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Abstract Purpose Cervical cancer (CC), a significant global health threat, necessitates comprehensive understanding for improved therapeutic interventions. Many research indicates that dysregulation of the Hippo-YAP1 pathway leads to uncontrolled proliferation and invasion of tumor cells, promoting the progression of various cancers. This article aims to elucidate the role of RNF6 in CC and its regulation of the Hippo-YAP1 signaling pathway. Methods The public tumor dataset analyses, immunohistochemistry, and western blotting were used to explore the expression of RNF6 in CC. Gain- and loss-of-function assays were conducted to elucidate the role of RNF6 in the proliferation and invasion of CC cells. Transcriptome sequencing was used to explore RNF6’s role in cervical cancer, with validation of its regulation of the Hippo-YAP1 pathway through western blotting and RT-qPCR. Co-transfection of YAP overexpression plasmids into RNF6-silenced CC cells were preformed to confirm YAP1’s pivotal role in RNF6-mediated CC progression. Animal experiments were preformed to further validate RNF6 interference’s inhibitory effect on CC proliferation in vivo. Results Clinical samples and bioinformatics analysis revealed high expression of RNF6 in CC, and closely associated with advanced FIGO (International Federation of Gynecology and Obstetrics) stage, larger tumor size, and poor prognosis. Cellular functional experiments demonstrate that RNF6 promotes the proliferation, invasion, and migration of CC cells, while knockdown of RNF6 yields the opposite effect. Transcriptome sequencing further reveals that RNF6 may promote CC progression through the Hippo-YAP signaling pathway. Western blotting and RT-qPCR further unveil that RNF6 enhances the upregulation of YAP1 protein levels, thereby activating downstream oncogenes CTGF and CYR61 transcription. Additionally, exogenous overexpression of YAP1 reverses the inhibitory effect of RNF6 silencing on CC proliferation and invasion. Furthermore, RNF6 interference significantly attenuates tumor growth in vivo experiments. Conclusion Our research reveals that RNF6 is highly expressed in CC, driving malignant progression by upregulating YAP1 protein expression and enhancing the transcription of downstream target genes CTGF and CYR61, offering potential therapeutic targets for CC treatment.

Abstract Despite the importance of radiation therapy as a nonsurgical treatment for non-small cell lung cancer (NSCLC), radiation resistance has always been a concern because of poor patient response and outcomes. Therefore, it is crucial to identify novel targets to increase the effectiveness of radiotherapy and investigate the mechanisms underlying radioresistance. Previously, we demonstrated that Spindlin 1 (SPIN1) was related to tumour initiation and progression. In this study, we found that SPIN1 expression was higher in NSCLC tissues and cell lines than in the corresponding controls. SPIN1 overexpression in NSCLC patients was closely correlated with disease progression and poor prognosis. Functionally, SPIN1 depletion inhibited cell proliferation, decreased the percentage of cells in the G2/M phase and suppressed cell migration and invasion. Moreover, SPIN1 knockdown decreased the clonogenic capacity, impaired double-strand break (DSB) repair and increased NSCLC radiosensitivity. Mechanistically, forkhead box M1 (FOXM1) was identified as a key downstream effector of SPIN1 in NSCLC cells. Furthermore, SPIN1 was found to facilitate MDM2-mediated FOXO3a ubiquitination and degradation, leading to FOXM1 upregulation. Moreover, restoration of FOXM1 expression markedly abolished the inhibitory effects and increased radiosensitivity induced by SPIN1 depletion. These results indicate that the SPIN1-MDM2-FOXO3a/FOXM1 signalling axis is essential for NSCLC progression and radioresistance and could serve as a therapeutic target for increasing radiotherapy efficacy.

This study delves into the design and deformation patterns of support structures in urban deep excavation projects, aiming to optimize the design of these structures to ensure their safety and stability. Initially, experimental research on steel-cement soil composite beams reveals their bending resistance and ductility under various loading conditions, confirming the effectiveness of the Soil Mixing Wall method in enhancing the stability of support structures. Subsequently, theoretical calculations using the method of elastic support points were conducted and validated through a deep excavation project in Xi’an, demonstrating that this method accurately calculates the trends of horizontal displacement in support structures. Additionally, FLAC3D numerical simulations are utilized to analyze the patterns of horizontal and vertical displacement during the excavation process. The simulation results generally align with the actual measured data, showing that the support structures optimized by the elastic support points method effectively control horizontal displacement (maximum displacement of 47.8 mm) and vertical displacement (maximum heave of 67.3 mm), validating the effectiveness of the numerical simulation methods. This research not only provides theoretical and practical guidance for deep excavation projects but also holds significant reference value for the design and construction of similar engineering projects.

