Discovery of pyrimidine-2,4-diamine analogues as efficiency anticancer drug by targeting GTSE1.

A series of pyrimidine-2,4-diamine analogues were designed and synthesized. Their anticancer activity and the underlying mechanism against colorectal cancer (CRC) HCT116 cells and non-small cell lung cancer (NSCLC) A549 cells were investigated. The results demonstrated that the active compound Y18 significantly inhibited cancer cell proliferation by inducing robust cell cycle arrest and cell senescence through the persistence of DNA damage. Additionally, Y18 exhibited significant inhibitory effects on the adhesion, migration and invasion of cancer cells in vitro. Mechanistically, Y18 achieved these anticancer activities by suppressing GTSE1 transcription and expression. Y18 also effectively inhibited tumor growth in vivo with minimal side effects. Furthermore, Y18 exhibited a suitable half-life and oral bioavailability (16.27%), with limited inhibitory activity on CYP isoforms. Taken together, these results suggested that Y18 could be a potential chemotherapeutic drug for cancer treatment, particularly in cases of GTSE1 overexpressed cancers.

Identification of inflammatory response-related molecular mechanisms based on the ATM/ATR/p53 pathway in tumor cells.

Inflammatory response is a crucial factor that affects prognosis and therapeutic effect in tumor cells. Although some studies have shown that inflammation could make DNA more vulnerable to external attacks, resulting in serious DNA damage, the underlying mechanism remains unknown. Then, using tumor necrosis factor α (TNF-α) and lipopolysaccharide (LPS), this research elevated the level of inflammation in cancer cells, and hydrogen peroxide (H2O2) and ultraviolet (UV) were utilized as common reactive oxygen species (ROS)-induced DNA damage agents. We show that either H2O2 or UV achieved a more substantial antiproliferative effect in the inflammation environment compared with H2O2 or UV treatment alone. The inflammation environment enhanced H2O2- or UV-induced cell apoptosis and ROS production. Although the phenomenon that inflammation itself could trigger ROS-dependent DNA damage was well known, the underlying mechanism for the sensitization of inflammation to trigger intense DNA damage via ROS in cancer cells remains unclear. In this study, the inflammation-related genes and the corresponding expression information were obtained from the TCGA and fetched genes associated with inflammatory factors. Screening of thirteen inflammatory-related, including ATM, and prognostic genes. In addition, KEGG analysis of prognostic genes shows that biological processes such as DNA replication. ATM and ATR, which belong to the PI3/PI4-kinase family, can activate p53. Inflammation promotes the vulnerability of DNA by activating the ATM/ATR/p53 pathway, while not affecting the DNA damage repair pathway. In brief, this research suggested that inflammation made DNA vulnerable due to the amplifying H2O2- or UV-induced ROS production and the motoring ATM/ATR/p53 pathway. In addition, our findings revealed that inflammation's motoring of the ATM/ATR/p53 pathway plays a crucial role in DNA damage. Therefore, exploring the mechanism between inflammation and ROS-dependent DNA damage would be extremely valuable and innovative. This study would somewhat establish a better understanding of inflammation, DNA damage, and cancer.

H2O2 promotes photodynamic efficacy of TMPyP4 against ovarian cancer in vitro by downregulating HIF-1α expression.

Photodynamic therapy (PDT), employing photosensitizers to induce formation of reactive oxygen species (ROS) for tumor elimination, is emerging as a promising treatment modality in oncology due to its unique benefits. However, the PDT application in ovarian cancer, the most prevalent and lethal type of gynecological malignancy with a severe hypoxic microenvironment, remains unknown. This study revealed that photosensitizer TMPyP4 exhibited enhanced efficacy under H2O2 stimulation, with minimal change in cytotoxicity compared to TMPyP4 alone. The results showed that H2O2 increased ROS production induced by TMPyP4, leading to exacerbated mitochondrial dysfunction and DNA damage, ultimately inhibiting proliferation and inducing apoptosis in ovarian cancer cells. Mechanistically, H2O2 primarily enhanced the therapeutic efficacy of PDT with TMPyP4 against ovarian cancer cells by degrading HIF-1α, which subsequently modulated the HIF-1 signaling pathway, thereby alleviating the hypoxic environment in ovarian cancer cells. Our findings underscore the therapeutic potential of targeting HIF-1α within the hypoxic microenvironment for PDT in ovarian cancer and propose a novel integrated strategy for PDT treatment of this malignancy in vitro.

