Development of an interfering peptide M1-20 with potent anti-cancer effects by targeting FOXM1.

Disrupting protein-protein interactions (PPIs) has emerged as a promising strategy for cancer drug development. Interfering peptides disrupting PPIs can be rationally designed based on the structures of natural sequences mediating these interactions. Transcription factor FOXM1 overexpresses in multiple cancers and is considered an effective target for cancer therapeutic drug development. Using a rational design approach, we have generated a peptide library from the FOXM1 C-terminal sequence and screened FOXM1-binding peptides. Combining FOXM1 binding and cell inhibitory results, we have obtained a FOXM1-targeting interfering peptide M1-20 that is optimized from the natural parent peptide to the D-retro-inverso peptide. With improved stability characteristics, M1-20 inhibits proliferation and migration, and induces apoptosis of cancer cells. Mechanistically, M1-20 inhibits FOXM1 transcriptional activities by disrupting its interaction between the MuvB complex and the transcriptional co-activator CBP. These are consistent with the results that M1-20 suppresses cancer progression and metastasis without noticeable toxic and side effects in wild-type mice. These findings reveal that M1-20 has the potential to be developed as an anti-cancer drug candidate targeting FOXM1.

The development of an anti-cancer peptide M1-21 targeting transcription factor FOXM1.

BACKGROUND: Transcription factor FOXM1 is a potential target for anti-cancer drug development. An interfering peptide M1-21, targeting FOXM1 and FOXM1-interacting proteins, is developed and its anti-cancer efficacy is evaluated. METHODS: FOXM1 C-terminus-binding peptides are screened by in silico protocols from the peptide library of FOXM1 (1-138aa) and confirmed by cellular experiments. The selected peptide is synthesized into its D-retro-inverso (DRI) form by fusing a TAT cell-penetrating sequence. Anti-cancer activities are evaluated in vitro and in vivo with tumor-grafted nude mice, spontaneous breast cancer mice, and wild-type metastasis-tracing mice. Anti-cancer mechanisms are analyzed. Distribution and safety profiles in mice are evaluated. RESULTS: With improved stability and cell inhibitory activity compared to the parent peptide, M1-21 binds to multiple regions of FOXM1 and interferes with protein-protein interactions between FOXM1 and its various known partner proteins, including PLK1, LIN9 and B-MYB of the MuvB complex, and ß-catenin. Consequently, M1-21 inhibits FOXM1-related transcriptional activities and FOXM1-mediated nuclear importation of ß-catenin and ß-catenin transcriptional activities. M1-21 inhibits multiple types of cancer (20 µM in vitro or 30 mg/kg in vivo) by preventing proliferation, migration, and WNT signaling. Distribution and safety profiles of M1-21 are favorable (broad distribution and > 15 h stability in mice) and the tested non-severely toxic dose reaches 200 mg/kg in mice. M1-21 also has low hemolytic toxicity and immunogenicity in mice. CONCLUSIONS: M1-21 is a promising interfering peptide targeting FOXM1 for the development of anti-cancer drugs.

Water requirement of Urban Green Infrastructure under climate change.

The increased uncertainty of rainfall and high urban temperatures resulting from climate change present challenges for water management in Urban Green Infrastructure (UGI). UGI is an important component of cities, and it plays a crucial role in addressing various environmental issues (e.g., floods, pollutants, heat islands, etc.). Effective water management of UGI is essential to ensure its environmental and ecological benefits in the face of climate change. However, previous studies have not adequately investigated water management strategies for UGI under climate change scenarios. This study aims to estimate the current and future water requirement and effective rainfall (rainwater stored in the soil and plant roots available for plant evapotranspiration) to determine the irrigation requirement of UGI during periods of rainfall deficit under current and future climate conditions. The results indicate that the water requirement for UGI will continue to increase under both RCP4.5 and RCP8.5 climate scenarios, with a larger increase projected under RCP8.5. For instance, the average annual water requirement for UGI in Seoul, South Korea is currently 731.29 mm, and it is projected to increase to 756.45 mm (RCP4.5) and 816.47 mm (RCP8.5) during the period of 2081-2100, assuming low managed water stress condition. In addition, the water requirement of UGI in Seoul is the highest in June (approximately 125-137 mm) and the lowest in December or January (about 5-7 mm). While irrigation is unnecessary in July and August due to sufficient rainfall, other months in Seoul require irrigation when rainfall is insufficient. For example, continuous insufficient rainfall from May to June 2100 and April to June 2081 would need >110 mm (RCP4.5) of irrigation requirement even under high managed water stress condition. The findings of this study provide a theoretical foundation for water management strategies in current and future UGI settings.