Previous studies have demonstrated that carbohydrate sulfotransferase family proteins (CHSTs) play a crucial role in the extracellular matrix structural constituent and cancer progression, however, the effect of CHSTs on gastric cancer is still superficial. To investigate these, our study seeks to provide a comprehensive understanding of CHSTs' expression, immune infiltration, and prognostic implications in gastric cancer, utilizing data from the TCGA, GEO and GTEx databases. Furthermore, we conducted experimental validation to elucidate the role of CHST14 specifically in gastric cancer. Our findings suggest that most CHSTs were highly expressed in gastric cancer. Gene copy number variations further indicated prevalent CHSTs amplification in gastric cancer, pointing to its potential relevance in disease progression. Intriguingly, we noted strong positive correlations between most CHSTs and immune cell infiltration. Importantly, most members of CHSTs were related to OS and PFI with gastric cancer, with particular emphasis on CHST14 and CHST9. Multifactorial regression analysis indicates that CHST14 is an independent prognostic factor influencing the overall survival of gastric cancer patients. In further experimental validation, our results demonstrate elevated expression of CHST14 in gastric cancer, and knocking down CHST14 inhibits gastric cancer cell proliferation, invasion, migration and EMT. Additionally, CHST14 may exert its function through the regulation of the Wnt pathway. In summary, our study comprehensively analyzes the hitherto undescribed role of CHSTs in gastric cancer through the analysis of multi-omics data. Importantly, we identify CHST14 as a pivotal promoter in the malignant progression of gastric cancer, offering potential targets for gastric cancer therapy.

Summary: Immune suppression within tumor microenvironments (TME) have been implicated in limited efficacy of immune check point inhibitors (ICIs) against solid tumors. Down-regulated VentX expression in tumor associated macrophages (TAMs) underlies phagocytotic anergic phenotype of TAMs, which govern immunological state of TME. In this study, using a tumor immune microenvironment enabling model system (TIME-EMS) of non-small cell lung cancer (NSCLC), we found that PD-1 antibody modestly activates cytotoxic T lymphocytes (CTLs) within the NSCLC-TME but not the status of TIME. We showed that the restoration of VentX expression in TAMs reignites the phagocytotic function of TAMs, which in turn, transforms TIME, activates CTLs in a tumor-specific manner and promotes efficacy of PD-1 antibody against NSCLC but not toxicity on normal lung epithelial cells. Supported by in vivo data on NSG-PDX models of primary human NSCLC, our study revealed potential venues to promote the efficacy of ICI against solid tumors through VentX-based mechanisms.

Extracellular vesicles (EVs), which play significant regulatory roles in maintaining homeostasis and influencing immune responses, significantly impact gut microbiota composition and function, affecting overall gut health. Despite considerable progress, there are still knowledge gaps regarding the mechanisms by which EVs, including plant-derived EVs (PDEVs), animal-derived EVs (ADEVs), and microbiota-derived EVs (MDEVs), modulate gut health. This review delves into the roles and mechanisms of EVs from diverse sources in regulating gut health, focusing on their contributions to maintaining epithelial barrier integrity, facilitating tissue healing, eliciting immune responses, controlling pathogens, and shaping microbiota. We emphasize open challenges and future perspectives for harnessing EVs in the modulation of gut health to gain a deeper understanding of their roles and impact. Importantly, a comprehensive research framework is presented to steer future investigations into the roles and implications of EVs on gut health, facilitating a more profound comprehension of this emerging field.

Abstract Background Large tumor suppressor kinase 1 (LATS1), one of the predominant components of the Hippo pathway, has been characterized as a key player controlling the proliferation and invasion of cancer cells, including gastric cancer (GC) cells. However, the mechanism by which the functional stability of LATS1 is modulated has yet to be elucidated. Methods Online prediction tools, immunohistochemistry and western blotting assays were used to explore the expression of WW domain-containing E3 ubiquitin ligase 2 (WWP2) in GC cells and tissues. Gain- and loss-of-function assays, as well as rescue experiments were performed to determine the role of the WWP2-LATS1 axis in cell proliferation and invasion. Additionally, the mechanisms involving WWP2 and LATS1 were assessed by coimmunoprecipitation (Co-IP), immunofluorescence, cycloheximide and in vivo ubiquitination assays. Results Our results demonstrate a specific interaction between LATS1 and WWP2. WWP2 was markedly upregulated and correlated with disease progression and a poor prognosis in GC patients. Moreover, ectopic WWP2 expression facilitated the proliferation, migration and invasion of GC cells. Mechanistically, WWP2 interacts with LATS1, resulting in its ubiquitination and subsequent degradation, leading to increased transcriptional activity of YAP1. Importantly, LATS1 depletion abolished the suppressive effects of WWP2 knockdown on GC cells. Furthermore, WWP2 silencing attenuated tumor growth by regulating the Hippo-YAP1 pathway in vivo. Conclusions Our results define the WWP2-LATS1 axis as a critical regulatory mechanism of the Hippo-YAP1 pathway that promotes GC development and progression. Video Abstract