Comprehensive Proteogenomic Profiling Reveals the Molecular Characteristics of Colorectal Cancer at Distinct Stages of Progression.

Colorectal cancer is the second most common malignant tumor worldwide. Analysis of the changes that occur during colorectal cancer progression could provide insights into the molecular mechanisms driving colorectal cancer development and identify improved treatment strategies. In this study, we performed an integrated multiomic analysis of 435 trace tumor samples from 148 patients with colorectal cancer, covering nontumor, intraepithelial neoplasia (IEN), infiltration, and advanced stage colorectal cancer phases. Proteogenomic analyses demonstrated that KRAS and BRAF mutations were mutually exclusive and elevated oxidative phosphorylation in the IEN phase. Chr17q loss and chr20q gain were also mutually exclusive, which occurred predominantly in the IEN and infiltration phases, respectively, and impacted the cell cycle. Mutations in TP53 were frequent in the advanced stage colorectal cancer phase and associated with the tumor microenvironment, including increased extracellular matrix rigidity and stromal infiltration. Analysis of the profiles of colorectal cancer based on consensus molecular subtype and colorectal cancer intrinsic subtype classifications revealed the progression paths of each subtype and indicated that microsatellite instability was associated with specific subtype classifications. Additional comparison of molecular characteristics of colorectal cancer based on location showed that ANKRD22 amplification by chr10q23.31 gain enhanced glycolysis in the right-sided colorectal cancer. The AOM/DSS-induced colorectal cancer carcinogenesis mouse model indicated that DDX5 deletion due to chr17q loss promoted colorectal cancer development, consistent with the findings from the patient samples. Collectively, this study provides an informative resource for understanding the driving events of different stages of colorectal cancer and identifying the potential therapeutic targets. Significance: Characterization of the proteogenomic landscape of colorectal cancer during progression provides a multiomic map detailing the alterations in each stage of carcinogenesis and suggesting potential diagnostic and therapeutic approaches for patients.

P4HA2 promotes tumor progression and is transcriptionally regulated by SP1 in colorectal cancer.

P4HA2 has been implicated in various malignant tumors; however, its expression and functional role in colorectal cancer (CRC) remain poorly elucidated. This study aims to investigate the involvement of P4HA2 in CRC metastasis and progression, uncovering the underlying mechanisms. In colorectal cancer (CRC), P4HA2 exhibited overexpression, and elevated levels of P4HA2 expression were associated with an unfavorable prognosis. Functional assays demonstrated P4HA2's regulation of cell proliferation, and epithelial-mesenchymal transition (EMT) both in vitro and in vivo. Additionally, the AGO1 expression was correlated with P4HA2, and depletion of AGO1 reversed the proliferation and EMT function induced by P4HA2. Chromatin immunoprecipitation (ChIP) and luciferase assays suggested that the transcription factor SP1 binds to the promoter sequence of P4HA2, activating its expression in CRC. This study unveiled SP1 as a transcriptional regulator of P4HA2 in CRC and AGO1 is a probable target of P4HA2. In conclusion, P4HA2 emerges as a potential prognostic biomarker and promising therapeutic target in colorectal cancer.

Aspirin-Mediated Acetylation of SIRT1 Maintains Intestinal Immune Homeostasis.

Aspirin, also named acetylsalicylate, can directly acetylate the side-chain of lysine in protein, which leads to the possibility of unexplained drug effects. Here, the study used isotopic-labeling aspirin-d3 with mass spectrometry analysis to discover that aspirin directly acetylates 10 HDACs proteins, including SIRT1, the most studied NAD+-dependent deacetylase. SIRT1 is also acetylated by aspirin in vitro. It is also identified that aspirin directly acetylates lysine 408 of SIRT1, which abolishes SIRT1 deacetylation activity by impairing the substrates binding affinity. Interestingly, the lysine 408 of SIRT1 can be acetylated by CBP acetyltransferase in cells without aspirin supplement. Aspirin can inhibit SIRT1 to increase the levels of acetylated p53 and promote p53-dependent apoptosis. Moreover, the knock-in mice of the acetylation-mimic mutant of SIRT1 show the decreased production of pro-inflammatory cytokines and maintain intestinal immune homeostasis. The study indicates the importance of the acetylated internal functional site of SIRT1 in maintaining intestinal immune homeostasis.

