TIME) in BC are still unclear. Hence, we procced to study the potential prognostic value of exosome-related genes and their relationship to immune microenvironment in BC. Methods: 121 exosome-related genes were provided by ExoBCD database and 7 final genes were selected from the intersection of 33 differential expression genes (DEGs) and 19 prognostic genes in BC. Based on the expression levels of the 7 genes, downloaded from The Cancer Genome Atlas (TCGA) database, as well as the regression coefficients, the exosome-related signature was constructed. As a result, the patients in TCGA and GEO database were separated into low- and high- risk groups, respectively. Subsequently, R clusterProfiler package was applied to identify the distinct enrichment pathways between high-risk group and low-risk group. The ESTIMATE method was used to calculate ESTIMATE Score and CIBERSORT was applied to evaluate the immune cell infiltration. Eventually, the different expression levels of immune checkpoint related genes were analyzed between the two risk groups. Results: Results of BC prognosis vary from different risk groups. The low-risk groups were identified with higher survival rate both in TCGA and GEO cohort. The DEGs between high- and low- risk groups were found to enrich in immunity, biological processes, and inflammation pathways. The BC patients with higher ESTIMATE scores were revealed to have better overall survival (OS). Subsequently, CD8+ T cells, naive B cells, CD4+ resting memory T cells, monocytes, and neutrophils were upregulated, while M0 macrophages and M2 macrophages were downregulated in the low-risk group. At last, 4 genes reported as the targets of immune checkpoint inhibitors were further analyzed. The low-risk groups in TCGA and GEO cohorts were indicated with higher expression levels of LAG-3, CD274, TIGIT and CTLA-4. Conclusion: According to this study, exosomes are closely associated with the prognosis and immune cell infiltration of BC patients. These findings may make contributions to improve immunotherapy and bring a new sight for BC treatment strategies.

Three principal methods are under discussion as possible pathways to “true” de-extinction; i.e., back-breeding, cloning, and genetic engineering.1,2 Of these, while the latter approach is most likely to apply to the largest number of extinct species, its potential is constrained by the degree to which the extinct species genome can be reconstructed. We explore this question using the extinct Christmas Island rat (Rattus macleari) as a model, an endemic rat species that was driven extinct between 1898 and 1908.3–5 We first re-sequenced its genome to an average of >60× coverage, then mapped it to the reference genomes of different Rattus species. We then explored how evolutionary divergence from the extant reference genome affected the fraction of the Christmas Island rat genome that could be recovered. Our analyses show that even when the extremely high-quality Norway brown rat (R. norvegicus) is used as a reference, nearly 5% of the genome sequence is unrecoverable, with 1,661 genes recovered at lower than 90% completeness, and 26 completely absent. Furthermore, we find the distribution of regions affected is not random, but for example, if 90% completeness is used as the cutoff, genes related to immune response and olfaction are excessively affected. Ultimately, our approach demonstrates the importance of applying similar analyses to candidates for de-extinction through genome editing in order to provide critical baseline information about how representative the edited form would be of the extinct species.

One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce emergence of antibody resistance. Here we engineer two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv)2 design (14-H-06) but not the CrossMAb design (14-crs-06) shows increased antigen-binding and virus-neutralizing activities against multiple SARS-CoV-2 variants as well as increased breadth of neutralizing activity compared to the cocktail. X-ray crystallography and cryo-EM reveal distinct binding models for individual cocktail antibodies, and computational simulations suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and multiple variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth. Published version This work was supported in part by a Welch Foundation grant AU-0042- 20030616 and Cancer Prevention and Research Institute of Texas (CPRIT) Grants RP150551 and RP190561 (Z.A.); NIH grants HHSN272201600013C, AI134907, AI145617, and UL1TR001439, and awards from the Sealy Smith Foundation, Kleberg Foundation, John S. Dunn Foundation, Amon G. Carter Foundation, Gillson Longenbaugh Foundation, and Summerfield Robert Foundation (P-Y.S.); and AcRF Tier 1 RG105/20 (J.L.).

