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The impact of efferocytosis-related genes (ERGs) on the diagnosis of colorectal cancer (CRC) remains unclear. In this study, efferocytosis-associated biomarkers for the diagnosis of CRC were identified by integrating data from transcriptome sequencing and public databases. Finally, the expression of biomarkers was validated by real-time quantitative polymerase chain reaction (RT-qPCR). Our study may provide a reference for CRC diagnosis. BACKGROUND: It has been shown that some efferocytosis related genes (ERGs) are associated with the development of cancer. However, it is still uncertain how ERGs may influence the diagnosis of colorectal cancer (CRC). METHODS: In our study, the CRC cohorts were gained from transcriptome sequencing and the gene expression omnibus (GEO) database (GSE71187). Efferocytosis related biomarkers with diagnostic utility for CRC were identified through combining differentially expressed analysis, machine learning algorithms, and receiver operating characteristic (ROC) analysis. Then, infiltration abundance of immune cells between CRC and control was evaluated. The regulatory networks (including mRNA-miRNA-lncRNA and miRNA/transcription factors (TF)-mRNA networks) were created. Finally, the expression of biomarkers was validated via real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: There were 3 biomarkers (ELMO3, P2RY12, and PDK4) related diagnosis for CRC patients gained. ELMO3 was highly expressed in CRC group, while P2RY12 and PDK4 was lowly expressed. Besides, the infiltrating abundance of 3 immune cells between CRC and control groups was significantly differential, namely activated CD4 memory T cells, macrophages M0, and resting mast cells. We then constructed a mRNA-miRNA-lncRNA network containing 3 mRNAs, 33 miRNAs, and 22 lncRNAs, and a miRNA/TF-mRNA network including 3 mRNAs, 33 miRNAs, and 7 TFs. Additionally, RT-qPCR results revealed that the expression trends of all biomarkers were consistent with the transcriptome sequencing data and GSE71187. CONCLUSION: Taken together, this study provides three efferocytosis related biomarkers (ELMO3, P2RY12, and PDK4) for diagnosis of CRC, providing a scientific reference for further studies of CRC.
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Biomarcadores Tumorais , Neoplasias Colorretais , Eferocitose , Humanos , Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Eferocitose/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , MicroRNAs/genética , TranscriptomaRESUMO
Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.
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Apoptose , Neoplasias , Transdução de Sinais , Proteína Supressora de Tumor p53 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismo , Neoplasias/genética , Apoptose/efeitos dos fármacos , Proteína Supressora de Tumor p53/metabolismo , Proteína Supressora de Tumor p53/genética , Transdução de Sinais/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genéticaRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. We examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells. We further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike were found to have increased cell viability as compared to control cells. Further observations on γ-H2AX expression in spike-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics. More efforts should be directed at studying the effects of the SARS-CoV-2 spike and other viral proteins on host DNA damage sensing, response and repair mechanisms. A goal would be to understand the structural basis for maximal anti-viral immunity while minimizing suppression of host defenses including the p53 DNA damage response and tumor suppression pathway. Such directions are relevant and important including not only in the context of viral infection and mRNA vaccines in general but also for patients with cancer who may be receiving cytotoxic or other cancer treatments.
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Sobrevivência Celular , Inibidor de Quinase Dependente de Ciclina p21 , Proteínas Proto-Oncogênicas c-mdm2 , Receptores do Ligante Indutor de Apoptose Relacionado a TNF , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Proteína Supressora de Tumor p53 , Humanos , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Sobrevivência Celular/efeitos dos fármacos , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/genética , SARS-CoV-2/fisiologia , Linhagem Celular Tumoral , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Antineoplásicos/farmacologia , Transfecção , COVID-19/virologia , COVID-19/metabolismoRESUMO
Electrochromic materials and devices with the capability of dynamic optical regulation have attracted considerable attention recently and have shown a variety of potential applications including energy-efficient smart windows, multicolor displays, atuto-diming mirrors, military camouflage, and adaptive thermal management due to the advantages of active control, wide wavelength modulation, and low energy consumption. However, its development still experiences a number of issues such as long response time and inadequate durability. Nanostructuring has demonstrated that it is an effective strategy to improve the electrochromic performance of the materials due to the increased reaction active sites and the reduced ion diffusion distance. Various advanced inorganic nanomaterials with high electrochromic performance have been developed recently, significantly contributing to the development of electrochromic applications. In this review, we systematically introduce and discuss the recent advances in advanced inorganic nanomaterials including zero-, one-, and two-dimensional materials for high-performance electrochromic applications. Finally, we outline the current major challenges and our perspectives for the future development of nanostructured electrochromic materials and applications.