Unveiling NRlncRNAs as prognostic biomarkers and therapeutic targets for head-and-neck squamous cell carcinoma through machine learning.

Head-and-neck squamous cell carcinoma (HNSCC) patients often exhibit insensitivity to immunotherapy, leading to treatment failure. Identifying potential biomarkers that can predict prognosis and improve the efficacy of treatment is crucial. In this study, we aimed to identify necroptosis-related long noncoding RNAs (NRlncRNAs) as potential therapeutic targets to improve the prognosis of HNSCC patients. By exploring the Genotype-Tissue Expression Project (GTEx) and the Cancer Genome Atlas (TCGA) databases, we identified NRlncRNAs and developed a risk model comprising 17 NRlncRNAs to predict the prognosis of HNSCC patients and to classify patients into two clusters based on their expression levels. We conducted various analyses, such as the Kaplan-Meier analysis, GSEA and IC50 prediction, to evaluate the differences in sensitivity to immunotherapy between the two clusters. Our findings suggest that NRlncRNAs have potential as therapeutic targets for improving the prognosis of HNSCC patients, and that individualized treatment approaches based on NRlncRNA expression levels can improve the sensitivity of immunotherapy and overall treatment outcomes. This study highlights new perspectives within clinical cancer informatics and provides insight into potential therapeutic strategies for HNSCC patients.

Unravelling chilling-stress resistance mechanisms in endangered Mangrove plant Lumnitzera littorea (Jack) Voigt.

Lumnitzera littorea (Jack) Voigt is one of the most endangered mangrove species in China. Previous studies have showed the impact of chilling stress on L. littorea and the repsonses at physiological and biochemical levels, but few attentions have been paid at molecular level. In this study, we conducted genome-wide investigation of transcriptional and post-transcriptional dynamics in L. littorea in response to chilling stress (8 °C day/5 °C night). In the seedlings of L. littorea, chilling sensing and signal transducing, photosystem II regeneration and peroxidase-mediated reactive oxygen species (ROS) scavenging were substantially enhanced to combat the adverse impact induced by chilling exposure. We further revealed that alternative polyadenylation (APA) events participated in chilling stress-responsive processes, including energy metabolism and steroid biosynthesis. Furthermore, APA-mediated miRNA regulations downregulated the expression of the genes involved in fatty acid biosynthesis and elongation, and protein phosphorylation, reflecting the important role of post-transcriptional regulation in modulating chilling tolerance in L. littorea. Our findings present a molecular view to the adaptive characteristics of L. littorea and shed light on the conservation genomic approaches of endangered mangrove species.

CERCAM is a prognostic biomarker associated with immune infiltration of macrophage M2 polarization in head and neck squamous carcinoma.

PURPOSE: This study aimed to investigate the relevance of cerebral endothelial cell adhesion molecule (CERCAM) expression to head and neck squamous cell carcinoma (HNSCC) prognosis and immune infiltration by macrophage M2 polarization. METHODS: Timer, UALCAN and HPA databases was used to analyze the differences in mRNA and protein levels of CERCAM expression in HNSCC. The Timer database was also applied to analyze the correlation between CERCAM in HNSCC and immune infiltration. TCGA-HNSCC database was applied to analyze the correlation between CERCAM expression levels and clinicopathological features, and its diagnostic and prognostic value in HNSCC was also assessed. The cBioPortal and MethSurv databases were then applied to analyze the genetic variation and methylation status of CERCAM. In vitro cellular assays were performed to provide evidence that CERCAM promotes malignant biological behavior of tumors and promotes macrophage M2 polarization in tumors. Finally, underlying pathophysiological mechanisms of CERCAM involvement in the development of HNSCC were predicted using a bioinformatics approach. RESULTS: CERCAM is significantly overexpressed in HNSCC and correlates with poor prognostic levels and has good performance in predicting survival status in HNSCC patients. Cox regression analysis indicates that CERCAM expression levels are independent risk factors for predicting OS, DSS, and PFI. CERCAM promotes tumor malignant biological behavior and promotes macrophage M2 polarization immune infiltration in HNSCC. In addition, CERCAM promotes tumor cell adhesion in head and neck squamous carcinoma and promotes tumor progression through several oncogenic signaling pathways. CONCLUSION: CERCAM may serve as a new diagnostic and prognostic biomarker in HNSCC and is a promising therapeutic target for HNSCC.