Comprehensive analysis of FOXM1 immune infiltrates, m6a, glycolysis and ceRNA network in human hepatocellular carcinoma.

Background: Forkhead box M1 (FOXM1) is a member of the Forkhead box (Fox) transcription factor family. It regulates cell mitosis, cell proliferation, and genome stability. However, the relationship between the expression of FOXM1 and the levels of m6a modification, immune infiltration, glycolysis, and ketone body metabolism in HCC has yet to be fully elucidated. Methods: Transcriptome and somatic mutation profiles of HCC were downloaded from the TCGA database. Somatic mutations were analyzed by maftools R package and visualized in oncoplots. GO, KEGG and GSEA function enrichment was performed on FOXM1 co-expression using R. We used Cox regression and machine learning algorithms (CIBERSORT, LASSO, random forest, and SVM-RFE) to study the prognostic value of FOXM1 and immune infiltrating characteristic immune cells in HCC. The relationship between FOXM1 and m6A modification, glycolysis, and ketone body metabolism were analyzed by RNA-seq and CHIP-seq. The competing endogenous RNA (ceRNA) network construction relies on the multiMiR R package, ENCORI, and miRNET platforms. Results: FOXM1 is highly expressed in HCC and is associated with a poorer prognosis. At the same time, the expression level of FOXM1 is significantly related to the T, N, and stage. Subsequently, based on the machine learning strategies, we found that the infiltration level of T follicular helper cells (Tfh) was a risk factor affecting the prognosis of HCC patients. The high infiltration of Tfh was significantly related to the poor overall survival rate of HCC. Besides, the CHIP-seq demonstrated that FOXM1 regulates m6a modification by binding to the promoter of IGF2BP3 and affects the glycolytic process by initiating the transcription of HK2 and PKM in HCC. A ceRNA network was successfully obtained, including FOXM1 - has-miR-125-5p - DANCR/MIR4435-2HG ceRNA network related to the prognosis of HCC. Conclusion: Our study implicates that the aberrant infiltration of Tfh associated with FOXM1 is a crucial prognostic factor for HCC patients. FOXM1 regulates genes related to m6a modification and glycolysis at the transcriptional level. Furthermore, the specific ceRNA network can be used as a potential therapeutic target for HCC.

Fast and Accurate Illumination Estimation Using LDR Panoramic Images for Realistic Rendering.

A high dynamic range (HDR) image is commonly used to reveal stereo illumination, which is crucial for generating high-quality realistic rendering effects. Compared to the high-cost HDR imaging technique, low dynamic range (LDR) imaging provides a low-cost alternative and is preferable for interactive graphics applications. However, the limited LDR pixel bit depth significantly bothers accurate illumination estimation using LDR images. The conflict between the realism and promptness of illumination estimation for realistic rendering is yet to be resolved. In this paper, an efficient method that accurately infers illuminations of real-world scenes using LDR panoramic images is proposed. It estimates multiple lighting parameters, including locations, types and intensities of light sources. In our approach, a new algorithm that extracts illuminant characteristics during the exposure attenuation process is developed to locate light sources and outline their boundaries. To better predict realistic illuminations, a new deep learning model is designed to efficiently parse complex LDR panoramas and classify detected light sources. Finally, realistic illumination intensities are calculated by recovering the inverse camera response function and extending the dynamic range of pixel values based on previously estimated parameters of light sources. The reconstructed radiance map can be used to compute high-quality image-based lighting of virtual models. Experimental results demonstrate that the proposed method is capable of efficiently and accurately computing comprehensive illuminations using LDR images. Our method can be used to produce better realistic rendering results than existing approaches.

