Search

Abstract The Indo-Pacific king mackerel, scientifically known as Scomberomorus guttatus, is a valued marine species that holds significant commercial importance in the Indo-Pacific region. However, the lack of genomic resources has hindered a comprehensive understanding of this species. In this study, we constructed a genome of Indo-Pacific king mackerel at the chromosome level using a combination of PacBio HiFi reads and a chromosome contact map (Hi-C). The resulting genome had high contig and scaffold N50 values of 8.84 Mb and 32.9 Mb, respectively. In the genome assembly, which is 797.66 Mb in size and consists of 24 chromosomes, we also identified 35.89% repetitive elements and predicted 25,886 protein-coding genes. Our study not only benefits to reveal the possible mechanism of adaptive evolution in this fish, but also offers insight for the future sustainable management of these valuable biological resources.

Abstract Cancer stem cells (CSCs) have the potential to self-renew and induce cancer, which may contribute to a poor prognosis by enabling metastasis, recurrence, and therapy resistance. Hence, this study was performed to identify the association between CSC-related genes and triple-negative breast cancer (TNBC) development. Stemness gene sets were downloaded from StemChecker. Based on the online databases, a consensus clustering algorithm was conducted for unsupervised classification of TNBC samples. The variations between subtypes were assessed with regard to prognosis, tumor immune microenvironment (TIME), and chemotherapeutic sensitivity. The stemness-related gene signature was established and random survival forest analysis was employed to identify the core gene for validation experiments and tumor sphere formation assays. 499 patients with TNBC were classified into three subgroups and the Cluster 1 had a better OS than others. After that, WGCNA study was performed to identify genes important for Cluster 1 subtype. Out of all 8 modules, the subtype of Cluster 1 and the yellow module with 103 genes demonstrated the largest positive association. After that, a four-gene stemness-related signature was established. Based on the yellow module, the 39 potential pivotal genes were subjected to the random forest survival analysis to find out the gene that was relatively important for OS. KIF15 was confirmed as the targeted gene by LASSO and random survival forest analyses. In vitro experiments, the downregulation of KIF15 promoted the stemness of TNBC cells. The expression levels of stem cell markers Nanog, SOX2, and OCT4 were found to be elevated in TNBC cell lines after KIF15 inhibition. A stemness-associated risk model was constructed to forecast the clinical outcomes of TNBC patients. The downregulation of KIF15 expression in a subpopulation of TNBC stem cells may promote stemness and possibly TNBC progression.

Abstract In the absence of an efficacious vaccine, chemotherapy remains crucial to prevent and treat malaria. Given its key role in haemoglobin degradation, falcilysin constitutes an attractive target. Here, we reveal the mechanism of enzymatic inhibition of falcilysin by MK-4815, an investigational new drug with potent antimalarial activity. Using X-ray crystallography, we determine two binary complexes of falcilysin in a closed state, bound with peptide substrates from the haemoglobin α and β chains respectively. An antiparallel β-sheet is formed between the substrate and enzyme, accounting for sequence-independent recognition at positions P2 and P1. In contrast, numerous contacts favor tyrosine and phenylalanine at the P1’ position of the substrate. Cryo-EM studies reveal a majority of unbound falcilysin molecules adopting an open conformation. Addition of MK-4815 shifts about two-thirds of falcilysin molecules to a closed state. These structures give atomic level pictures of the proteolytic cycle, in which falcilysin interconverts between a closed state conducive to proteolysis, and an open conformation amenable to substrate diffusion and products release. MK-4815 and quinolines bind to an allosteric pocket next to a hinge region of falcilysin and hinders this dynamic transition. These data should inform the design of potent inhibitors of falcilysin to combat malaria.

Abstract At present, tumor immunotherapy has been widely applied to treat various cancers. However, the accuracy of predicting treatment efficacy has not yet achieved a significant breakthrough. This study aimed to construct a prediction model based on the modified WGCNA algorithm to precisely judge the anti-tumor immune response. First, we used a murine colon cancer model to screen corresponding DEGs according to different groups. GSEA was used to analyze the potential mechanisms of the immune-related DEGs (irDEGs) in each group. Subsequently, the intersection of the irDEGs in every group was acquired, and 7 gene-modules were mapped. Finally, 4 gene-modules including cogenes, antiPD-1 immu-genes, chemo immu-genes and comb immu-genes, were selected for subsequent study. Furthermore, a clinical dataset of gastric cancer patients receiving immunotherapy was enrolled, and the irDEGs were identified. A total of 34 vital irDEGs were obtained from the intersections of the vital irDEGs and the four gene-modules. Next, the vital irDEGs were analyzed by the modified WGCNA algorithm, and the correlation coefficients between the 4 gene-modules and the response status to immunotherapy were calculated. Thus, a prediction model based on correlation coefficients was built, and the corresponding model scores were acquired. The AUC calculated according to the model score was 0.727, which was non-inferior to that of the ESTIMATE score and the TIDE score. Meanwhile, the AUC calculated according to the classification of the model scores was 0.705, which was non-inferior to that of the ESTIMATE classification and the TIDE classification. The prediction accuracy of the model was validated in clinical datasets of other cancers.

