Two-layer cascaded catalytic hairpin assemblies based on locked nucleic acids for one-step and highly sensitive ctDNA detection.

Enzyme-free signal amplification of catalytic hairpin assembly (CHA) has enabled sensitive detection of circulating tumor DNA (ctDNA) in early clinical diagnosis. Conventional CHA strategies are restrained by the limited amplification efficiency of the single-stage system, and signal leakage from "breathing" influence and nuclease degradation. Here, we introduced two-layer cascaded locked nucleic acid (LNA)-assisted CHA circuits with the intelligent incorporation of LNA in the hairpins and reporter for the highly sensitive one-step detection of scarce ctDNA. The target-triggered upstream CHA reaction continuously generates hybrid products to catalyze the downstream CHA reaction for transducing the primary sensing event, and the released target and the produced hybrid product trigger the next catalytic reaction round at the same time and finally cascade to amplify the target ctDNA fluorescence output signal. Meanwhile, the stronger binding affinity of the LNA-DNA duplex endows the two-layer LNA-assisted CHA system with thermodynamic stability and nuclease resistance, and thus our designed system exhibits an excellent detection performance for target ctDNA in the range from 2 pM to 5 nM with a low detection limit of 0.6 pM. Significantly, the two-layer LNA-assisted CHA circuits have been successfully implemented for the feasible analysis of clinical samples. This two-layer cascaded LNA-assisted CHA strategy provides a promising high sensitivity tool for one-step detection of scarce ctDNA from complex clinical samples and would facilitate the reconfiguration of DNA circuit-based DNA nanotechnology for the precise analysis of other biomarkers in clinical research fields.

An injectable, in situ forming and NIR-responsive hydrogel persistently reshaping tumor microenvironment for efficient melanoma therapy.

BACKGROUND: Melanoma is a highly aggressive form of skin cancer with increasing incidence and mortality rates. Chemotherapy, the primary treatment for melanoma, is limited by hypoxia-induced drug resistance and suppressed immune response at the tumor site. Modulating the tumor microenvironment (TME) to alleviate hypoxia and enhance immune response has shown promise in improving chemotherapy outcomes. METHODS: In this study, a novel injectable and in situ forming hydrogel named MD@SA was developed using manganese dioxide (MnO2) nanosheets pre-loaded with the chemotherapy drug doxorubicin (DOX) and mixed with sodium alginate (SA). The sustainable drug delivery, oxygen generation ability, and photothermal property of MD@SA hydrogel were characterized. The therapeutic efficacy of hydrogel was studied in B16F10 in vitro and B16F10 tumor-bearing mice in vivo. The immune effects on macrophages were analyzed by flow cytometry, real-time quantitative reverse transcription PCR, and immunofluorescence analyses. RESULTS: The MD@SA hydrogel catalyzed the tumoral hydrogen peroxide (H2O2) into oxygen, reducing the hypoxic TME, down-regulating hypoxia-inducible factor-1 alpha (HIF-1α) and drug efflux pump P-glycoprotein (P-gp). The improved TME conditions enhanced the uptake of DOX by melanoma cells, enhancing its efficacy and facilitating the release of tumor antigens. Upon NIR irradiation, the photothermal effect of the hydrogel induced tumor apoptosis to expose more tumor antigens, thus re-educating the M2 type macrophage into the M1 phenotype. Consequently, the MD@SA hydrogel proposes an ability to constantly reverse the hypoxic and immune-inhibited TME, which eventually restrains cancer proliferation. CONCLUSION: The injectable and in situ forming MD@SA hydrogel represents a promising strategy for reshaping the TME in melanoma treatment. By elevating oxygen levels and activating the immune response, this hydrogel offers a synergistic approach for TME regulation nanomedicine.

A rapid and highly sensitive ctDNA detection platform based on locked nucleic acid-assisted catalytic hairpin assembly circuits.