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Rechargeable zinc-air batteries (ZABs) have been considered promising as next-generation sustainable energy storage devices; however, their large-scale deployment is hampered by the unsatisfactory cyclic lifespan. Employing neutral and mild-acidic electrolytes is effective in extending the cyclability, but the rapid performance degradation of the bifunctional catalysts owing to different microenvironmental requirements of the alternative oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is still a serious limitation of their cyclic life. Herein, we propose a "self-decoupling" strategy to significantly improve the stability of the bifunctional catalysts by constructing a smart interface in the bifunctional air electrode. This smart interface, containing a resistance-switchable sulfonic acid doped polyaniline nanoarray interlayer, is nonconductive at high potential but conductive at low potential, which enables spontaneous electrochemical decoupling of the bifunctional catalyst for the ORR and OER, respectively, and thus protects it from degradation. The resulting self-decoupled mild-acidic ZAB delivers stable cyclic performances in terms of a negligible energy efficiency loss of 0.015% cycle-1 and 3 times longer cycle life (â¼1400 h) compared with the conventional mild-acidic ZAB using a normal bifunctional air electrode and the same low-cost ZnCo phosphide/nitrogen-doped carbon bifunctional catalyst. This work provides an effective strategy for tolerating alternative oxidation-reduction reactions and emphasizes the importance of smart nanostructure design for more sustainable batteries.
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p53 is a transcription factor that regulates the expression of genes involved in tumor suppression. p53 mutations mediate tumorigenesis and occur in approximately 50% of human cancers. p53 regulates hundreds of target genes that induce various cell fates including apoptosis, cell cycle arrest, and DNA damage repair. p53 also plays an important role in anti-tumor immunity by regulating TRAIL, DR5, TLRs, Fas, PKR, ULBP1/2, and CCL2; T-cell inhibitory ligand PD-L1; pro-inflammatory cytokines; immune cell activation state; and antigen presentation. Genetic alteration of p53 can contribute to immune evasion by influencing immune cell recruitment to the tumor, cytokine secretion in the TME, and inflammatory signaling pathways. In some contexts, p53 mutations increase neoantigen load which improves response to immune checkpoint inhibition. Therapeutic restoration of mutated p53 can restore anti-cancer immune cell infiltration and ameliorate pro-tumor signaling to induce tumor regression. Indeed, there is clinical evidence to suggest that restoring p53 can induce an anti-cancer immune response in immunologically cold tumors. Clinical trials investigating the combination of p53-restoring compounds or p53-based vaccines with immunotherapy have demonstrated anti-tumor immune activation and tumor regression with heterogeneity across cancer type. In this Review, we discuss the impact of wild-type and mutant p53 on the anti-tumor immune response, outline clinical progress as far as activating p53 to induce an immune response across a variety of cancer types, and highlight open questions limiting effective clinical translation.
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Tissue-like cultured meats of some livestock have successfully been established by different approaches. However, the production of a structure similar to fish fillets is still challenging. Here, we develop tissue-like cultured fish fillets by assembly of large yellow croaker muscle fibers and adipocytes with 3D-printed gel. Inhibition of Tgf-ß and Notch signals significantly promoted myogenic differentiation of piscine satellite cells (PSCs). The mixture of fish gelatin and sodium alginate combined with a p53 inhibitor and a Yap activator supported PSC viability and proliferation. Based on the texture of fish muscle tissue, a 3D scaffold was constructed by gelatin-based gel mixed with PSCs. After proliferation and differentiation, the muscle scaffold was filled with cultured piscine adipocytes. Finally, tissue-like fish fillets with 20 × 12 × 4 mm were formed, consisting of 5.67 × 107 muscles and 4.02 × 107 adipocytes. The biomanufacture of tissue-like cultured fish fillet here could be a promising technology to customize meat production with high fidelity.
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Neutral/near-neutral electrolyte rechargeable zinc-air batteries (NN-ZABs) with long cycling lifetime are an evolutionary design of the conventional alkaline ZABs, but the extremely sluggish kinetics of oxygen electrocatalysis in mild pH solutions in the air-cathode has notably affected the energy efficiency of the NN-ZABs. Herein, we present a dynamic self-catalysis as the air-cathode chemistry to boost the energy efficiency of NN-ZABs, which is based on in situ reversible generation of highly active electrocatalysts from the electrolyte during the discharge and charge operations of ZABs, respectively. Two reversible redox reactions of Cu(I)/Cu(II) and Mn(II)/Mn(IV) in the NH4Cl-ZnCl2-based electrolyte are integrated with oxygen electrocatalysis in the air-cathode to in situ generate Cu(I)-O-Cl deposits during discharging and Cu-MnO2 deposits during charging, which directly catalyze the subsequent oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), respectively. The in situ generated electrocatalysts deliver good oxygen electrocatalytic activities due to their distinctive surface structures and can be dissolved by potential reversal in a subsequent battery operation. The NN-ZAB designed as such delivers a record-high energy efficiency of 69.0% and a cycling life of 1800 h with an areal capacity of 10 mA h cm-2, surpassing the performances of NN-ZABs with preloaded electrocatalysts reported to date.