IntroductionCoastal marine ecosystems are among the most ecologically and socio-economically dynamic regions on Earth, and the study of eukaryotic planktonic communities is an important aspect of aquatic ecology. It is essential to monitor plankton biodiversity and identify influencing factors in order to measure human effects on coastal waters and help contribute to ecosystem preservation. Environmental DNA (eDNA) metabarcoding analysis is an advanced toolfor detecting the presence of aquatic organisms, which has revolutionary significance for biodiversity monitoring and real-time detection of wild environments.MethodsIn this study, eDNA metabarcoding was used to study seasonal changes in eukaryotic plankton communities in subtropical coastal waters of the northern South China Sea, to explore how various trophic groups affect the complexity and stability of the species network.ResultsThe results showed that the summer interaction network is looser and had has reduce biodiversitycompared to the spring interaction network. As an important part of the planktonic community, the abundance and diversity of algae reflect the interactions between different species and the influence of environmental factors on the dominant species, particularly temperature and nutrients. In addition, producer diversity set the basis for species network complexity and indirectly affected network stability, while consumer diversity and its flexible predation strategies may directly lead to differences in network stability across seasons. There were close correlations among species interaction, environmental factors and species diversity.DiscussionThis study can help us understand the ecosystem functions throughout the year and the complex interactions of planktonic communities from a multiple trophic level perspective, and provide effective methods for sustainable resource utilization and ecological environmental protection in the future.

Abstract Background Papillary thyroid carcinoma (PTC) is the most frequent malignant tumor in thyroid carcinoma. The aim of this study was to explore the risk factors associated with central lymph node metastasis in papillary thyroid microcarcinoma (PTMC) and establish a nomogram model that can assess the probability of central lymph node metastasis (CLNM). Methods The clinicopathological data of 377 patients with cN0 PTMC were collected and analyzed from The Second Affiliated Hospital of Fujian Medical University from July 1st, 2019 to December 30th, 2021. All patients were examined by underwent ultrasound (US), found without metastasis to central lymph nodes, and diagnosed with PTMC through pathologic examination. All patients received thyroid lobectomy or total thyroidectomy with therapeutic or prophylactic central lymph node dissection (CLND). R software (Version 4.1.0) was employed to conduct a series of statistical analyses and establish the nomogram. Results A total of 119 patients with PTMC had central lymph node metastases (31.56%). After that, age (P

Abstract The changing landscape of 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. The functional activity of neutralizing antibodies is linked to their quaternary changes occurring as a result of antibody-Spike trimer interactions. Here, we reveal the conformational dynamics and allosteric perturbations linked to binding of novel human antibodies and the viral Spike protein. We identified epitope hotspots, and associated changes in Spike dynamics that distinguish weak, moderate and strong neutralizing antibodies. We show the impact of mutations in Wuhan-Hu-1, Delta, and Omicron variants on differences in the antibody-induced conformational changes in Spike and illustrate how these render certain antibodies ineffective. Antibodies with similar binding affinities may induce destabilizing or stabilizing allosteric effects on Spike, with implications for neutralization efficacy. Our results provide mechanistic insights into the functional modes and synergistic behavior of human antibodies against COVID-19 and may assist in designing effective antiviral strategies.

Abstract 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. 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. 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. Circ_ZNF778_006 promoted ESCC progression by upregulating HIF-1α expression via sponging miR-18b-5p.

Abstract Exosomes, nanosized vesicles, play a vital role in breast cancer (BC) occurrence, development, and drug resistance. Hence, we proceeded to study the potential prognostic value of exosome-related genes and their relationship to the immune microenvironment in BC. 121 exosome-related genes were provided by the ExoBCD database, and 7 final genes were selected to construct the prognostic signature. Besides, the expression levels of the 7 exosome-related genes were validated by the experiment in BC cell lines. Based on the signature, BC patients from the training and validation cohorts were separated into low- and high-risk groups. Subsequently, the R clusterProfiler package was applied to identify the distinct enrichment pathways between high-risk groups and low-risk groups. The relevance of the tumor immune microenvironment and exosome-related gene risk score were analyzed in BC. Eventually, the different expression levels of immune checkpoint-related genes were compared between the two risk groups. Based on the risk model, the low-risk groups were identified with a higher survival rate both in the training and validation cohorts. A better overall survival was revealed in patients with higher scores evaluated by the estimation of stromal and immune cells in malignant tumor tissues using expression (ESTIMATE) algorithm. Subsequently, BC patients with lower risk scores were indicated by higher expression levels of some immune checkpoint-related genes and immune cell infiltration. Exosomes are closely associated with the prognosis and immune cell infiltration of BC. These findings may contribute to improving immunotherapy and provide a new vision for BC treatment strategies.