Arsenic speciation in freshwater fish: challenges and research needs.

Food and water are the main sources of human exposure to arsenic. It is important to determine arsenic species in food because the toxicities of arsenic vary greatly with its chemical speciation. Extensive research has focused on high concentrations of arsenic species in marine organisms. The concentrations of arsenic species in freshwater fish are much lower, and their determination presents analytical challenges. In this review, we summarize the current state of knowledge on arsenic speciation in freshwater fish and discuss challenges and research needs. Fish samples are typically homogenized, and arsenic species are extracted using water/methanol with the assistance of sonication and enzyme treatment. Arsenic species in the extracts are commonly separated using high-performance liquid chromatography (HPLC) and detected using inductively coupled plasma mass spectrometry (ICPMS). Electrospray ionization tandem mass spectrometry, used in combination with HPLC and ICPMS, provides complementary information for the identification and characterization of arsenic species. The methods and perspectives discussed in this review, covering sample preparation, chromatography separation, and mass spectrometry detection, are directed to arsenic speciation in freshwater fish and applicable to studies of other food items. Despite progress made in arsenic speciation analysis, a large fraction of the total arsenic in freshwater fish remains unidentified. It is challenging to identify and quantify arsenic species present in complex sample matrices at very low concentrations. Further research is needed to improve the extraction efficiency, chromatographic resolution, detection sensitivity, and characterization capability.

Amorphous Transparent Cu(S,I) Thin Films with Very High Hole Conductivity.

Amorphous transparent conductors (a-TCs) are key materials for flexible and transparent electronics but still suffer from poor p-type conductivity. By developing an amorphous Cu(S,I) material system, record high hole conductivities of 103-104 S cm-1 have been achieved in p-type a-TCs. These high conductivities are comparable with commercial n-type TCs made of indium tin oxide and are 100 times greater than any previously reported p-type a-TCs. Responsible for the high hole conduction is the overlap of large p-orbitals of I- and S2- anions, which provide a hole transport pathway insensitive to structural disorder. In addition, the bandgap of amorphous Cu(S,I) can be modulated from 2.6 to 2.9 eV by increasing the iodine content. These unique properties demonstrate that the Cu(S,I) system holds great potential as a promising p-type amorphous transparent electrode material for optoelectronics.

Quantifying the spatial spillover effects of non-pharmaceutical interventions on pandemic risk.

BACKGROUND: Non-pharmaceutical interventions (NPIs) implemented in one place can affect neighboring regions by influencing people's behavior. However, existing epidemic models for NPIs evaluation rarely consider such spatial spillover effects, which may lead to a biased assessment of policy effects. METHODS: Using the US state-level mobility and policy data from January 6 to August 2, 2020, we develop a quantitative framework that includes both a panel spatial econometric model and an S-SEIR (Spillover-Susceptible-Exposed-Infected-Recovered) model to quantify the spatial spillover effects of NPIs on human mobility and COVID-19 transmission. RESULTS: The spatial spillover effects of NPIs explain [Formula: see text] [[Formula: see text] credible interval: 52.8-[Formula: see text]] of national cumulative confirmed cases, suggesting that the presence of the spillover effect significantly enhances the NPI influence. Simulations based on the S-SEIR model further show that increasing interventions in only a few states with larger intrastate human mobility intensity significantly reduce the cases nationwide. These region-based interventions also can carry over to interstate lockdowns. CONCLUSIONS: Our study provides a framework for evaluating and comparing the effectiveness of different intervention strategies conditional on NPI spillovers, and calls for collaboration from different regions.

Dramatic decline of observed atmospheric CO2 and CH4 during the COVID-19 lockdown over the Yangtze River Delta of China.