The susceptibility to trace metals and legacy POPs is different between terrestrial and marine mammals. In this study, we established the first cell line from Indo-Pacific finless porpoises and compared the cellular responses of skin fibroblast cells from Pygmy killer whales, Pantropic spotted dolphins, Indo-Pacific finless porpoises, mice, and humans following exposure to copper, methylmercury, cadmium, PCB126, PCB153, and BDE47 to better understand the interspecies sensitivities of mammals to chemical pollutants. We conducted a risk assessment by comparing no-observed effect concentrations (NOEC), lowest-observed effect concentrations (LOEC), and half maximal effective concentrations (EC50) from cell viability assays and previously reported pollutant body burdens in mammals. Based on the in vitro data, Indo-Pacific finless porpoises were more sensitive to copper and methylmercury than other mammals. PCB153 exposure reduced cell viability in all mammals except humans, while PCB126 was more potent, with 13.33 μg/mL exposure reducing cell viability in all mammals. In contrast, BDE47 exposure reduced cell viability only in terrestrial mammals in addition to pantropic spotted dolphin. Based on the in vitro data and the natural context of metal concentrations, both methylmercury and cadmium posed a higher risk to cetaceans than human, while copper posed a lower risk to cetaceans. All three legacy POPs (PCB126, PCB153, and BDE47) posed minor risk to cetaceans for short-term exposure. This study demonstrated that a species-specific in vitro model may provide more accurate information on the potential risk of pollutants to mammals. However, due to the bioamplification of POPs and their potential impact on the endocrine system and immune system of cetaceans, risk assessment with long-term exposure with more in vitro models should be further studied.

BackgroundAs a kind of small membrane vesicles, exosomes are secreted by most cell types from multivesicular endosomes, including tumor cells. The relationship between exosomes and immune response plays a vital role in the occurrence and development of tumors. Nevertheless, the interaction between exosomes and the microenvironment of tumors remains unclear. Therefore, we set out to study the influence of exosomes on the triple-negative breast cancer (TNBC) microenvironment.MethodOne hundred twenty-one exosome-related genes were downloaded from ExoBCD database, and IVL, CXCL13, and AP2S1 were final selected because of the association with TNBC prognosis. Based on the sum of the expression levels of these three genes, provided by The Cancer Genome Atlas (TCGA), and the regression coefficients, an exosome risk score model was established. With the median risk score value, the patients in the two databases were divided into high- and low-risk groups. R clusterProfiler package was employed to compare the different enrichment ways between the two groups. The ESTIMATE and CIBERSORT methods were employed to analyze ESTIMATE Score and immune cell infiltration. Finally, the correlation between the immune checkpoint-related gene expression levels and exosome-related risk was analyzed. The relationship between selected gene expression and drug sensitivity was also detected.ResultsDifferent risk groups exhibited distinct result of TNBC prognosis, with a higher survival rate in the low-risk group than in the high-risk group. The two groups were enriched by immune response and biological process pathways. A better overall survival (OS) was demonstrated in patients with high scores of immune and ESTIMATE rather than ones with low scores. Subsequently, we found that CD4+-activated memory T cells and M1 macrophages were both upregulated in the low-risk group, whereas M2 macrophages and activated mast cell were downregulated in the low-risk group in patients from the TCGA and GEO databases, respectively. Eventually, four genes previously proposed to be targets of immune checkpoint inhibitors were evaluated, resulting in the expression levels of CD274, CTLA4, LAG3, and TIM3 being higher in the low-risk group than high-risk group.ConclusionThe results of our study suggest that exosome-related risk model was related to the prognosis and ratio of immune cell infiltration in patients with TNBC. This discovery may make contributions to improve immunotherapy for TNBC.

Despite androgen dependence in a majority of castration-resistant prostate cancers, some cancer cells are independent of androgen receptor (AR) function, a feature of heterogeneity in prostate cancer. One of the aggressive variants of prostate cancer that are AR independent is neuroendocrine prostate cancer (NEPC). This manuscript will focus on the new finding of human one cut domain family member 2 (ONECUT2) transcription factor and its role in castration resistance, especially in NEPC.