Reflux esophagitis (RE), an esophageal inflammation caused by reflux of gastric contents, often damages the lower esophagus, seriously affecting the quality of life of patients. This study aims to investigate the therapeutic effects and underlying molecular mechanisms of atractylenolide III (ATL III) on RE model rats. In this research, the RE rat model is established sequentially following hemipyloric ligation, cardia transection, and hydrochloric acid perfusion. Further, the RE-induced rats are intragastrically administrated with ATL III (0.6, 1.2, and 2.4 mg/kg/D) for 28 days to evaluate ATL III therapeutic effects. To study the molecular mechanism, RE rats are treated with a phosphoinositide-3 kinase (PI3K) agonist (740 Y–P) combined with ATL III. The histopathological changes in the esophagus are eventually observed by hematoxylin & eosin (H&E) staining. In addition to changes in gastric pH and levels of reactive oxygen species (ROS), enzyme-linked immunosorbent assay (ELISA) and Western blot analyses are used to detect the expression levels of tumor necrosis factor-α (TNF-α, mmol/L), interleukin (IL)-8, IL-6, IL-1β in the esophageal tissues. As a result, the lesions in the esophageal tissues of RE rats are alleviated, decreasing the macroscopic observation scores of the esophageal mucosa after ATL III treatment,. The experimental results indicated significantly increased pH value of the gastric contents and reduced ROS, thiobarbituric acid reactants (TBARS), TNF-α, IL-8, IL-6, and IL-1β levels, as well as expression levels of p-PI3K, p-AKT, iNOS, and nuclear NF-κB proteins in esophageal tissues. In conclusion, the study indicated that ATL III could efficiently treat RE in rats by inhibiting oxidative stress and inflammatory damage through the PI3K/AKT/NF-κB/iNOS pathway.

This study evaluates and compares the effects of five actual solid filling materials (SFMs) on the operation and mechanical characteristics of liquid sodium thermoclinic heat storage (THS) tank, including the quartzite, high-temperature concrete, copper foam, silicon carbide and alumina ceramics. By utilizing the computational fluid dynamics method, the charging, discharging and mechanical performances of the THS tank using different SFMs as well as with no SFM are compared. The results demonstrate that the introduction of SFM can enhance the charging and discharging performances of the THS tank. The high-temperature concrete can lead to the maximum average discharging power of 4.93×105 J/s and the second maximum total discharging quantity of 7.55×109 J, and the alumina ceramics could bring the maximum total discharging quantity of 8.59×109 J and the second maximum average discharging power of 4.77×105 J/s. The THS tank using high-temperature concrete has the largest discharging efficiency of 90.14% as well as the smallest peak maximum mechanical stress of the THS tank wall (42.4 MPa). The THS tank with no SFM has the smallest total charging quantity and lowest discharging efficiency, which are 4.62×109 J and 77.84%. In general, the THS tanks using alumina ceramics and high-temperature concrete both have better operation performances, and the high-temperature concrete can bring the best mechanical performance of the THS tank.

Abstract 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 some other small molecules. 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. 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, 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 and the immunophenoscore were further analyzed between different risk groups. Different risk groups exhibited different prognosis, with lower survival rate in the high-risk group. The differentially expressed genes 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. 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.

Bispecific antibodies can have advantages compared to antibody cocktails. Here, the authors engineer and characterize two different approaches for generating bispecific SARS-CoV-2 specific antibodies and find that only one design increases antigen-binding and virus neutralizing activities.

The safety of spike-based adenovirus type-5 vectored COVID-19 vaccine is evaluated, showing it neither affects the survival and function of human cardiac cells and engineered heart tissues nor aggravates heart damage in mice after ischemic injury.

IntroductionB vitamins play a crucial role in shaping phytoplankton and zooplankton communities in marine ecosystems, yet their impact on community dynamics remains poorly understood.MethodsWe carried out in situ incubation experiments of B vitamins supplementation to explore the response pattern of phytoplankton and zooplankton community compositions.ResultsThe results showed that vitamins B1, B2, B6 and B12 promoted the growth of phytoplankton, and the total Chl α in 87.5% of the supplemented B vitamin treatments showed a significant positive response (p < 0.05). Supplementation with these B vitamins significantly altered the community composition of phytoplankton, and 75% of the B vitamin-supplemented treatments showed an increase in the relative abundance of Minutocellus, Thalassiosirales, Odontella, Prymnesiales and Ditylum, considered mainly to be the result of B vitamin auxotrophy. In contrast, a significant decrease in Copepoda, including Calanoida and Cyclopoida, was observed in 87.5% of treatments. The observed shifts in community composition were attributed to the auxotrophy of certain diatoms and Prymnesiales for B vitamins. These shifts subsequently led to negative correlations (Spearman Rho < -0.8) between the abundance of these phytoplankton species and Copepoda populations.DiscussionThese findings advance our understanding of the complex interactions between micronutrient availability and plankton community dynamics.