As a promising biomarker of liquid biopsy, circulating tumor DNA (ctDNA) plays a paramount role in the early diagnosis of noninvasive cancer. The isothermal catalytic hairpin assembly (CHA) strategy has great potential for in vitro detection of ctDNA in low abundance. However, a traditional CHA strategy for ctDNA detection at the earlier stages of cancer remains extremely challenging, as annoying signal leakage from the 'breathing' phenomenon and nuclease degradation occur. Herein, we report a locked nucleic acid (LNA)-incorporated CHA circuit for the rapid and sensitive detection of target ctDNA. The target ctDNA intelligently catalyzed LNA-modified hairpins H1 and H2via a range of toehold-mediated strand displacement processes, leading to the continuous generation of an H1-H2 hybrid for the amplified fluorescence signal. In comparison to conventional CHA circuits, the stronger binding affinity of LNA-DNA bases greatly inhibited the breathing effect, which endowed it with greater thermodynamic stability and resistance to nuclease degradation in the LNA-assisted CHA system, thus achieving a high signal gain. The developed CHA circuit demonstrated excellent performance during target ctDNA detection, with a linear range from 10 pM to 5 nM, and its target detection limit was reached at 3.3 pM. Moreover, this LNA-assisted CHA system was successfully applied to the analysis of target ctDNA in clinical serum samples of breast cancer patients. This updated CHA system provides a general and robust platform for the sensitive detection of biomarkers of interest, thus facilitating the accurate identification and diagnosis of cancers.

Rapid Evaluation of Lung Adenocarcinoma Progression by Detecting Plasma Extracellular Vesicles with Lateral Flow Immunoassays.

Extracellular vesicles (EVs) have been widely used in liquid biopsy to diagnose and monitor cancers. However, since samples containing EVs are usually body fluids with complex components, the cumbersome separation steps for EVs during detection limit the clinical application and promotion of EV detection methods. In this study, a dyad lateral flow immunoassay (LFIA) strip for EV detection, containing CD9-CD81 and EpCAM-CD81, was developed to detect universal EVs and tumor-derived EVs, respectively. The dyad LFIA strip can directly detect trace plasma samples and effectively distinguish the cancerous sample from healthy plasma. The limit of detection for detecting universal EVs was 2.4 × 105 mL-1. The whole immunoassay can be performed in 15 min and only consumes 0.2 µL of plasma for one test. To improve the suitability of a dyad LFIA strip in complex scenarios, a smartphone-based photographic method was developed, which provided a consistency of 96.07% to a specialized fluorescence LFIA strip analyzer. In further clinical testing, EV-LFIA discriminated lung cancer patient groups (n = 25) from healthy controls (n = 22) with 100% sensitivity and 94.74% specificity at the best cutoff. The detection of EpCAM-CD81 tumor EVs (TEVs) in lung cancer plasma revealed the differences in TEVs in individuals, which reflected the different treatment effects. TEV-LFIA results were compared with CT scan findings (n = 30). The vast majority of patients with increased TEV-LFIA detection intensity had lung masses that enlarged or remained unchanged in size, which reported no response to treatment. In other words, patients who reported no response (n = 22) had a high TEV level compared with patients who reported a response to treatment (n = 8). Taken together, the developed dyad LFIA strip provides a simple and rapid platform to characterize EVs to monitor lung cancer therapy outcomes.

Sb-doped FeOCl nanozyme-based biosensor for highly sensitive colorimetric detection of glutathione.

Nanozymes have been emerging as substitutes for natural enzymes to construct biosensors towards biomolecular detection. However, the detection of glutathione (GSH) by nanozyme-based biosensors still remains a great challenge for research on catalytic activity enhancement and the detection mechanism. In this work, Sb-doped iron oxychloride (Sb-FeOCl) with a well-defined nanorod-like structure is prepared by high-temperature calcination. Sb-FeOCl nanorods have high peroxidase-like activity, which can catalyze the decomposition of H2O2 into ·OH and then oxidize 3,3',5,5'-tetramethylbenzidine (TMB). In view of these intriguing observations, a reliable colorimetric method with a simple mixing and detection strategy is developed for the detection of GSH. The linear range of GSH detection is 1-36 µM. The detection limit of GSH reaches a low level of 0.495 µM (3σ/slope). The GSH sensing system also exhibits excellent specificity and anti-interference. Taking advantage of the advantages of the Sb-FeOCl nanorod-based biosensor, it can be used to quantitatively detect GSH levels in human serum. It can be anticipated that the Sb-FeOCl nanorods have broad prospects in the field of enzymatic biochemical reactions.