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Background: Hepatocellular carcinoma (HCC) is the most common form of liver cancer. Circular RNAs (circRNAs) play a vital role in cancer development and progression. This study investigated the role and potential mechanism of circRNA filamin binding LIM protein 1 (circFBLIM1) in HCC. Methods: Exosomes were identified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blot assay. The levels of circFBLIM1, miR-338, and low-density lipoprotein receptor-related protein 6 (LRP6) were measured by quantitative real-time polymerase chain reaction or Western blot. Glycolysis was analyzed by detecting glucose consumption, lactate production, ATP level, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR). Cell viability was evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell apoptosis was detected by flow cytometry. Xenograft assay was performed to analyze tumor growth in vivo. The interaction among circFBLIM1, miR-338, and LRP6 was confirmed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. This study was approved by the Institutional Review Board of the First Affiliated Hospital of Guizhou University of Traditional Chinese Medicine. Results: CircFBLIM1 was highly expressed in HCC serum exosomes and HCC cells. Inhibition of circFBLIM1 confined HCC glycolysis and progression. CircFBLIM1 knockdown blocked tumorigenesis in vivo. CircFBLIM1 was a sponge of miR-338 and promoted HCC progression and glycolysis by regulating miR-338. Moreover, miR-338 suppressed HCC progression and glycolysis via targeting LRP6. Mechanistically, circFBLIM1 functioned as an miR-338 sponge to upregulate LRP6. Conclusion: CircFBLIM1 facilitated HCC progression and glycolysis via modulating the miR-338/LRP6 axis, which may provide promising therapeutic targets for HCC.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , MicroRNAs , Humanos , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Apoptose , MicroRNAs/genética , Proliferação de Células , Linhagem Celular Tumoral , GlicóliseRESUMO
Although the 50% inhibitory concentration (IC50) is a commonly used measurement of chemosensitivity in cancer cells, it has been known to vary with the density of the treated cells (in that more densely seeded cells are more resistant to chemotherapeutic agents). Indeed, density-dependent chemoresistance may be a significant independent mechanism of therapy resistance. We examine the nature of cell density-dependent chemoresistance and explore possible underlying mechanisms. CellTiter-Glo assays and ethidium homodimer staining revealed that response to chemotherapy is density-dependent in all cancer cell lines tested. Our results prompted us to develop a novel cancer cell seeding density index of chemosensitivity, the ISDS (IC50-Seeding Density Slope), which we propose can serve as an improved method of analyzing how cancer cells respond to chemotherapeutic treatment compared to the widely-used IC50. Furthermore, western blot analysis suggests that levels of autophagy and apoptotic markers are modulated by cancer cell density. Cell viability experiments using the autophagy inhibitor chloroquine showed that chloroquine's efficacy was reduced at higher cell densities and that chloroquine and cisplatin exhibited synergy at both higher and lower cell densities in TOV-21G cells. We discuss alternative mechanisms of density-dependent chemoresistance and in vivo/clinical applications, including challenges of adjuvant chemotherapy and minimal residual disease. Taken together, our findings show that cell density is a significant contributor in shaping cancer chemosensitivity, that the ISDS (aka the Ujwal Punyamurtula/Wafik El-Deiry or Ujwal-WAF Index) can be used to effectively assess cell viability and that this phenomenon of density-dependent chemoresistance may be leveraged for a variety of biologic and cancer therapeutic applications.
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TP53 is a tumor suppressor gene that encodes a sequence-specific DNA-binding transcription factor activated by stressful stimuli; it upregulates target genes involved in growth suppression, cell death, DNA repair, metabolism, among others. TP53 is the most frequently mutated gene in tumors, with mutations not only leading to loss-of-function (LOF), but also gain-of-function (GOF) that promotes tumor progression, and metastasis. The tumor-specific status of mutant p53 protein has suggested it is a promising target for cancer therapy. We summarize the current progress of targeting wild-type and mutant p53 for cancer therapy through biotherapeutic and biopharmaceutical methods for (1) boosting p53 activity in cancer, (2) p53-dependent and p53-independent strategies for targeting p53 pathway functional restoration in p53-mutated cancer, (3) targeting p53 in immunotherapy, and (4) combination therapies targeting p53, p53 checkpoints, or mutant p53 for cancer therapy.