This study aims to find a feasible photovoltaic/thermal (PV/T) utilization method based on film-based beam splitting technology. In contrast with previous studies, the main novelty of this paper is proposing the design of an innovative PV/T system using both parabolic trough concentrator (PTC) and film-based beam splitter (FBS). The design approach of the PV/T system is presented. A new FBS used for this PV/T system is designed by using the Needle method, and its average reflectivity and transmissivity are 27.2% and 72.8%. By using Ray Tracing and Computational Fluid Dynamics (CFD) simulation methods, the performance evaluation of the PV/T system is conducted. The evaluation results reveal that when the East-West sun tracking error is 0.2°, the optical efficiencies of the photovoltaic module and the solar thermal collector tube (TCT) can be kept at 95% and 93.9%. Moreover, when the heat transfer fluid (HTF) in the TCT is selected to be the ethylene glycol, the operation analysis results demonstrate that the photoelectric efficiency of the photovoltaic module is 25.4% and the thermal efficiency of the PV/T system is 17.24%. The thermal performance of the system can be improved when the HTF flow velocity is increased properly or when the inlet HTF temperature is decreased. The technical feasibility of the proposed PV/T system can be revealed from the analysis results of this study.

Abstract 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.

This paper presents an influence estimate of typical factors on heat release and mechanics performances of the latent thermal energy storage (LTES) tank with phase change material (PCM) by using the liquid-structure coupled calculation approach. Two heat transfer material temperatures are evaluated, including the cold molten salt temperature (MST) and hot MST. The results demonstrate that when the cold MST decreases from 610 K to 530 K, the HR duration will be reduced, the total heat release quantity (HRQ) increases, the average heat release power (HRP) increases from 3.22 MW to 7.98 MW, but the peak maximum mechanical stress (MMS) of the tank wall also rises. As the hot MST rises from 730 K to 810 K, the HRQ increases obviously, the average HRP increases from 5.09 MW to 6.63 MW, but the peak MMS also increases to 159.6 MPa. Hence, to improve the HR performance of the LTES system, under the condition of ensuring the structural safety of the LTES system, the hot MST should appropriately be increased, and the cold MST should be decreased properly.

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.

This study aims at proposing a public-private partnership project including the government (GOVT), coal-fired power plant (CTPP) and solar photovoltaic power plant (PVPP) toward carbon emission reduction and neutralization in China. The project is formed using the CO2 capture and utilization (CCU) and solar PV hydrogen production technologies. When all the participators cooperate, the influence of typical factors on the project is evaluated using the evolutionary game theory method. The results show that increasing the CCU subsidy can strengthen the participating intention of the CTPP but will reduce that of the GOVT. Improving the green electricity subsidy can strengthen the participating intention of the PVPP but will decrease that of the GOVT. To ensure the smooth running of the project, a relatively higher carbon emission penalty and a higher sales price of methanol should be ensured, the PVPP should control its daily working hours appropriately, and the proportion of electricity quantity of the PVPP used for hydrogen production should be increased. In this study, the suggested ranges of CCU and green electricity subsidy coefficients are 0.03–0.05 $/kWh and 0.0035–0.0045 $/kWh, the carbon emission penalty coefficient should be greater than 11 $/t, and the suggested range of daily working hours of the PVPP is 7–8 h.

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.

BackgroundCell metabolic reprogramming is a hallmark of tumor prognosis, and fatty acid metabolism (FAM) plays a crucial role in the tumor microenvironment (TME). However, the relationship between FAM, TME, and prognosis of acute myeloid leukemia (AML) patients remains elusive.MethodsWe extracted the single-cell RNA sequencing (scRNA-Seq) and bulk transcriptome data of AML patients from the TCGA and GEO databases and assessed the relationship between FAM, TME, and AML patient prognosis. We also performed functional enrichment (FE) assay to evaluate the significance of FAM in anti-AML immunosurveillance.ResultsOur scRNA-Seq analysis revealed that the leukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. Using these FAM-related genes, we developed a prognostic model that accurately estimated AML patient outcome. FE analysis showed that FAM was strongly related to alterations of TME-based immunosurveillance in AML patients. More importantly, we demonstrated that FAM inhibition via pharmaceutical targeting of PLA2G4A, a highly expressed FAM gene in AML patients with poor prognosis, enhanced the NK cell-mediated immunosurveillance in leukemia cells.ConclusionsLeukemic stem cell (LSC)-enriched population exhibited elevated levels of FAM-related genes. We have successfully established the FAM formula that predicts AML patient prognosis and alterations in the TME-based immunosurveillance. We also found that PLA2G4A was a highly expressed FAM gene in AML patients with poor prognoses. Pharmaceutical targeting of PLA2G4A increased the expression of NKG2DL in leukemia cells in vitro and thus enhanced the NK cell-mediated immunosurveillance.