Highly Sensitive Colorimetric Detection of Glutathione in Human Serum Based on Iron-Copper Metal-Organic Frameworks.

Emerging metal-organic framework (MOF)-based mimic enzymes have been exploited to design a colorimetric sensor for the detection of biomolecules. However, it is challenging to figure out the glutathione (GSH) detection method and the corresponding sensing mechanism using an MOF-based colorimetric sensor. In this work, a novel iron-copper MOF with high activity is synthesized by a wet-chemical method. A GSH colorimetric sensor based on the peroxidase-like properties of the iron-copper MOF is developed. Hydrogen peroxide is converted to hydroxyl radicals by the peroxidase-like properties of the iron-copper MOF mimic enzyme, which can catalyze the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue oxidized TMB (ox-TMB). The kinetic constant of the MOF mimic enzyme (0.02 mM for H2O2) is superior to horseradish peroxidase (HRP). The GSH content can be quantified by proposing a sensor based on the colorimetric method and color turn-off mechanism. The turn-off mechanism of GSH analysis includes two aspects. On the one hand, the blue ox-TMB can be deoxidized to colorless TMB by GSH. On the other hand, hydroxyl radicals (•OH) can be consumed by GSH. The linear range and limit of detection are 2-20 and 0.439 µM, respectively. At the same time, GSH detection also shows good specificity and anti-interference characteristics. Therefore, MOF-based colorimetric sensors have been used to qualitatively and quantitatively measure GSH contents in human serum. The mechanism and application of the iron-copper MOF pave a way for the development of mimic enzymes with polymetallic active sites in the field of colorimetric sensing.

Platinum nanoparticles (PtNPs)-based CRISPR/Cas12a platform for detection of nucleic acid and protein in clinical samples.

Early rapid screening diagnostic assay is essential for the identification, prevention, and evaluation of many contagious or refractory diseases. The optical density transducer created by platinum nanoparticles (PtNPs) (OD-CRISPR) is reported in the present research as a cheap and easy-to-execute CRISPR/Cas12a-based diagnostic platform. The OD-CRISPR uses PtNPs, with ultra-high peroxidase-mimicking activity, to increase the detection sensitivity, thereby enabling the reduction of detection time and cost. The OD-CRISPR can be utilized to identify nucleic acid or protein biomarkers within an incubation time of 30-40min in clinical specimens. In the case of taking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) N gene as an instance, when compared to a quantitative reverse transcription-polymerase chain reaction (RT-qPCR), the OD-CRISPR test attains a sensitivity of 79.17% and a specificity of 100%. In terms of detecting prostate-specific antigen (PSA), aptamer-based OD-CRISPR assay achieves the least discoverable concentration of 0.01 ng mL-1. In general, the OD-CRISPR can detect nucleic acid and protein biomarkers, and is a potential strategy for early rapid screening diagnostic tools.

Mechanism and Application of Surface-Charged Ferrite Nanozyme-Based Biosensor toward Colorimetric Detection of l-Cysteine.

Peroxidase-like nanozymes with robust catalytic capacity and detection specificity have been proposed as substitutes to natural peroxidases in biochemical sensing. However, the catalytic activity enhancement, detection mechanism, and application of nanozyme-based biosensors toward l-cysteine (l-Cys) detection still remain significant challenges. In this work, a doped ferrite nanozyme with well-defined structure and surface charges is fabricated by a two-step method of continuous flow coprecipitation and high-temperature annealing. The resulted ferrite nanozyme possesses an average size of 54.5 nm and a zeta-potential of 6.45 mV. A high-performance biosensor is manufactured based on the peroxidase-like catalytic feature of the doped ferrite. The ferrite nanozyme can oxidize the 3,3',5,5'-tetramethylbenzidine (TMB) with the assistance of H2O2 because of the instinctive capacity to decompose H2O2 into ·OH. The Michaelis-Menten constants (0.0911 mM for TMB, 0.140 mM for H2O2) of the ferrite nanozyme are significantly smaller than those of horseradish peroxidase. A reliable colorimetric method is established to selectively analyze l-Cys via a facile mixing-and-detecting methodology. The detection limit and linear range are 0.119 µM and 0.2-20 µM, respectively. Taking the merits of the ferrite nanozyme-based biosensors, the l-Cys level in the human serum can be qualitatively detected. It can be anticipated that the surface-charged ferrite nanozyme shows great application prospects in the fields of bioanalytical chemistry and point-of-care testing.