BackgroundLymphangio vascular invasion (LVI) and perineural invasion (PNI) are associated with survival following resection for gastrointestinal cancer. But the relationship between LVI/PNI and survival of esophageal squamous cell carcinoma (ESCC) is still unclear. We aim to demonstrate the prognostic significance of LVI/PNI in ESCC.MethodsA total of 195 ESCC patients underwent curative surgery from 2012 to 2018 was collected in the 2nd Affiliated Hospital of Fujian Medical University. All the patients were divided into four groups based on the status of the neurovascular invasion: (1) neither LVI nor PNI (V0N0); (2) LVI alone (V1N0); (3) PNI alone (V0N1); (4) combined LVI and PNI (V1N1). First, the analysis included the Kaplan-Meier survival estimates with the Log rank test were performed to determine median overall survival (OS) in different groups divided according to the clinical factor, respectively. And the association between OS with multi clinical factors was examined using Cox regression analysis. Next, the risk factors for recurrence in patients with V1N1 were analyzed with univariate and multivariate logistic regression analyses, respectively.ResultsThe cases in V0N0, V1N0, V0N1, and V1N1 groups were 91 (46.7%), 62 (31.8%), 9 (4.6%) and 33 (16.9%), respectively. The OS in the four groups was different (P< 0.001). The 1-, 3- and 5-year OS in V0N0 group was higher than that in V1N1 group, respectively (1-year OS: 93.4%vs75.8%, 3-year OS: 53.8 %vs24.2%, 5-year OS: 48.1%vs10.5%). The OS in stage I-II for patients with V1N1 was significantly lower than that in the other groups (V0N0, V1N0, V0N1) (P< 0.001). The postoperative adjuvant chemotherapy was a significant impact factor of OS for ESCC patients with V1N1 (P= 0.004). Lymphatic invasion and LVI were significantly prognosis factors associated (P= 0.036,P= 0.030, respectively). The ulcerative type is a risk factor for V1N1 occurance (P= 0.040).ConclusionsThe LVI and PNI are important prognosis factors for ESCC patients. ESCC patients with simultaneous lymphangio vascular and perineural invasion (V1N1) showed worse OS than patients with either lymphangio vascular or perineural invasion alone (V1N0 or V0N1) or none (V0N0). In addition, adjuvant chemotherapy may prolong the OS for ESCC patients with V1N1.

More than one-third of the world's population is exposed to Plasmodium vivax malaria, mainly in Asia1. P. vivax preferentially invades reticulocytes (immature red blood cells)2-4. Previous work has identified 11 parasite proteins involved in reticulocyte invasion, including erythrocyte binding protein 2 (ref. 5) and the reticulocyte-binding proteins (PvRBPs)6-10. PvRBP2b binds to the transferrin receptor CD71 (ref. 11), which is selectively expressed on immature reticulocytes12. Here, we identified CD98 heavy chain (CD98), a heteromeric amino acid transporter from the SLC3 family (also known as SLCA2), as a reticulocyte-specific receptor for the PvRBP2a parasite ligand using mass spectrometry, flow cytometry, biochemical and parasite invasion assays. We characterized the expression level of CD98 at the surface of immature reticulocytes (CD71+) and identified an interaction between CD98 and PvRBP2a expressed at the merozoite surface. Our results identify CD98 as an additional host membrane protein, besides CD71, that is directly associated with P. vivax reticulocyte tropism. These findings highlight the potential of using PvRBP2a as a vaccine target against P. vivax malaria.

Purpose of Review Androgen deprivation therapy (ADT) is the standard of care for the treatment of advanced prostate cancer (PC). ADT, particularly with GnRH agonists, leads to increased risk of cardiovascular disease, including myocardial infarction, hypertension, and stroke. This review discusses the options of ADT, the mechanism of ADT-associated cardiovascular side effects, and potential benefit by using GnRH antagonists. Recent Findings GnRH antagonists have relatively less cardiovascular adverse effects compared to GnRH agonists. We highlight on a recently published phase III clinical trial on the oral GnRH antagonist, relugolix, and its comparative benefit to traditional GnRH agonist regarding development of cardiovascular disease. Summary Recent data reinforces that GnRH antagonists have a more favorable cardiovascular outcomes compared to GnRH agonists yet maintain a similar efficacy profile. From the data we reviewed, GnRH antagonists may be the preferred method of ADT for PC, but further data with primary cardiovascular outcomes are warranted.