ß -Glucan Improves Protective Qi Status in Adults with Protective Qi Deficiency-A Randomized, Placebo-Controlled, and Double-Blinded Trial.

OBJECTIVE: To test the hypothesis that ß -glucan enhances protective qi (PQi), an important Chinese medicine (CM) concept which stipulates that a protective force circulates throughout the body surface and works as the first line of defense against "external pernicious influences". METHODS: A total of 138 participants with PQi deficiency (PQD) were randomized to receive ß -glucan (200 mg daily) or placebo for 12 weeks. Participants' PQi status was assessed every 2 weeks via conventional diagnosis and a standardized protocol from which a PQD severity and risk score was derived. Indices of participants' immune and general health status were also monitored, including upper respiratory tract infection (URTI), saliva secretory IgA (sIgA), and self-reported measures of physical and mental health (PROMIS). RESULTS: PQi status was not significantly different between the ß -glucan and placebo treatment groups at baseline but improved significantly in the ß -glucan (vs. placebo) group in a time-dependent manner. The intergroup differences [95% confidence interval (CI)] in severity score (scale: 1-5), risk score (scale: 0-1), and proportion of PQD participants (%) at finish line was 0.49 (0.35-0.62), 0.48 (0.35-0.61), and 0.36 (0.25-0.47), respectively. Additionally, ß -glucan improved URTI symptom (scale: 1-9) and PROMIS physical (scale: 16.2-67.7) and mental (scale: 21.2-67.6) scores by a magnitude (95% CI) of 1.0 (0.21-1.86), 5.7 (2.33-9.07), and 3.0 (20.37-6.37), respectively, over placebo. CONCLUSIONS: ß -glucan ameliorates PQi in PQD individuals. By using stringent evidence-based methodologies, our study demonstrated that Western medicine-derived remedies, such as ß -glucan, can be employed to advance CM therapeutics. (ClinicalTrial.Gov registry: NCT03782974).

Proof-of-Concept and Feasibility Study to Evaluate the Effect of ß-Glucan on Protective Qi Deficiency in Adults.

OBJECTIVE: To preliminarily explore the potential effect of ß-glucan on Chinese medicine (CM) concept protective qi deficiency (PQD), and the methodology for future definitive studies. METHODS: To have a standardized assessment of PQD, a list of 13 potentially PQD-relevant parameters were firstly created, each with defined quantitative or categorial scales. Using the data from 37 participants with (21 cases) or without (16 cases) PQD, multivariate logistic modeling was conducted to create a preliminary diagnostic PQD risk score. Subsequently, 21 participants diagnosed with PQD were treated with ß-glucan in a dose of 200 mg/day for 8 weeks. Data were collected for trial acceptability measures (rate of recruitment, withdrawal, and compliance), and the participants were assessed for PQD status at baseline and every 2 weeks thereafter. RESULTS: The preliminary logistic model consisted of 3 parameters (low voice and apathy, aversion to wind and cold, and Cun pulse). The resulting risk score demonstrated a degree of PQD-predicting accuracy that, as evaluated by statistical (discrimination and classification) methods, was higher than those obtained from any of the individual candidate parameters. The 21 PQD participants treated with ß-glucan demonstrated good receptibility and a time-dependent improvement in PQD status as evidenced by the decrease of PQD participant to 9.5% at the end of study. CONCLUSIONS: This study demonstrated the effect of proof-of-concept of ß-glucan on improving PQD and the proof-of-concept of a multivariate-model-derived diagnostic PQD risk score. It also indicated feasibility for future definitive studies. Studies like this embody an innovative approach that uses therapies derived from the mainstream biomedicine to enrich therapeutics guided by CM principle. (Trial registration No. NCT03829228).