Identification of LHFPL3-AS2 as a prognostic biomarker in lung adenocarcinoma.

Background: Deregulation of long noncoding RNAs (lncRNAs) was considered one of the main characteristics of several human cancers. However, detailed genome-wide expression and functional significance studies of lnc RNAs in lung adenocarcinoma are still limited. This study aims to discover a new lncRNA that may play an important role in regulating the pathogenesis of lung adenocarcinoma (ADC). Methods: We conducted a comprehensive analysis of three Gene Expression Omnibus (GEO) microarray datasets and TCGA datasets. Differentially expressed lncRNAs between ADC and normal tissues were screened and verified using Gene Expression Profiling Interactive Analysis (GEPIA). Moreover, Kaplan-Meier plotter was used to construct the gene prognosis profile. The downstream targets of miRNA and related functional pathways were predicted and validated. Results: With microarray gene expression analysis, we found that only lncRNAs-PCAT6 was commonly upregulated among four datasets, and four lncRNAs (LINC00968, PGM5-AS1, LHFPL3-AS2 and SFTA1P) were significantly downregulated in the ADC samples as compared to the normal tissues. Meanwhile, for LHFPL3-AS2, high-risk patients showed better overall survival (HR=0.6 or 0.62; P < .0001 or P = 0.0014), overall survival from TCGA datasets (HR=0.72; P = 0.015) and recurrence-free survival (HR=0.72; P = 0.015). Then, LHFPL3-AS2 was predicted to bind to two miRNAs, miR-127-5p and miR-424-5p. Finally, validation and functional enrichment analysis of the downstream key mRNAs showed significant enrichment in some cancer-related pathways, such as cell adhesion in cancer and small cell lung cancer. Conclusions: Taken together, our study indicated that LHFPL3-AS2 was associated with tumorigenesis, and it could be used as a useful biomarker in the diagnosis, prognosis and treatment of ADC.

Deoxyribonuclease 1-like 3 may be a potential prognostic biomarker associated with immune infiltration in colon cancer.

Colon adenocarcinoma (COAD) is a common cancer of the digestive system. It's high morbidity and mortality make it one of the leading causes of cancer deaths. In this study, we studied the microenvironment of colon cancer to find new diagnostic markers and immunotherapy targets for colon cancer. Tumor purity of colon cancer samples in TCGA database were obtained by ESTIMATE algorithm. Then, we analyzed the association of Immune, Stromal, and Estimate scores with tumor prognosis and clinicopathological features. By comparing the gene expression profiles between tumor and normal samples, the high and low immune score groups, 117 intersecting differentially expressed genes (DEGs) were obtained. The function, molecular pathway, and prognostic value of these 117 DEGs pointed toward the importance of deoxyribonuclease 1-like 3 (DNASE1L3). Validation results from multiple databases showed low expression of DNASE1L3 in colon cancer. A single GSEA and correlation analysis of immune cells indicated that DNASE1L3 was closely related to immunity. The low expression of DNASE1L3 in colon cancer samples was measured with qRT-PCR. The scratch and cell proliferation experiments suggested that DNASE1L3 may affect cell migration. Therefore, we concluded that DNASE1L3 might be a biomarker associated with prognosis and immune infiltration in colon cancer.

Distribution of serum Thrombospondin-2, a novel tumor marker, in general population and cancer patients in China.