This paper described our efforts to develop dianilinopyrimidines as novel EGFR inhibitors. All the target compounds were tested for inhibitory effects against wild type EGFR (EGFRwt) and three tumour cells, including A549, PC-3, and HepG2. Some of the compounds performed well in antitumor activities. Especially, compound 4c 2-((2-((4-(3-fluorobenzamido)phenyl)amino)-5-(trifluoromethyl) pyrimidin-4-yl)amino)-N-methylthiophene-3-carboxamide showed higher anti-tumour activities than Gefitinib. The IC50 values of compound 4c against A549, PC-3, and HepG2. reached 0.56 μM, 2.46 μM, and 2.21 μM, respectively. In addition, further studies indicated that compound 4c could induce apoptosis against A549 cells and arrest A549 cells in the G2/M phase. Molecular docking studies showed that compound 4c could closely interact with EGFR. Generally, compound 4c was the potential for developing into an anti-tumour drug.

A new series of 5-trifluoromethylpyrimidine derivatives were designed and synthesised as EGFR inhibitors. Three tumour cells A549, MCF-7, PC-3 and EGFR kinase were employed to evaluate their biological activities. The results were shown that most of the target compounds existed excellent antitumor activities. In particular, the IC50 values of compound 9u (E)-3-((2-((4-(3-(3-fluorophenyl)acrylamido)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)amino)-N-methylthiophene-2-carboxamide against A549, MCF-7, PC-3 cells and EGFR kinase reached to 0.35 μM, 3.24 μM, 5.12 μM, and 0.091 μM, respectively. Additionally, further researches revealed that compound 9u could induce early apoptosis of A549 cells and arrest the cells in G2/M phase. Taken together, these findings indicated that compound 9u was potential for developing as antitumor reagent.

Chlorella pyrenoidosa (C. pyrenoidosa) has been widely used in commercial food and feed production for numerous years. Its high protein content and cost-effectiveness make it an attractive source of novel protein. With a focus on sustainable development and the search for green natural products, current research is dedicated to maximizing the utilization of C. pyrenoidosa protein (CPP) and peptide. Various techniques, such as the use of ionic liquids, freeze–thawing, ultrasonication, enzyme digest, microwaving are employed in the extraction of CPP. The extracted CPP has demonstrated antioxidant, anti-inflammatory, and bacteriostatic properties. It can also stimulate immune regulation, prevent cardiovascular disease, protect red blood cells, and even be used in wastewater treatment. Furthermore, CPP has shown some potential in combating obesity. Additionally, CPP is being explored in three-dimensional (3D) printing applications, particularly for the creation of biological scaffolds. It is also anticipated to play a role in 3D food printing. This review aimed to supply a comprehensive summary of CPP and C. pyrenoidosa peptide extraction methods, their functions, and practical applications in various industries. By doing so, it seeks to underpin subsequent research efforts, highlight current research limitations, and identify future research directions in this field.

Summary: Limited therapeutic efficacy and severe side effects represent the central hurdles facing cancer chemotherapy. Immune suppression within tumor immune microenvironments (TIME) has been implicated in chemoresistance. In this study, using a TIME-enabling model system (TIME-EMS), we demonstrate that the chemotherapeutic agent doxorubicin has cytocidal effects on tumor cells at high dosage but induces changes in the immune landscape of the TIME at low noncytotoxic concentrations via NF-κB-mediated induction of homeobox protein VentX expression in tumor-associated macrophages (TAMs). We demonstrated that VentX-regulated TAMs drastically promote tumor chemosensitivity >10-fold but exert little effect on chemotoxicity to normal cells through activating cytotoxic T lymphocytes in a tumor-specific manner. Supported by the in vivo synergy of VentX-regulated TAMs and low-dosage noncytotoxic doxorubicin, our data suggest a cell-death-independent immune mechanism for improving the therapeutic index of chemotherapeutic agents.

