Causal inference of the effect of plasma proteins on the incidence of oral cancer: two-sample Mendelian randomization.

OBJECTIVE: This study is aimed to investigate the causal relationship between plasma proteins and oral cancer risk using two-sample MR (Mendelian randomization). METHODS: Summary-level GWAS (genome-wide association study) data on plasma protein levels (4,907 proteins) and oral cancer (6,034 cases, 6,585 controls) of European ancestry were utilized. SNPs (single nucleotide polymorphisms) associated with proteins at genome-wide significance were selected as instrumental variables. Multiple MR methods including IVW (inverse-variance weighted), MR-Egger, weighted median, simple mode and weighted mode were applied to estimate causal effects. Sensitivity analyses were conducted. RESULTS: Eight plasma proteins (CCDC167, MID2, NDRG4, PEAR1, PIAS4, RCAN1, SAMHD1 and TNMD) were identified to have significant causal associations with oral cancer risk. NDRG4, RCAN1, SAMHD1 and TNMD were associated with increased oral cancer risk while PEAR1 was associated with decreased risk. The causal estimates were consistent across different methods. Sensitivity analyses indicated the results were robust without significant heterogeneity or horizontal pleiotropy. Multivariable MR adjusting for smoking, alcohol intake and periodontal disease showed CCDC167, MID2, NDRG4, PEAR1, PIAS4 and SAMHD1 still had direct effects on oral cancer. CONCLUSION: This two-sample MR study provides evidence for potentially causal effects of several plasma proteins on oral cancer risk. The identified proteins may serve as biomarkers and shed light on biological mechanisms underlying oral carcinogenesis. Further research is warranted to validate and extend these findings.

Effects of host plants on aphid feeding behavior, fitness, and Buchnera aphidicola titer.

Aphids are sap-feeding plant pests that depend on their symbiotic relationships with the primary endosymbiont Buchnera aphidicola to adapt to impoverished diets. However, how the host plant affects the aphid primary symbiont and aphid adaptation to host plant transfer are poorly known. In this study, aphid symbiont screening and genotype identification were used to establish 2 aphid strains (Rhopalosiphum maidis [Rm] and Rhopalosiphum padi [Rp] strains) containing only Buchnera without any secondary symbionts for both wheat aphid species (R. maidis and R. padi). Aphid fitness and Buchnera titers were unstable on some of these host plants after transferring to novel host plants (G1-G5), which were influenced by host plant species and generations; however, they stabilized after prolonged feeding on the same plants for 10 generations. The electropenetrography (EPG) records showed that the allocation of aphid feeding time was significantly distinct in the 6 host plants; aphids had more intracellular punctures and spent more nonprobing time on green bristlegrass which was not conducive to its growth compared with other plants. The content of soluble sugar, soluble protein, and amino acid in the leaves of the 6 host plants were also clearly separated. The correlation coefficient analysis showed that the nutrient contents of host plants had significant correlations with aphid feeding behaviors, fitness, and Buchnera titers. In the meantime, aphid fitness, and Buchnera titers were also affected by aphid feeding behaviors. Also, Buchnera titers of aphid natural populations on 6 host plants showed a visible difference. Our study deepened our understanding of the interaction among aphids, endosymbionts, and host plants, indicating that the host plant nutrient content is a predominant factor affecting aphid adaptation to their diet, initially affecting aphid feeding behaviors, and further affecting aphid fitness and Buchnera titers, which would further contribute to exploiting new available strategies for aphid control.

Cross-sectional survey and analysis of factors influencing the prevalence of dental caries among older individuals aged 65-74 in Guangdong Province in 2021.

BACKGROUND: The prevalence of oral diseases is subject to change over time. In 2021, Guangdong Province conducted its fourth survey assessing the oral health status of individuals aged 65-74. MATERIALS AND METHODS: Evaluation criteria and potential influencing factors were identified. A sample of residents aged 65-74 from 13 designated monitoring sites in Guangdong Province was randomly selected for the study. Spearman correlation analysis was employed to investigate the clinical correlation between influencing factors and evaluation criteria. Negative binomial and zero-inflated negative binomial regression models were utilized to examine the factors influencing caries prevalence. In contrast, logistic regression was employed to identify the risk factors for caries occurrence. A p-value of ≤0.05 was considered statistically significant. RESULTS: The prevalence of caries rate of crowns, roots, and teeth were 76.36%, 52.25%, and 79.2%, respectively. Individuals with periodontal pockets exhibited a significantly higher risk of root caries. The presence of dental calculus significantly exacerbated the occurrence of crown, root, and dental caries, and increased the risk of crown and dental caries. Consuming sweet foods once or more a week notably increased the average root decayed score (D of roots), the prevalence rate of root caries, and the D score of the Decayed, Missing, and Filled teeth [DMFT] index in individuals already afflicted with this condition. Similarly, the consumption of sweetened drinks significantly elevated the risk of crown and root caries, exacerbating overall caries progression. Frequencies of manual toothbrush and toothpick cleaning showed a negative correlation with average tooth missing score (MT). In contrast, the frequency of manual/electric toothbrush and toothpick cleaning was negatively correlated with the DMFT index. Engaging in dental diagnosis and treatment behaviors significantly increased the number of filled crowns (F), MT, and DMFT scores while reducing the prevalence of dental caries. CONCLUSIONS: In Guangdong Province, caries prevalence among older individuals aged 65-74 remains substantial. Relevant professionals and institutions must provide comprehensive guidance and assistance to the older population, emphasizing the importance of reducing the consumption of sweets and sweetened beverages, adopting correct tooth brushing techniques and frequency (at least twice daily), timely treatment of periodontal diseases, conducting regular epidemiological caries surveys, and addressing economic barriers to accessing caries diagnosis and treatment services.