PURPOSE: Distribution of serum thrombospondin-2 in general population and cancer patients in China have not been reported. METHODS: This study evaluated the expression level of serum thrombospondin-2 in general population and various cancer patients, the 95% confidence interval was used for the derivation of reference range. The comparison of the expression levels in controls for age and gender was performed. The associations between candidate biomarkers (thrombospondin-2 [THBS2]) expression and tumor metastasis status were also explored. RESULTS: 125 healthy controls and 193 various cancer patients were enrolled. The mean ± SD in serum THBS2 levels in general population was 42.37 ± 12.24 ng/ml, there was no significant sex and age difference, the reference range is 18.37-66.36 ng/ml. Most cancer patients present a decreased serum THBS2 level except hepatoma and lymphoma which most patients showed a relatively high level of THBS2. There was no statistical difference of serum THBS2 level between metastasis and non-metastasis group in breast, lung, cervical, colorectal cancer, nasopharyngeal carcinoma and hepatoma (P > 0.05) while a significant negative correlation was observed in ovarian cancer (P = 0.0209). CONCLUSIONS: The distribution of serum THBS2 displayed an obvious heterogeneity among various cancers comparing to health controls, ovarian cancer patients detected with low THBS2 expression may be more prone to develop metastasis in China.

Identification of LINC00665-miR-let-7b-CCNA2 competing endogenous RNA network associated with prognosis of lung adenocarcinoma.

Prognosis of patients with lung cancer remains extremely poor; thus, we sought to unearth novel competing endogenous RNA (ceRNA) networks associated with the prognosis of lung adenocarcinoma (LUAD). Aberrant mRNAs were identified from the intersection of three Gene Expression Omnibus (GEO) datasets. A protein-protein interaction (PPI) network was constructed, and miRNAs and long noncoding RNAs (lncRNAs) upstream of mRNAs were predicted. In the present study, 402 upregulated and 638 downregulated genes in lung cancer tissues were identified. Functional analysis showed significant enrichment of cancer pathways. In these top hub genes, 10 upregulated and 7 downregulated genes had substantial prognostic values in LUAD. Thirty-seven miRNAs were predicted to target 17 key genes, and only five miRNAs exhibited prognostic correlation. Through stepwise reverse prediction and validation from miRNA to lncRNA, four key lncRNAs were identified using expression and survival analysis. Ultimately, the co-expression analysis identified LINC00665-miR-let-7b-CCNA2 as the key ceRNA network associated with the prognosis of LUAD. We successfully constructed a novel ceRNA network wherein each component was significantly associated with the prognosis of LUAD. Hence, we propose that this network may provide key biomarkers or potential therapeutic targets for LUAD prognosis.

A Novel AKR1C3 Specific Prodrug TH3424 With Potent Antitumor Activity in Liver Cancer.

Overexpression of AKR1C3, an aldo-keto reductase, was recently discovered in liver cancers. In this study, an inverse correlation between AKR1C3 expression and survival of patients with liver cancer was observed. AKR1C3 inhibitors, however, failed to suppress liver cancer cell growth. The prodrug TH3424, which releases a DNA alkylating reagent upon reduction by AKR1C3, was developed to target tumors with overexpression of AKR1C3. TH3424 showed specific killing of liver cancer cells with AKR1C3 overexpression both in vitro and in vivo. In patient-derived mouse xenograft models, TH3424 at doses as low as 1.5 mg/kg eliminated liver tumors with no apparent toxicity. Therefore, TH3424 is a promising drug candidate for liver cancer and other types of cancers overexpressing AKR1C3.

Role of ATF3 as a prognostic biomarker and correlation of ATF3 expression with macrophage infiltration in hepatocellular carcinoma.

BACKGROUND: The abnormal expression of activating transcription factor 3 (ATF3), a member of the basic leucine zipper (bZIP) family of transcription factors, is associated with carcinogenesis. However, the expression pattern and exact role of ATF3 in the development and progression of hepatocellular carcinoma (HCC) remain unclear. METHODS: We used UALCAN, ONCOMINE, Kaplan-Meier plotter, and cBioPortal databases to investigate the prognostic value of ATF3 expression in HCC. RESULTS: ATF3 was found to be expressed at low levels in multiple HCC tumor tissues. Moreover, low ATF3 expression was significantly associated with clinical cancer stage and pathological tumor grade in patients with HCC. Therefore, low expression of ATF3 was significantly associated with poor overall survival in patients with HCC. Functional network analysis showed that ATF3 regulates cytokine receptors and signaling pathways via various cancer-related kinases, miRNAs, and transcription factors. ATF3 expression was found to be correlated with macrophage infiltration levels and with macrophage immune marker sets in HCC patients. CONCLUSIONS: Using data mining methods, we clarified the role of ATF3 expression and related regulatory networks in HCC, laying a foundation for further functional research. Future research will validate our findings and establish clinical applications of ATF3 in the diagnosis and treatment of HCC.