Recent advances in modified TiO2 for photo-induced organic synthesis.

Over the last decade, chemists have made great progress in photocatalysis. Compared with the well-developed homogenous photocatalysis for organic synthesis, heterogeneous photoredox catalysis is still in its infancy. In this review, we summarized the recent developments of TiO2-based materials in heterogeneous photocatalysis for organic synthesis. Generally, modified TiO2 shows enhanced photocatalysis with a narrow band gap or broad absorption spectrum. Based on the present work, the future perspectives of modified TiO2 photocatalysts for organic synthesis are presented.

An evidence-based approach to globally assess the covariate-dependent effect of the MTHFR single nucleotide polymorphism rs1801133 on blood homocysteine: a systematic review and meta-analysis.

Background: The single nucleotide polymorphism of the gene 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T (or rs1801133) is the most established genetic factor that increases plasma total homocysteine (tHcy) and consequently results in hyperhomocysteinemia. Yet, given the limited penetrance of this genetic variant, it is necessary to individually predict the risk of hyperhomocysteinemia for an rs1801133 carrier. Objective: We hypothesized that variability in this genetic risk is largely due to the presence of factors (covariates) that serve as effect modifiers, confounders, or both, such as folic acid (FA) intake, and aimed to assess this risk in the complex context of these covariates. Design: We systematically extracted from published studies the data on tHcy, rs1801133, and any previously reported rs1801133 covariates. The resulting metadata set was first used to analyze the covariates' modifying effect by meta-regression and other statistical means. Subsequently, we controlled for this modifying effect by genotype-stratifying tHcy data and analyzed the variability in the risk resulting from the confounding of covariates. Results: The data set contains data on 36 rs1801133 covariates that were collected from 114,799 participants and 256 qualified studies, among which 6 covariates (sex, age, race, FA intake, smoking, and alcohol consumption) are the most frequently informed and therefore included for statistical analysis. The effect of rs1801133 on tHcy exhibits significant variability that can be attributed to effect modification as well as confounding by these covariates. Via statistical modeling, we predicted the covariate-dependent risk of tHcy elevation and hyperhomocysteinemia in a systematic manner. Conclusions: We showed an evidence-based approach that globally assesses the covariate-dependent effect of rs1801133 on tHcy. The results should assist clinicians in interpreting the rs1801133 data from genetic testing for their patients. Such information is also important for the public, who increasingly receive genetic data from commercial services without interpretation of its clinical relevance. This study was registered at Research Registry with the registration number reviewregistry328.

Evaluating the Prognostic Accuracy of Biomarkers for Glioblastoma Multiforme Using The Cancer Genome Atlas Data.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. Previous studies on GBM biomarkers focused on the effect of the biomarkers on overall survival (OS). Until now, no study has been published that evaluates the performance of biomarkers for prognosing OS. We examined the performance of microRNAs, gene expressions, gene signatures, and methylation that were previously identified to be prognostic. In addition, we investigated whether using clinical risk factors in combination with biomarkers can improve the prognostic performance. METHODS: The Cancer Genome Atlas, which provides both biomarkers and OS information, was used in this study. The time-dependent receiver operating characteristic (ROC) curve was used to evaluate the prognostic accuracy. RESULTS: For prognosis of OS by 2 years from diagnosis, the area under the ROC curve (AUC) of microRNAs, Mir21 and Mir222, was 0.550 and 0.625, respectively. When age was included in the risk prediction score of these biomarkers, the AUC increased to 0.719 and 0.701, respectively. The SAMSN1 gene expression attains an AUC of 0.563, and the "8-gene" signature identified by Bao achieves an AUC of 0.613. CONCLUSIONS: Although some biomarkers are significantly associated with OS, the ability of these biomarkers for prognosing OS events is limited. Incorporating clinical risk factors, such as age, can greatly improve the prognostic performance.