Understanding the Reversible Transition of Unipolar and Bipolar Resistive Switching Characteristics in Solution-Derived Nanocrystalline Au-Co3O4 Thin-Film Memristors.

Nanocrystalline Au-Co3O4 thin films were fabricated through a facile solution-processing method, and voltage-polarity-dependent resistive switching (RS) characteristics including variability of Set/Reset voltages, stability of cycling endurance, and carriers transport mechanism were studied in the Pt/Au-Co3O4/Pt memory devices. The switching voltages of the Set and Reset processes in the bipolar RS memristors exhibited lower variability as compared to the unipolar resistance switching devices. Moreover, the switching performance of cycle-to-cycle endurance in bipolar mode had a smaller fluctuation than those of unipolar switching behavior. Based on the current-voltage curve fitting analysis, it was found that Ohmic-conduction behaviors dominated the carriers transport of low-resistance state regardless of unipolar or bipolar switching behaviors. The carrier transport of high resistance state was governed following Poole-Frenkel emission and Schottky emission mechanisms in the unipolar and bipolar switching modes, respectively. The physical switching mechanism of Pt/Au-Co3O4/Pt memory devices was proposed using the model by means of growth and disruption of conducting filaments, involved in memory effects of thermochemical mechanism and valence change mechanism in the unipolar and bipolar RS, respectively. The proposed model following the finite element method revealed the roles of electrical field distribution and temperature gradient to further clarify the RS mechanism. Our results open a door for understanding and optimizing oxide-based thin-film resistance switching memory devices.

Visceral to subcutaneous fat area ratio predicts severe abdominal adhesions in definitive surgery for anastomotic fistula after small intestine resection.

Abdominal adhesions manifests following abdominal infections triggered by intestinal fistulas. The severity of such adhesions depends on the extent of fiber deposition and peritoneal fibrinolysis following peritoneal injury, which may be influenced by sustained inflammation within the abdominal cavity. In this regard, the visceral-to-subcutaneous fat area (VFA/SFA) ratio has been implicated as a potential marker of inflammation. This study aimed to explore the relationship between VFA/SFA and abdominal adhesions. This multicenter study was conducted across four tertiary institutions and involved patients who had undergone definitive surgery (DS) for intestinal fistula from January 2009 and October 2023. The presence of abdominal adhesions was determined intraoperatively. VFA/SFA was investigated as a potential risk factor for severe adhesions. The study comprised 414 patients with a median age of 50 [interquartile range (IQR) 35-66] years and a median body mass index of 20.0 (IQR 19.2-22.4) kg/m2, including 231 males with a median VFA/SFA of 1.0 (IQR 0.7-1.2) and 183 females a median VFA/SFA of 0.8 (0.6-1.1). VFA/SFA was associated with severe abdominal adhesions in males [odds ratio (OR) = 3.34, 95% CI 1.14-9.80, p = 0.03] and females (OR = 2.99, 95% CI 1.05-8.53, p = 0.04). J-shaped association between VFA/SFA ratio and severe adhesions was revealed in both sex. The increasing trend can be revealed when OR more than 0.8, and 0.6 in males and females respectively. Preoperative VFA/SFA demonstrates predictive value for statues of severe abdominal adhesions in DS for anastomotic fistula after small intestine resection.

Advancements in Functional Nanomaterials Inspired by Viral Particles.

Virus-like particles (VLPs) are nanostructures composed of one or more structural proteins, exhibiting stable and symmetrical structures. Their precise compositions and dimensions provide versatile opportunities for modifications, enhancing their functionality. Consequently, VLP-based nanomaterials have gained widespread adoption across diverse domains. This review focuses on three key aspects: the mechanisms of viral capsid protein self-assembly into VLPs, design methods for constructing multifunctional VLPs, and strategies for synthesizing multidimensional nanomaterials using VLPs. It provides a comprehensive overview of the advancements in virus-inspired functional nanomaterials, encompassing VLP assembly, functionalization, and the synthesis of multidimensional nanomaterials. Additionally, this review explores future directions, opportunities, and challenges in the field of VLP-based nanomaterials, aiming to shed light on potential advancements and prospects in this exciting area of research.