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Neoplasias , Proteína Supressora de Tumor p53 , Morte Celular , Humanos , Proteínas Mutantes/metabolismo , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Bacterial biofilms formed by pathogens are known to be hundreds of times more resistant to antimicrobial agents than planktonic cells, making it extremely difficult to cure biofilm-based infections despite the use of antibiotics, which poses a serious threat to human health. Therefore, there is an urgent need to develop promising alternative antimicrobial therapies to reduce the burden of drug-resistant bacterial infections caused by biofilms. As natural enemies of bacteria, bacteriophages (phages) have the advantages of high specificity, safety and non-toxicity, and possess great potential in the defense and removal of pathogenic bacterial biofilms, which are considered to be alternatives to treat bacterial diseases. This work mainly reviews the composition, structure and formation process of bacterial biofilms, briefly discusses the interaction between phages and biofilms, and summarizes several strategies based on phages and their derivatives against biofilms and drug-resistant bacterial infections caused by biofilms, serving the purpose of developing novel, safe and effective treatment methods against biofilm-based infections and promoting the application of phages in maintaining human health.
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Increased reactive oxygen species (ROS) and hyperstabilized mutant p53 are common in cancer. Hyperstabilized mutant p53 contributes to its gain of function (GOF) which confers resistance to chemotherapy and radiotherapy. Targeting mutant p53 degradation is a promising cancer therapeutic strategy. We used a small-molecule NSC59984 to explore elimination of mutant p53 in cancer cells, and identified an inducible ROS-ERK2-MDM2 axis as a vulnerability for induction of mutant p53 degradation in cancer cells. NSC59984 treatment promotes a constitutive phosphorylation of ERK2 via ROS in cancer cells. The NSC59984-sustained ERK2 activation is required for MDM2 phosphorylation at serine-166. NSC59984 enhances phosphorylated-MDM2 binding to mutant p53, which leads to mutant p53 ubiquitination and degradation. High cellular ROS increases the efficacy of NSC59984 targeting mutant p53 degradation and antitumor effects. Our data suggest that mutant p53 stabilization has a vulnerability under high ROS cellular conditions, which can be exploited by compounds to target mutant p53 protein degradation through the activation of a ROS-ERK2-MDM2 axis in cancer cells. IMPLICATIONS: An inducible ROS-ERK2-MDM2 axis exposes a vulnerability in mutant p53 stabilization and can be exploited by small-molecule compounds to induce mutant p53 degradation for cancer therapy.
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Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Nitrofuranos , Fosforilação , Piperazinas , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease characterized by early metastasis, late detection, and poor prognosis. Progress towards effective therapy has been slow despite significant efforts. Novel treatment approaches are desperately needed and autophagy, an evolutionary conserved process through which proteins and organelles are recycled for use as alternative energy sources, may represent one such target. Although incompletely understood, there is growing evidence suggesting that autophagy may play a role in PDAC carcinogenesis, metastasis, and survival. Early clinical trials involving autophagy inhibiting agents, either alone or in combination with chemotherapy, have been disappointing. Recently, evidence has demonstrated synergy between the MAPK pathway and autophagy inhibitors in PDAC, suggesting a promising therapeutic intervention. In addition, novel agents, such as ONC212, have preclinical activity in pancreatic cancer, in part through autophagy inhibition. We discuss autophagy in PDAC tumorigenesis, metabolism, modulation of the immune response, and preclinical and clinical data with selected autophagy modulators as therapeutics.
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Recently, owing to well-controlled release, enhanced distribution and increased permeability, nanocarriers used for alternative drug and food-delivery strategies have received increasingly attentions. Nanocarriers have attracted a large amount of interest as potential carriers of various bioactive molecules for multiple applications. Drug and food-based delivery via polymeric-based nanocarriers and lipid-based nanocarriers has been widely investigated. Nanocarriers, especially liposomes, are more and more widely used in the area of novel nano-pharmaceutical or food-based design. Herein, we aimed to discuss the recent advancement of different surface-engineered nanocarriers type, along with cutting-edge applications for food and nanomedicine and highlight the alternative of phytochemical as nanocarrier. Additionally, safety concern of nanocarriers was also highlighted.