The temporal variation of greenhouse gas concentrations in China during the COVID-19 lockdown in China is analyzed in this work using high resolution measurements of near surface △CO2, △CH4 and △CO concentrations above the background conditions at Lin'an station (LAN), a regional background station in the Yangtze River Delta region. During the pre-lockdown observational period (IOP-1), both △CO2 and △CH4 exhibited a significant increasing trend relative to the 2011-2019 climatological mean. The reduction of △CO2, △CH4 and △CO during the lockdown observational period (IOP-2) (which also coincided with the Chinese New Year Holiday) reached up to 15.0 ppm, 14.2 ppb and 146.8 ppb, respectively, and a reduction of △CO2/△CO probably due to a dramatic reduction from industrial emissions. △CO2, △CH4 and △CO were observed to keep declining during the post-lockdown easing phase (IOP-3), which is the synthetic result of lower than normal CO2 emissions from rural regions around LAN coupled with strong uptake of the terrestrial ecosystem. Interestingly, the trend reversed to gradual increase for all species during the later easing phase (IOP-4), with △CO2/△CO constantly increasing from IOP-2 to IOP-3 and finally IOP-4, consistent with recovery in industrial emissions associated with the staged resumption of economic activity. On average, △CO2 declined sharply throughout the days during IOP-2 but increased gradually throughout the days during IOP-4. The findings showcase the significant role of emission reduction in accounting for the dramatic changes in measured atmospheric △CO2 and △CH4 associated with the COVID-19 lockdown and recovery.

Expedient delivery of quinolinone drugs via a traceless N-nitroso enabled oxidative Heck/amidation cascade.

The exploration of green C-H oxidation for the rapid construction of functional molecules, remains a permanent goal in synthetic chemistry. Herein, a traceless N-nitroso enabled oxidative Heck and amidation cascade was realized, leading to quinolinones that feature green oxidation and great functional group tolerance. The expedient construction of quinolinone containing pharmaceuticals including Flucarbril, Clostamide and Aripiprazole was achieved in a concise and environmentally friendly manner.

Preparation and mechanism of lightweight wood fiber/poly(lactic acid) composites.

The high density and poor thermal insulation of traditional wood-plastic composites limited the application in the field of building materials. In this paper, wood fiber (WF) and PLA were used as raw materials and azodicarbonamide was used as the foaming agent. Lightweight WF/PLA composites were prepared by the hot-pressing foaming method, aiming to obtain renewable, low-density material with high strength-to-weight ratio and thermal insulation performance. The results showed that after adding 20 % WF into PLA, the cell morphology was excellent and the cell size was uniform. The magnification reached the minimum value of 0.36 g/cm3 and the foaming magnification was 3.42 times. The impact strength and compressive strength were 3.16 kJ/m3 and 4.12 MPa, its comprehensive mechanical properties were outstanding. The thermal conductivity of foamed materials was 0.110-0.148 (W/m·K), which was significantly lower than that of unfoamed materials and common wood. Its excellent mechanical properties and thermal insulation can be suitable for application in the construction field to replace traditional wood.

Solar-assisted self-heating Ti3C2Tx-decorated wood aerogel for adsorption and recovery of highly viscous crude oil.

Frequent oil-spill accidents have posed serious threats to ecosystem balance and the efficiency of resources use. Hydrophobic adsorbents that can adsorb and recover oil without causing secondary pollution are ideal candidates for the remediation of oil contamination in water. However, these composites are inefficient for crude oil-spills cleanup because crude oil has low liquidity of at room temperature. Increasing the temperature can effectively enhance the flowability of crude oil. To achieve efficient crude-oil heating and removal in situ, wood aerogels were immersed in Ti3C2Tx suspensions and then coated with polydimethylsiloxane (PDMS) to obtain a solar-heated adsorbent (PT-WA). The prepared PT-WA exhibits super-hydrophobicity (water contact angle: 154° ± 2°), mechanical robustness (withstanding 20 loading-unloading cycles under 50% strain without structural damage), strong solar absorption, and favorable photothermal-conversion capability (rising to ~85 °C within 90 s under 1.5 sun). Owing to these advantages, PT-WA is an effective adsorbent for crude oil cleanup. In addition, a 'self-heating crude oil collector' was assembled for the fast adsorption and restoration of crude oil from the water surface. This solar-assisted self-heating sorbent offers a competitive platform for the cleanup and recycling of viscous crude oil spills.

Comparison of Properties of Poly(Lactic Acid) Composites Prepared from Different Components of Corn Straw Fiber.