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.

Abstract 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.

The current study conducts the performance estimate of a new photovoltaic thermal (PV/T) system using compact linear Fresnel reflector (CLFR) and Ag/CoSO4-PG nanofluids beam splitting device (BSD). Design method and working flow of the PV/T system are introduced. The absorption rate of the nanofluids BSD is 58.6% in the full spectral range. The optical behaviour evaluation results reveal a relatively high uniform sunlight irradiance distribution on the nanofluids BSD bottom and a single-peak shape sunlight irradiance distribution on the PV module. The optical efficiency of the PV/T system is 91.5% with a sun-tracking error of 0.2°. The operation behaviour of the PV/T system is analyzed by using the Computational Fluid Dynamics method. The analysis results indicate that the photoelectric efficiency of the PV module and thermal efficiency of the PV/T system are 30.2% and 49.3%. The thermal efficiency will increase when the inlet nanofluids flow velocity augments, or when the inlet nanofluids temperature decreases.

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.

This study presents the design and performance evaluation of a novel concentration photovoltaic/thermal (PV/thermal) system based on parabolic trough concentrator and indium tin oxide-ethylene glycol (ITOEG) nanofluid spectral filter. The overall design principle of the PV/thermal system is introduced, and the ITOEG nanofluid spectral filter is prepared and experimentally tested. For the full spectrum, the average transmittance and absorbance of the nanofluid spectral filter are 69.1% and 30.9%. The optical behaviour evaluation results reveal a double-peak radiation flux density distribution on the nanofluid channel bottom surface as well as on the solar cell module surface. When the north-south sun-tracking error increases to 0.2°, the optical efficiency of the PV/thermal system decreases to 93.7%. That means the system has a relatively good adaptability to the sun-tracking error. The thermodynamic analysis results reveal that the theoretical photoelectric conversion and solar thermal efficiencies of the PV/thermal system are 29.1% and 17.2%. The thermal efficiency of the PV/thermal system can be increased by increasing the nanofluid inlet flow velocity or by decreasing the nanofluid inlet temperature properly.

This study proposes a novel hybrid solar-gas power and hydrogen-production system, which is comprised by the solar tower thermal system, gas-steam turbine combined cycle and organic Rankine cycle-based hydrogen-production system. Based on the Ebsilon code, the operation processes of the hybrid system are simulated. The results show that the output power and electric efficiency of the hybrid system are 103.9 MW and 41.3%, and the daily hydrogen output is 62.2 kg. The operation simulation results of the hybrid system reveal that the gas-steam combined cycle and solar island can both achieve stable operations, and the power generation section and hydrogen-production device can both work effectively, which means the hybrid system is technically feasible. The exergy estimate results of the hybrid system show that the combustion chamber and solar receiver have the two largest exergy destructions, which are 56.5 MW and 45.3 MW. That means the performances of the two components can be further improved. For the hydrogen-production system, the exergy destructions of the proton exchange membrane electrolyzer, turbine, condenser and evaporator of the organic Rankine cycle are 0.156 MW, 0.111 MW, 2.338 MW and 1.891 MW, and the corresponding exergy efficiencies are 51.2%, 92.6%, 80.7% and 79.5%, respectively.

Background Lymphangio 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. Methods A 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. Results The 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% vs 75.8%, 3-year OS: 53.8 % vs 24.2%, 5-year OS: 48.1% vs 10.5%). 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). Conclusions The 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.