Urbanization and climate change pose significant challenges to urban ecosystems, underscoring the necessity for innovative strategies to enhance urban green infrastructure. Tree planting, a crucial aspect of green infrastructure, has been analyzed for optimized positioning using data metrics, priority scoring, and GIS. However, due to the dynamic nature of environmental information, the accuracy of current approaches is compromised. This study aims to present a novel approach integrating deep learning and cellular automata to prioritize urban tree planting locations to anticipate the optimal urban tree network. Initially, GIS data were collated and visualized to identify a suitable study site within London. CycleGAN models were trained using cellular automata outputs and forest mycorrhizal network samples. The comparison validated cellular automata’s applicability, enabled observing spatial feature information in the outputs and guiding the parameter design of our 3D cellular automata system for predicting tree planting locations. The locations were optimized by simulating the network connectivity of urban trees after planting, following the spatial-behavioral pattern of the forest mycorrhizal network. The results highlight the role of robust tree networks in fostering ecological stability and cushioning climate change impacts in urban contexts. The proposed approach addresses existing methodological and practical limitations, providing innovative strategies for optimal tree planting and prioritization of urban green infrastructure, thereby informing sustainable urban planning and design. Our findings illustrate the symbiotic relationship between urban trees and future cities and offer insights into street tree density planning, optimizing the spatial distribution of trees within urban landscapes for sustainable urban development.

In this paper, a set of 3-methylquniazolinone derivatives were designed, synthesised, and studied the preliminary structure-activity relationship for antiproliferative activities. All target compounds performed significantly inhibitory effects against wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and tumour cells (A431, A549, MCF-7, and NCI-H1975). In particular, compound 4d 3-fluoro-N-(4-((3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methoxy)phenyl)benzamide showed higher antiproliferative activities against all tumour cells than Gefitinib (IC50 of 3.48, 2.55, 0.87 and 6.42 μM, respectively). Furthermore, compound 4d could induce apoptosis of MCF-7 cells and arrest in G2/M phase at the tested concentration. Molecular docking and ADMET studies showed that compound 4d could closely form many hydrogen bonds with EGFRwt-TK. Therefore, compound 4d is potential to develop as novel anti-cancer drug.

In this paper, a series of novel 3-methyl-quinazolinone derivatives was designed, synthesised and evaluated for antitumor activity in vitro on wild type epidermal growth factor receptor tyrosine kinase (EGFRwt-TK) and three human cancer cell lines including A549, PC-3, and SMMC-7721. The results displayed that some of the compounds had good activities, especially 2-{4-[(3-Fluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 g), 2-{4-[(3,4-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5k) and 2-{4-[(3,5-Difluoro-phenylimino)-methyl]-phenoxymethyl}-3-methyl-3H-quinazolin-4-one (5 l) showed high antitumor activities against three cancer cell lines. Moreover, compound 5k could induce late apoptosis of A549 cells at high concentrations and arrest cell cycle of A549 cells in the G2/M phase at tested concentrations. Also, compound 5k could inhibit the EGFRwt-TK with IC50 value of 10 nM. Molecular docking data indicates that the compound 5k may exert inhibitory activity by forming stable hydrogen bonds with the R817, T830 amino acid residues and cation-Π interaction with the K72 residue of EGFRwt-TK.

In some industrial embedded systems, functions with different safety integrity levels (SILs) are integrated into the same hardware platform to share resources, and usually, the schedulability of applications should be met first. Meanwhile, development costs' optimization of applications is also an important requirement, because some industries, such as automotive, are cost-sensitive for the mass market. To minimize the development costs of applications while satisfying their schedulability, an optimization method is presented based on a key path tabu search algorithm combined with a message movement strategy. The key path tabu search algorithm uses the tree-based tabu list to find a schedulable solution with low development cost. The message movement strategy is proposed to significantly reduce the development cost caused by the recursive elevation of the SILs of tasks for the sharing of partitions. The results of experiments using real-life benchmark and simulated benchmark show that the proposed method is effective.

Tumour associated macrophages (TAMs) polarize into either pro-tumor or anti-tumor phenotypes. Here the authors show that the homeobox protein VentX is downregulated in clinical samples of colorectal cancer and regulates TAMs plasticity with its forced re-expression converting TAMs into an anti-tumor phenotype.

Brainstem metastases offer a unique challenge in cancer treatment, yet stereotactic radiosurgery (SRS) has proven to be an effective modality in treating these tumors. This report discusses the clinical outcomes of patients with brainstem metastases treated at Indiana University with Gamma Knife (GK) radiosurgery from 2008 to 2016. 19 brainstem metastases from 14 patients who had follow-up brain imaging were identified. Median tumor volume was 0.04 cc (range: 0.01–2.0 cc). Median prescribed dose was 17.5 Gy to the 50% isodose line (range: 14–22 Gy). Median survival after GK SRS treatment to brainstem lesion was 17.2 months (range: 2.8–45.6 months). The experience at Indiana University confirms the safety and efficacy of range of GK SRS prescription doses (14–22 Gy) to brainstem metastases.