In recent years, under the pressure of resource shortage and white pollution, the development and utilization of biodegradable wood-plastic composites (WPC) has become one of the hot spots for scholars' research. Here, corn straw fiber (CSF) was chosen to reinforce a poly(lactic acid) (PLA) matrix with a mass ratio of 3:7, and the CSF/PLA composites were obtained by melt mixing. The results showed that the mechanical properties of the corn straw fiber core (CSFC) and corn straw fiber skin (CSFS) loaded PLA composites were stronger than those of the CSFS/PLA composites when the particle size of CSF was low. The tensile strength and bending strength of CSFS/CSFC/PLA are 54.08 MPa and 87.24 MPa, respectively, and the elongation at break is 4.60%. After soaking for 8 hours, the water absorption of CSF/PLA composite reached saturation. When the particle size of CSF is above 80 mesh, the saturated water absorption of the material is kept below 7%, and CSF/PLA composite has good hydrophobicity, which is mainly related to the interfacial compatibility between PLA and CSF. By observing the microstructure of the cross section of the CSF/PLA composite, the research found that the smaller the particle size of CSF, the smoother the cross section of the composite and the more unified the dispersion of CSF in PLA. Therefore, exploring the composites formed by different components of CSF and PLA can not only expand the application range of PLA, but also enhance the application value of CSF in the field of composites.

Different human papillomavirus types share early natural history transitions in immunocompetent women.

Necessary stages of cervical carcinogenesis include acquisition of a carcinogenic human papillomavirus (HPV) type, persistence associated with the development of precancerous lesions, and invasion. Using prospective data from immunocompetent women in the Guanacaste HPV Natural History Study (NHS), the ASCUS-LSIL Triage Study (ALTS) and the Costa Rica HPV Vaccine Trial (CVT), we compared the early natural history of HPV types to inform transition probabilities for health decision models. We excluded women with evidence of high-grade cervical abnormalities at any point during follow-up and restricted the analysis to incident infections in all women and prevalent infections in young women (aged <30 years). We used survival approaches accounting for interval-censoring to estimate the time to clearance distribution for 20 529 HPV infections (64% were incident and 51% were carcinogenic). Time to clearance was similar across HPV types and risk classes (HPV16, HPV18/45, HPV31/33/35/52/58, HPV 39/51/56/59 and noncarcinogenic HPV types); and by age group (18-29, 30-44 and 45-54 years), among carcinogenic and noncarcinogenic infections. Similar time to clearance across HPV types suggests that relative prevalence can predict relative incidence. We confirmed that there was a uniform linear association between incident and prevalent infections for all HPV types within each study cohort. In the absence of progression to precancer, we observed similar time to clearance for incident infections across HPV types and risk classes. A singular clearance function for incident HPV infections has important implications for the refinement of microsimulation models used to evaluate the cost-effectiveness of novel prevention technologies.

Contribution of Etiologic Cofactors to CIN3+ Risk Among Women With Human Papillomavirus-Positive Screening Test Results.

OBJECTIVE: The US screening and management guidelines for cervical cancer are based on the absolute risk of precancer estimated from large clinical cohorts and trials. Given the widespread transition toward screening with human papillomavirus (HPV) testing, it is important to assess which additional factors to include in clinical risk assessment to optimize management of HPV-infected women. MATERIALS AND METHODS: We analyzed data from HPV-infected women, ages 30-65 years, in the National Cancer Institute-Kaiser Permanente Northern California Persistence and Progression study. We estimated the influence of HPV risk group, cytology result, and selected cofactors on immediate risk of cervical intraepithelial neoplasia grade 3 or higher (CIN 3+) among 16,094 HPV-positive women. Cofactors considered included, age, race/ethnicity, income, smoking, and hormonal contraceptive use. RESULTS: Human papillomavirus risk group and cytology test result were strongly correlated with CIN 3+ risk. After considering cytology and HPV risk group, other cofactors (age, race/ethnicity, income, smoking, and hormonal contraceptive use) had minimal impact on CIN 3+ risk and did not change recommended management based on accepted risk thresholds. We had insufficient data to assess the impact of long-duration heavy smoking, parity, history of sexually transmitted infection, or immunosuppression. CONCLUSIONS: In our study at the Kaiser Permanente Northern California, the risk of CIN 3+ was determined mainly by HPV risk group and cytology results, with other cofactors having limited impact in adjusted analyses. This supports the use of HPV and cytology results in risk-based management guidelines.