Background The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and circulating tumor cells (CTCs) have been associated with survival in castration-resistant prostate cancer (CRPC). However, no study has examined the prognostic value of NLR and PLR in the context of CTCs. Methods Baseline CTCs from mCRPC patients were enumerated using the CellSearch System. Baseline NLR and PLR values were calculated using the data from routine complete blood counts. The associations of CTC, NLR, and PLR values, individually and jointly, with progression-free survival (PFS) and overall survival (OS), were evaluated using Kaplan-Meier analysis, as well as univariate and multivariate Cox models. Results CTCs were detected in 37 (58.7%) of 63 mCRPC patients, and among them, 16 (25.4%) had ≥5 CTCs. The presence of CTCs was significantly associated with a 4.02-fold increased risk for progression and a 3.72-fold increased risk of death during a median follow-up of 17.6 months. OS was shorter among patients with high levels of NLR or PLR than those with low levels (log-rank P = 0.023 and 0.077). Neither NLR nor PLR was individually associated with PFS. Among the 37 patients with detectable CTCs, those with a high NLR had significantly shorter OS (log-rank P = 0.024); however, among the 26 patients without CTCs, the OS difference between high- and low-NLR groups was not statistically significant. Compared to the patients with CTCs and low NLR, those with CTCs and high levels of NLR had a 3.79-fold risk of death (P = 0.036). This association remained significant after adjusting for covariates (P = 0.031). Combination analyses of CTC and PLR did not yield significant results. Conclusion Among patients with detectable CTCs, the use of NLR could further classify patients into different risk groups, suggesting a complementary role for NLR in CTC-based prognostic stratification in mCRPC. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08405-3.

Objectives There is no study published regarding the benefit of radiation therapy (RT) in combination with immune checkpoint inhibitors (ICIs) for the treatment of metastatic renal cell cancer (mRCC). This report is part of an exploratory study aiming to determine the immunomodulatory activity of RT alone or in combination with pembrolizumab in solid tumors. Materials and methods mRCC patients were treated with a combination of RT (8 Gy×1 or 4 Gy×5) followed by pembrolizumab with or without lead-in dose of pembrolizumab. Treatment response was measured based on the modified Response Evaluation Criteria in Solid Tumors criteria. Adverse events were monitored and graded. Pre-RT and post-RT tumor biopsies were obtained to evaluate programmed death-ligand 1 expression. Immune markers from peripheral blood before, during, and after treatment were analyzed using flow cytometry. Results Twelve mRCC patients who progressed on prior antiangiogenic therapy were enrolled. Half had 2 lines of prior therapy. Two patients (16.7%) had partial responses and were on study for 12.4 and 14.5 months. Three patients had stable disease for a period ranging from 4.2 to 10.4 months, whereas 7 patients had progressive disease. Median progression-free survival was 8.6 months and median overall survival was 32.3 months. Three patients had grade ≥3 events (hyperglycemia, thrombocytopenia, transaminitis). Biopsied tissue programmed death-ligand 1 expression and tumor-infiltrating lymphocytes were numerically higher in responders comparing to nonresponders (Modified Proportion Score 45% vs. 30.45%; tumor-infiltrating lymphocytes odds ratio 4.92). Conclusion Combining RT with pembrolizumab in pretreated mRCC is well-tolerated and appears to have comparable efficacy with single-agent nivolumab.

Pellino1 is an E3 ubiquitin ligase that plays a key role in positive regulation of innate immunity signaling, specifically required for the production of interferon when induced by viral double-stranded RNA. We report the identification of the tumor suppressor protein, p53, as a binding partner of Pellino1. Their interaction has a K𝘥 of 42 ± 2 μM and requires phosphorylation of Thr18 within p53 and association with the forkhead-associated (FHA) domain of Pellino1. We employed laser micro-irradiation and live cell microscopy to show that Pellino1 is recruited to newly occurring DNA damage sites, via its FHA domain. Mutation of a hitherto unidentified nuclear localization signal within the N-terminus of Pellino1 led to its exclusion from the nucleus. This study provides evidence that Pellino1 translocates to damaged DNA in the nucleus and has a functional role in p53 signaling and the DNA damage response. Agency for Science, Technology and Research (A*STAR) This research was supported by Academic Research Fund Tier 1 (Singapore) grant 2014-T1-001-274 (RG53/14) to PCFC and BMRC (Singapore) grant 0912219/599 to JL.