BackgroundThyroid carcinoma (TC) is the most common malignant endocrine tumor worldwide. Several studies have documented that male patients with TC have a higher rate of metastasis and disease recurrence than female patients. However, the mechanism underlying this observation is not completely clear. The goal of our research was to investigate the potential key candidate genes and pathways related to TC progression in male patients at the molecular level.MethodsA total of 320 samples were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Hub genes were screened out using weighted gene coexpression network analysis (WGCNA) and a protein–protein interaction (PPI) network analysis. Survival analysis was used to identify hub genes associated with disease-free survival (DFS) rates. Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression (ESTIMATE) data were used to assess the relationship between hub genes and immune cell infiltration. The molecular mechanism and biological functions of hub genes were explored using RT-qPCR, Western blot, Cell Counting Kit-8 Assay, flow cytometry, Transwell assays, and scratch assays.ResultsForty-seven hub genes were identified, and the survival analysis demonstrated that anti-silencing function 1B (ASF1B) was the sole independent risk factor for poor DFS in male TC patients. Possible associations between the results from the ESTIMATE analysis showed that the ASF1B expression level was related to the ESTIMATE score, immune score, and T-cell regulatory (Treg) infiltration level. Through in vitro cell function experiments, we verified that knockdown of ASF1B inhibited KTC-1 cell proliferation, promoted cell apoptosis, and blocked cell cycle. The silencing of ASF1B reduced protein kinase B (AKT), phospho-AKT (p-AKT), and forkhead box p3 (FOXP3) in KTC-1 cells. Moreover, FOXP3 overexpression markedly restored the cell migration, invasion, and proliferation abilities repressed by ASF1B knockdown.ConclusionsOur results indicate that ASF1B can be considered a prognostic marker, therapeutic target, and predictor of immunotherapy response in male thyroid cancer patients. However, further in-depth studies are required to validate this finding.

The current study proposes a novel solar PV and thermal (PVT) system based on the combination of linear Fresnel reflector (LFR) concentrator and ITO-EG nano-fluids optical filter. Preparation and relevant measurements of the ITO nano-particles as well as the ITO-EG nano-fluids are conducted. The test results reveal that the optical filter has an average absorptivity of 30.9% in the spectrum range of 250.0–2500.0 nm. The solar concentration behaviour of the PVT system is revealed and the sensitivity analysis results of sun tracking error indicate that when the north-south tracking error is 0.2°, the overall optical efficiency is 90.12%, which means the PVT system has a relatively good adaptive faculty on sun tracking error. Theoretical thermodynamic calculation and CFD simulation methods are utilized to estimate the operation behaviour of the PVT system. The results demonstrate that the PVT system has a photoelectric conversion efficiency of 29.6% as well as a thermal efficiency of 18.52%. Parametric analysis results show that the thermal efficiency of the PVT system can be improved by increasing the inlet nano-fluids flow velocity as well as the ambient temperature, or by reducing the inlet nano-fluids temperature or convection heat transfer coefficient.

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.

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 (Neophocaena phocaenoides). Microbial richness increased from the foregut to the hindgut with variation in the composition of microbes. Fusobacteria (67.51% ± 5.10%), Firmicutes (22.00% ± 2.60%), and Proteobacteria (10.47% ± 5.49%) were the dominant phyla in the gastrointestinal tract, while Proteobacteria (76.11% ± 0.54%), Firmicutes (22.00% ± 2.60%), and Bacteroidetes (10.13% ± 0.49%) were the dominant phyla in the skin wounds. The genera Photobacterium, Actinobacillus, Vibrio, Erysipelothrix, Tenacibaculum, and Psychrobacter, considered potential pathogens for mammals, were identified in the gut and skin wounds of the stranded Indo-Pacific finless porpoise. A comparison of the gut microbiome in the Indo-Pacific finless porpoise and other cetaceans revealed a possible species-specific gut microbiome in the Indo-Pacific finless porpoise. There was a significant difference between the skin wound microbiomes in terrestrial and marine mammals, probably due to habitat-specific differences. Our results show potential species specificity in the microbiome structure and a potential threat posed by environmental pathogens to cetaceans.

Hypoxia-inducible factor (HIF), an important mediator of hypoxia response, is implicated in tumorigenesis in the setting of pseudohypoxia, such as in the inactivation of von Hippel–Lindau tumor suppressor protein (pVHL), leading to development and progression of clear cell renal cell carcinoma (ccRCC). Targeting downstream molecules in HIF pathway, such as vascular endothelial growth factor (VEGF), has led to improvement in clinical outcome for patients with advanced ccRCC, but such therapy thus far has been limited by eventual resistance and treat-ment failure. Following the discovery of HIF-2 alpha playing a key role in ccRCC carcinogenesis, inhibitors targeting HIF-2 alpha have been developed and have demonstrated encouraging efficacy and safety profile in clinical trials. This review discusses HIF-2 alpha as a promising therapeutic target for ccRCC.