Bromodomain 4 is a potent prognostic marker associated with immune cell infiltration in breast cancer.

Bromodomain 4 (BRD4), a member of the bromodomain and extra-terminal domain protein family, has become a promising epigenetic target in cancer and inflammatory diseases; however, the detailed biological role of BRD4 in breast cancer (BRCA) remains undetermined. We analysed the BRD4 expression levels using the Oncomine and TIMER databases and evaluated the clinical impact of BRD4 on BRCA prognosis using Kaplan-Meier plot and PrognoScan. The correlation between BRD4 and tumour-infiltrating immune cells was investigated using TIMER. Furthermore, the correlation between BRD4 expression levels was also analysed using TIMER in addition to the GEPIA database for immune cell gene markers. BRD4 expression was significantly higher in BRCA tissues than in normal tissues, which was significantly correlated with poor overall survival (OS). Specifically, high BRD4 expression was correlated with worse OS and progression-free survival in patients with BRCA. In addition, BRD4 expression was correlated with levels of infiltrating monocytes (CSF1R, cor = 0.204, P = 9.19e-12), tumour-associated macrophages (CD68, cor = 0.129, P = 1.81e-05), M1/M2 macrophages and different effector T cells (including Th1/Th2/Treg) in BRCA. These findings suggest that BRD4 could be used as a prognostic biomarker for determining prognosis and immune cell infiltration levels in BRCA.

Expansion of Polymorphonuclear Myeloid-Derived Suppressor Cells in Patients With Gout.

Gout is an inflammatory joint disease caused by monosodium urate (MSU) crystals; however, the mechanism underlying MSU-induced inflammation is unclear. Previous research has suggested that inflammation or cancer can drive the expansion of myeloid-derived suppressor cells (MDSCs). In this study, the role of MDSCs in MSU-induced gout inflammation was evaluated. A total of 28 patients with gout, and 20 healthy controls were recruited for the study. MDSCs, and their functions, were analyzed by flow cytometry and a T cell co-culture assay, respectively. We observed a higher frequency of PMN-MDSCs, and a stronger immunosuppressive function, in patients with gout compared to the controls. Moreover, circulating PMN-MDSCs were positively correlated with pathological indicators, including uric acid and C-reactive protein levels. We also demonstrated that MSU can induce significant PMN-MDSC expansion, using in vivo and in vitro experiments. Finally, MSU-induced PMN-MDSCs produced higher levels of IL-1ß, which mediated gout inflammatory progression. Our results demonstrate that MSU modulates the expansion and suppressive function of PMN-MDSCs, providing insights into a novel mechanism underlying the pathogenesis of MSU-induced gout. Thus, MDSCs may be useful for the development of novel therapeutic strategies for the prevention and treatment of gout.

Construction of an 11-microRNA-based signature and a prognostic nomogram to predict the overall survival of head and neck squamous cell carcinoma patients.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a fatal malignancy owing to the lack of effective tools to predict overall survival (OS). MicroRNAs (miRNAs) play an important role in HNSCC occurrence, development, invasion and metastasis, significantly affecting the OS of patients. Thus, the construction of miRNA-based risk signatures and nomograms is desirable to predict the OS of patients with HNSCC. Accordingly, in the present study, miRNA sequencing data of 71 HNSCC and 13 normal samples downloaded from The Cancer Genome Atlas (TCGA) were screened to identify differentially expressed miRNAs (DEMs) between HNSCC patients and normal controls. Based on the exclusion criteria, the clinical information and miRNA sequencing data of 67 HNSCC samples were selected and used to establish a miRNA-based signature and a prognostic nomogram. Forty-three HNSCC samples were assigned to an internal validation cohort for verifying the credibility and accuracy of the primary cohort. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore the functions of 11 miRNA target genes. RESULTS: In total, 11 DEMs were successfully identified. An 11-miRNA risk signature and a prognostic nomogram were constructed based on the expression levels of these 11 DEMs and clinical information. The signature and nomogram were further validated by calculating the C-index, area under the curve (AUC) in receiver-operating characteristic curve analysis, and calibration curves, which revealed their promising performance. The results of the internal validation cohort shown the reliable predictive accuracy both of the miRNA-based signature and the prognostic nomogram. GO and KEGG analyses revealed that a mass of signal pathways participated in HNSCC proliferation and metastasis. CONCLUSION: Overall, we constructed an 11-miRNA-based signature and a prognostic nomogram with excellent accuracy for predicting the OS of patients with HNSCC.