Background: Although aminoglycosides are often used as treatment for Gram-negative infections, optimal dosing regimens remain unclear, especially in ICU patients. This is due to a large between- and within-subject variability in the aminoglycoside pharmacokinetics in this population. Objective: This review provides comprehensive data on the pharmacokinetics of aminoglycosides in patients hospitalized in the ICU by summarizing all published PopPK models in ICU patients for amikacin, gentamicin, and tobramycin. The objective was to determine the presence of a consensus on the structural model used, significant covariates included, and therapeutic targets considered during dosing regimen simulations. Method: A literature search was conducted in the Medline/PubMed database, using the terms: ‘amikacin’, ‘gentamicin’, ‘tobramycin’, ‘pharmacokinetic(s)’, ‘nonlinear mixed effect’, ‘population’, ‘intensive care’, and ‘critically ill’. Results: Nineteen articles were retained where amikacin, gentamicin, and tobramycin pharmacokinetics were described in six, 11, and five models, respectively. A two-compartment model was used to describe amikacin and tobramycin pharmacokinetics, whereas a one-compartment model majorly described gentamicin pharmacokinetics. The most recurrent significant covariates were renal clearance and bodyweight. Across all aminoglycosides, mean interindividual variability in clearance and volume of distribution were 41.6% and 22.0%, respectively. A common consensus for an optimal dosing regimen for each aminoglycoside was not reached. Conclusions: This review showed models developed for amikacin, from 2015 until now, and for gentamicin and tobramycin from the past decades. Despite the growing challenges of external evaluation, the latter should be more considered during model development. Further research including new covariates, additional simulated dosing regimens, and external validation should be considered to better understand aminoglycoside pharmacokinetics in ICU patients.

The ability of corals to withstand changes in their surroundings is a critical survival mechanism for coping with environmental stress. While many studies have examined responses of the coral holobiont to stressful conditions, its capacity to reverse responses and recover when the stressor is removed is not well-understood. In this study, we investigated among-colony responses of Pocillopora acuta from two sites with differing distance to the mainland (Kusu (closer to the mainland) and Raffles Lighthouse (further from the mainland)) to heat stress through differential expression analysis of target genes and quantification of photophysiological metrics. We then examined how these attributes were regulated after the stressor was removed to assess the recovery potential of P. acuta. The fragments that were subjected to heat stress (2 °C above ambient levels) generally exhibited significant reduction in their endosymbiont densities, but the extent of recovery following stress removal varied depending on natal site and colony. There were minimal changes in chl a concentration and maximum quantum yield (Fv/Fm, the proportion of variable fluorescence (Fv) to maximum fluorescence (Fm)) in heat-stressed corals, suggesting that the algal endosymbionts’ Photosystem II was not severely compromised. Significant changes in gene expression levels of selected genes of interest (GOI) were observed following heat exposure and stress removal among sites and colonies, including Actin, calcium/calmodulin-dependent protein kinase type IV (Camk4), kinesin-like protein (KIF9), and small heat shock protein 16.1 (Hsp16.1). The most responsive GOIs were Actin, a major component of the cytoskeleton, and the adaptive immune-related Camk4 which both showed significant reduction following heat exposure and subsequent upregulation during the recovery phase. Our findings clearly demonstrate specific responses of P. acuta in both photophysiological attributes and gene expression levels, suggesting differential capacity of P. acuta corals to tolerate heat stress depending on the colony, so that certain colonies may be more resilient than others.

Aqueous extract of Aconitum carmichaeli Debx is fermented by saccharomyces cerevisiae where the transformations in alkaloids are analyzed with HPLC. In the yeast-fermented Aconitum chloroform extract, the content of hypaconitine is lessened from 63.6% to 14.8%; the content of songorine increases from 7.5% to 34.5% in relation to original Aconitum. In tail clip test on mice, both original (ED50, 0.25 ± 0.04 mg/kg) and yeast- fermented Aconitum (ED50, 0.44 ± 0.12 mg/kg) showed a potent analgesic action. However, the fermentation process may certainly relieve the toxicity of Aconitum. The LD50 values of original and yeast- fermented Aconitum are about 1.44 mg/kg and 13.80 mg/kg, respectively, but the latter has a greater therapeutic scope than the former. This discovery may provide a way to develop new analgesics.