Breast cancer (BC) is the most common malignancy in female, but the role of androgen receptor (AR) in triple-negative breast cancer (TNBC) is still unclear. This study aimed to exam the performance of innovative biomarkers for AR positive TNBC in diagnosis and therapies. Four datasets (GSE42568, GSE45827, GSE54002 and GSE76124) were analyzed by bioinformatic methods and the differential expression genes (DEGs) between the AR positive TNBC tissues and normal tissues were firstly identified by limma package and Venn diagrams. Next, Gene Ontologies (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to explore the relationship between these DEGs. Then, the Protein-protein interaction (PPI) network was constructed. CytoHubba and bioinformatic approaches including Molecular Complex Detection (MCODE), Gene Expression Profiling Interactive Analysis (GEPIA), the Kaplan–Meier (KM) plotter and The Human Pro-tein Atlas (THPA) were used to identify the hub genes. Lastly, a miRNA-hub-gene regulatory axis was constructed by use of Target Scan database and ENCORI database. As a result, a total of 390 common DEGs were identified, including 250 up-regulated and 140 down-regulated. GO and KEGG enrichment analysis showed that the up-regulated DEGs were mostly enriched in the cell division, mitotic nuclear division, nucleosome, midbody, protein heterodimerization activity, cadherin binding involved in cell−cell adhesion, systemic lupus erythematosus and alcoholism, while the down-regulated DEGs were mainly enriched in carbohydrate metabolic process, extracellular space, extracellular region, zinc ion binding and microRNAs in cancer. Then, 13 hub genes (CCNB2, FOXM1, HMMR, MAD2L1, RRM2, TPX2, TYMS, CEP55, AURKA, CCNB1, CDK1, TOP2A, PBK) were selected. The survival analysis revealed that only CCNB1 was associated with significantly poor survival (P

The critical role of bacterial biofilms in chronic human infections calls for novel anti-biofilm strategies targeting the regulation of biofilm development. However, the regulation of biofilm development is very complex and can include multiple, highly interconnected signal transduction/response pathways, which are incompletely understood. We demonstrated previously that in the opportunistic, human pathogen P. aeruginosa, the PP2C-like protein phosphatase SiaA and the di-guanylate cyclase SiaD control the formation of macroscopic cellular aggregates, a type of suspended biofilms, in response to surfactant stress. In this study, we demonstrate that the SiaABC proteins represent a signal response pathway that functions through a partner switch mechanism to control biofilm formation. We also demonstrate that SiaABCD functionality is dependent on carbon substrate availability for a variety of substrates, and that upon carbon starvation, SiaB mutants show impaired dispersal, in particular with the primary fermentation product ethanol. This suggests that carbon availability is at least one of the key environmental cues integrated by the SiaABCD system. Further, our biochemical, physiological and crystallographic data reveals that the phosphatase SiaA and its kinase counterpart SiaB balance the phosphorylation status of their target protein SiaC at threonine 68 (T68). Crystallographic analysis of the SiaA-PP2C domain shows that SiaA is present as a dimer. Dynamic modelling of SiaA with SiaC suggested that SiaA interacts strongly with phosphorylated SiaC and dissociates rapidly upon dephosphorylation of SiaC. Further, we show that the known phosphatase inhibitor fumonisin inhibits SiaA mediated phosphatase activity in vitro. In conclusion, the present work improves our understanding of how P. aeuruginosa integrates specific environmental conditions, such as carbon availability and surfactant stress, to regulate cellular aggregation and biofilm formation. With the biochemical and structural characterization of SiaA, initial data on the catalytic inhibition of SiaA, and the interaction between SiaA and SiaC, our study identifies promising targets for the development of biofilm-interference drugs to combat infections of this aggressive opportunistic pathogen.

Abstract Malaria causes every year over half-a-million deaths. The emergence of parasites resistant to available treatments makes the identification of new targets and their inhibitors an urgent task for the development of novel anti-malaria drugs. Protein kinase CK2 is an evolutionary-conserved eukaryotic serine/threonine protein kinase that in Plasmodium falciparum (PfCK2) has been characterized as a promising target for chemotherapeutic intervention against malaria. Here we report a crystallographic structure of the catalytic domain of PfCK2α (D179S inactive single mutant) in complex with ATP at a resolution of 3.0 Å. Compared to the human enzyme, the structure reveals a subtly altered ATP binding pocket comprising five substitutions in the vicinity of the adenine base, that together with potential allosteric sites, could be exploited to design novel inhibitors specifically targeting the Plasmodium enzyme. We provide evidence for the dual autophosphorylation of residues Thr63 and Tyr30 of PfCK2. We also show that CX4945, a human CK2 inhibitor in clinical trials against solid tumor cancers, is effective against PfCK2 with an IC50 of 13.2 nM.

Management of men with prostate cancer is fraught with uncertainty as physicians and patients balance efficacy with potential toxicity and diminished quality of life. Utilization of genomics as a prognostic biomarker has improved the informed decision-making process by enabling more rationale treatment choices. Recently investigations have begun to determine whether genomic information from tumor transcriptome data can be used to impact clinical decision-making beyond prognosis. Here we discuss the potential of genomics to alter management of a patient who presented with high-risk prostate adenocarcinoma. We suggest that this information help selecting patients for advanced imaging, chemotherapies, or clinical trial.