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To promote Agaricus sinodeliciosus var. Chaidam ZJU-TP-08 growth and metabolites accumulation, a novel integrated strategy was developed by adopting high levels of metal ions coupled with light treatment. The results revealed that yellow and blue light could significantly promote biomass and exopolysaccharides production, respectively. Furthermore, the yellow-blue light shift strategy could stimulate exopolysaccharides formation. Ca2+ ions coupled with blue light mostly promoted exopolysaccharides production related to oxidative stress, which was 42.00% and 58.26% higher than that of Ca2+ ions coupled with the non-light and dark cultivation without Ca2+ ions in 5-L bioreactor. RNA-seq was performed to uncover the underlined molecular mechanism regulated by light-induced gene expressions in exopolysaccharides biosynthesis and oxidative stress. The findings of this work provide valuable insights into adopting metal ions coupled with the light-assisted method for the macrofungus submerged fermentation for exopolysaccharides production.
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The integrated stress response (ISR) is an evolutionarily conserved intra-cellular signaling network which is activated in response to intrinsic and extrinsic stresses. Various stresses are sensed by four specialized kinases, PKR-like ER kinase (PERK), general control non-derepressible 2 (GCN2), double-stranded RNA-dependent protein kinase (PKR) and heme-regulated eIF2α kinase (HRI) that converge on phosphorylation of serine 51 of eIF2α. eIF2α phosphorylation causes a global reduction of protein synthesis and triggers the translation of specific mRNAs, including activating transcription factor 4 (ATF4). Although the ISR promotes cell survival and homeostasis, when stress is severe or prolonged the ISR signaling will shift to regulate cellular apoptosis. We review the ISR signaling pathway, regulation and importance in cancer therapy.
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Colorectal cancer (CRC) caused over 900,000 deaths worldwide in 2020. A majority of late-stage CRC patients are treated with 5-fluorouracil (5-FU) combined with either irinotecan (CPT-11), oxaliplatin, or both. Despite their widespread use, the mechanisms of efficacy and toxicity of these drugs remain incompletely understood. While previous work has investigated cellular responses to these agents individually, we directly compare the transcriptomic and cytokine profiles of HCT116 wild-type and p53-/- colorectal cancer cells treated with these drugs and report pan-drug, drug-specific, drug class-specific, p53-independent, and p53-dependent signatures. We observed downregulation of histone genes by 5-FU (that significantly correlates with improved survival in CRC patients) and upregulation of FOS and ATF3 by oxaliplatin (which may contribute to peripheral neuropathy). BTG2 was identified as a top gene upregulated by all four drugs, suggesting its critical role in the cellular response to chemotherapy in CRC. Soluble TRAILR2 (death receptor 5; DR5) is a decoy receptor for TRAIL, an apoptosis-inducing cytokine. TRAILR2 was down-regulated by oxaliplatin and 5-FU, was not affected by CPT-11, and was increased by cisplatin. There was an increase in IL-8 by oxaliplatin and increase in ferritin by cisplatin which may contribute to cancer cell survival. Novel drug-specific mechanisms of efficacy or toxicity identified in these signatures may be targeted with combination therapies or development of new targeted therapies. Together, the findings here contribute to our understanding of the molecular bases of efficacy and toxicity of chemotherapeutic agents often used for treatment of GI cancer such as CRC.
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Immunotherapy is an established treatment modality in oncology. However, in addition to primary or acquired therapy resistance with immune checkpoint blockade (ICB), hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. A validated and predictive animal model would help investigate HPD/HP to develop new approaches for this challenging clinical entity. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immunodeficient NCRU-nude athymic mice bearing mismatch repair-deficient (MMR-d) human colon carcinoma HCT116 p53-null (but not wild-type p53) tumor xenograft, we observed accelerated tumor growth after PD-1 blockade with pembrolizumab administration. There was increased colon tumor cell proliferation as determined by immunohistochemical Ki67 staining of tumor sections. There was no increase in MDM2 or MDM4/MDMX in the p53-null HCT116 cells versus the wild-type p53-expressing isogenic tumor cells, suggesting the effects in this model may be MDM2 or MDM4/MDMX-independent. Human cytokine profiling revealed changes in IFN-γ, TRAIL-R2/TNFRSF10B, TRANCE/TNFSF11/RANK L, CCL2/JE/MCP-1, Chitinase 3-like 1, IL-4 and TNF-α. This represents a novel humanized HPD mouse model with a link to deficiency of the p53 pathway of tumor suppression in the setting of MMR-d. Our novel humanized preclinical TALL-104/p53-null HCT116 mouse model implicates p53-deficiency in an MMR-d tumor as a possible contributor to HPD/HP and may help with evaluating therapeutic strategies in cancer immunotherapy to extend clinical benefits of ICB's in a broader patient population.