Prognostic value of S1PR1 and its correlation with immune infiltrates in breast and lung cancers.

BACKGROUND: Sphingosine-1-phosphate receptor (S1PR1) is involved in vascular development, a key process in tumorigenesis. This study aimed to evaluate its roles in tumor development and prognosis. METHODS: S1PR1 expression levels were analyzed using TIMER and Oncomine database, and the prognostic significance of S1PR1 was assessed using PrognoScan and Kaplan-Meier plotter databases. The relationship between S1PR1 and tumor-infiltrated immune cells was analyzed using TIMER. RESULTS: S1PR1 expression was remarkably lower in breast and lung cancer tissues than in the corresponding normal tissues. Lower expression was related to poor overall survival and disease-free survival in breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). A functional network analysis confirmed the function of S1PR1 in regulating vasculogenesis. In addition, S1PR1 levels were significantly negative with regard to the tumor purity of BRCA (r = - 0.508, P = 1.76e-66), LUAD (r = - 0.353, P = 6.05e-16), and LUSC (r = - 0.402, P = - 5.20e-20). Furthermore, S1PR1 levels were significantly positive with regard to infiltrating CD8+ (r = 0.38, P = 5.91e-35) and CD4+ T cells (r = 0.335, P = 1.03e-26), macrophages (r = 0.219, P = 3.67e-12), neutrophils (r = 0.168, P = 2.03e-7), and dendritic cells (DCs) (r = 0.208, P = 9.14e-11) in BRCA; S1PR1 levels were significantly positive with regard to CD8+ T cells (r = 0.308, P = 3.61e-12), macrophages (r = 0.376, P = 1.01e-17), neutrophils (r = 0.246, P = 4.15e-8), and DCs (r = 0.207, P = 4.16e-6) in LUAD; and positive with regard to B cells (r = 0.356, P = 1.57e-15), CD8+ (r = 0.459, P = 3.83e-26) and CD4+ T cells (r = 0.338, P = 3.98e-14), macrophages (r = 0.566, P = 2.61e-45), neutrophils (r = 0.453, P = 1.79e-25), and DCs (r = 0.56, P = 2.12e-40) in LUSC. CONCLUSIONS: S1PR1 levels are positively correlated with multiple immune markers in breast and lung cancer. These observed correlations between S1PR1 and the prognosis and immune cell infiltration provide a foundation for further research on its immunomodulatory role in cancer.

Rapid review for the anti-coronavirus effect of remdesivir.

The outbreak of SARS-CoV-2 rapidly spread across China and worldwide. Remdesivir had been proposed as a promising option for treating coronavirus disease 2019 (COVID-19). We provided a rapid review to critically assess the potential anti-coronavirus effect of remdesivir on COVID-19 and other coronaviruses based on the most up-to-date evidence. Even though remdesivir was proposed as a promising option for treating COVID-19 based on laboratory experiments and reports from compassionate use, its safety and effect in humans requires high-quality evidence from well-designed and adequately-powered clinical trials for further clarification.

An AKR1C3-specific prodrug with potent anti-tumor activities against T-ALL.

AKR1C3 overexpression has been reported in various types of cancers, including T-ALL. AST-006 (TH-3424), an AKR1C3-specific prodrug, was reported recently to have potent cytotoxicity against liver cancer cells overexpressing AKR1C3 and T-ALL. In this study, AST-006 demonstrated potent anti-tumor activity against different T-ALL cell lines in vitro and in vivo, including patient-derived xenograft (PDX) model. AST-006 also exhibited minimal cytotoxicity against primary human T-cells in vitro and lymphocytes in cynomolgus monkeys in vivo, indicating that AST-006 is a promising therapeutic for T-ALL.