Abstract Background Pembrolizumab is a monoclonal antibody that is designed against programmed cell death protein 1 (PD-1). Pembrolizumab and other immunocheckpoint-blocking monoclonal antibodies work by modulating a patient’s own immune system to increase anti-tumor activity. While immunocheckpoint blockade has shown promising results, only 20–40 % of patients experience objective clinical benefit. Differences in individual tumor biology and the presence multiple immune checkpoints present a challenge for treatment. Because radiotherapy has immunomodulatory effects on the tumor microenvironment, it has the potential to synergize with immunotherapy and augment tumor response. NCT02318771 is a phase 1 clinical trial designed to investigate the immunomodulatory effects of radiation therapy in combination with pembrolizumab. Case presentation The patient is a 64-year-old male with metastatic clear cell renal cell carcinoma, Fuhrman grade 4, pathologically staged as T3 N0. Metastatic disease was well controlled for several years with sunitinib. Following disease progression, he was switched to axitinib. When disease progression continued, the patient was enrolled in NCT02318771, a phase 1 clinical trial combining radiotherapy and pembrolizumab. The patient experienced unusually rapid disease progression during treatment, which was confirmed by repeated CT scans to rule out pseudoprogression. Tissue biopsies and peripheral blood draws were obtained before, during, and after treatment. Samples were analyzed to provide plausible rationale for rapid treatment failure. Conclusions Biomarker analysis demonstrated an absence of TILs, which may be a cause of treatment failure as pembrolizumab works through T cell-dependent mechanisms. Furthermore, the presence of other non-redundant immune checkpoints in the periphery and tumor microenvironment presents a treatment challenge. Additionally, the radiation dose and fractionation schedule may have played a role in treatment failure as these factors play a role in the effect radiotherapy on the tumor microenvironment as well as the potential for synergy with immunotherapy. Trial registration An Exploratory Study to Investigate the Immunomodulatory Activity of Radiation Therapy (RT) in Combination With MK-3475 in Patients With Recurrent/Metastatic Head and Neck, Renal Cell Cancer, Melanoma and Lung Cancer, NCT02318771 .

Background. Denosumab has become the preferred agent over zolendronic acid to help prevent skeletal-related events in patients with metastatic bone disease and multiple myeloma because it is approved for use in those with kidney dysfunction. However, denosumab has been linked to cases of hypocalcemia, particularly in those with advanced kidney disease. Case Presentation. We present the case of a patient with metastatic prostate cancer and chronic kidney disease due to obstructive nephropathy who developed severe hypocalcemia and hypomagnesemia after denosumab injection, which required intensive care unit admission, aggressive calcium supplementation, and hemodialysis assistance. We reviewed the evidence behind the safety profile of denosumab in chronic kidney disease, and we also looked at additional factors that may precipitate severe hypocalcemia with denosumab in advanced kidney disease. Conclusion. We believe that denosumab should be avoided in advanced chronic kidney disease due to the potential life-threatening, severe hypocalcemia that has been observed.

Histone deacetylase inhibitors (HDACis) re-express silenced tumor suppressor genes and are currently undergoing clinical trials. Although HDACis have been known to induce gene expression, an equal number of genes are downregulated upon HDAC inhibition. The mechanism behind this downregulation remains unclear. Here we provide evidence that several DNA repair genes are downregulated by HDAC inhibition and provide a mechanism involving the E2F1 transcription factor in the process.Applying Analysis of Functional Annotation (AFA) on microarray data of prostate cancer cells treated with HDACis, we found a number of genes of the DNA damage response and repair pathways are downregulated by HDACis. AFA revealed enrichment of homologous recombination (HR) DNA repair genes of the BRCA1 pathway, as well as genes regulated by the E2F1 transcription factor. Prostate cancer cells demonstrated a decreased DNA repair capacity and an increased sensitization to chemical- and radio-DNA damaging agents upon HDAC inhibition. Recruitment of key HR repair proteins to the site of DNA damage, as well as HR repair capacity was compromised upon HDACi treatment. Based on our AFA data, we hypothesized that the E2F transcription factors may play a role in the downregulation of key repair genes upon HDAC inhibition in prostate cancer cells. ChIP analysis and luciferase assays reveal that the downregulation of key repair genes is mediated through decreased recruitment of the E2F1 transcription factor and not through active repression by repressive E2Fs.Our study indicates that several genes in the DNA repair pathway are affected upon HDAC inhibition. Downregulation of the repair genes is on account of a decrease in amount and promoter recruitment of the E2F1 transcription factor. Since HDAC inhibition affects several pathways that could potentially have an impact on DNA repair, compromised DNA repair upon HDAC inhibition could also be attributed to several other pathways besides the ones investigated in this study. However, our study does provide insights into the mechanism that governs downregulation of HR DNA repair genes upon HDAC inhibition, which can lead to rationale usage of HDACis in the clinics.