Influence and mechanism of typical transition metal ions on the denitrification performance of heterotrophic nitrification-aerobic denitrification bacteria.

To investigate the inhibitory effects of various transition metal ions on nitrogen removal and their underlying mechanisms, the single and combined effects of Cu2+ Ni2+ and Zn2+ on Heterotrophic nitrification-aerobic denitrification (HN-AD) bacteria Acinetobacter sp. TAC-1 were studied in a batch experiment system. The results revealed that increasing concentrations of Cu2+ and Ni2+ had a detrimental effect on the removal of ammonium nitrogen (NH4+-N) and total nitrogen (TN). Specifically, Cu2+ concentration of 10 mg/L, the TN degradation rate was 55.09%, compared to 77.60% in the control group. Cu2+ exhibited a pronounced inhibitory effect. In contrast, Zn2+ showed no apparent inhibitory effect on NH4+-N removal and even enhanced TN removal at lower concentrations. However, when the mixed ion concentration of Zn2++Ni2+ exceeded 5 mg/L, the removal rates of NH4+-N and TN were significantly reduced. Moreover, transition metal ions did not significantly impact the removal rates of chemical oxygen demand (COD). The inhibition model fitting results indicated that the inhibition sequence was Cu2+ > Zn2+ > Ni2+. Transcriptome analysis demonstrated that metal ions influence TAC-1 activity by modulating the expression of pivotal genes, including zinc ABC transporter substrate binding protein (znuA), ribosomal protein (rpsM), and chromosome replication initiation protein (dnaA) and DNA replication of TAC-1 under metal ion stress, leading to disruptions in transcription, translation, and cell membrane structure. Finally, a conceptual model was proposed by us to summarize the inhibition mechanism and possible response strategies of TAC-1 bacteria under metal ion stress, and to address the lack of understanding regarding the influence mechanism of TAC-1 on nitrogen removal in wastewater co-polluted by metal and ammonia nitrogen. The results provided practical guidance for the management of transition metal and ammonia nitrogen co-polluted water bodies, as well as the removal of high nitrogen.

Effect of smoking on prostate cancer: Results from the National Health and Nutrition Examination Survey 2003-2018 and Mendelian randomization analyses.

INTRODUCTION: The controversial relationship between smoking and prostate cancer (PCa) risk prompted us to conduct a cross-sectional study using the National Health and Nutrition Examination Survey (NHANES) database and apply Mendelian randomization (MR) analyses in order to clarify the possible causal effect of smoking on PCa risk. METHODS: Using univariate and multivariate logistic regression methods, a secondary analysis of the pooled 2003-2018 NHANES dataset was performed to explore the association between smoking and PCa risk. Propensity-score matching was used to reduce selection bias. Then, we conducted subsequent MR analysis study to investigate the potential causal effect of smoking on PCa risk, with genetic variants of four exposure factors including the lifetime smoking index, light smoking, smoking initiation, and the amount of smoking per day obtained from genome-wide association studies, and PCa summary statistics obtained from three database populations. Inverse-variance weighting was the primary analytical method, and weighted median and MR-Egger regression were used for sensitivity analyses. The MR results for the three PCa databases were combined using meta-analysis. RESULTS: The study included 16073 NHANES subjects, comprising 554 with PCa and 15519 without PCa. Logistic regression before and after matching did not reveal any significant association. Meta-analysis of the MR results also did not support an association of PCa risk with lifetime smoking index (OR=0.95; 95% CI: 0.83-1.09), light smoking (OR=1.00; 95% CI: 0.95-1.06), smoking initiation (OR=0.99, 95% CI=0.99-1.00), or the amount of smoking per day (OR=1.00; 95% CI: 0.99-1.00) and PCa risk. CONCLUSIONS: There was no evidence for an association between smoking and the risk of PCa. Further studies are needed to determine if there are any associations of other forms of smoking with the risk of PCa at different stages.

Nomogram for predicting intolerable postoperative early enteral nutrition following definitive surgery for small intestinal fistula: a cohort study.

BACKGROUND: This study was designed to develop and validate a nomogram for predicting intolerable early enteral nutrition (EEN) following definitive surgery (DS) for small intestinal fistula. METHODS: A total of 377 patients, recruited from January 2016 to September 2023, was randomly allocated into development (n=251) and validation (n=126) groups in a 2:1 ratio. Risk factors were identified using the nomogram. Its performance was assessed based on calibration, discrimination, and clinical utility, with validation confirming its effectiveness. RESULTS: Of the 377 patients, 87 (23.1%) were intolerant to EEN, including 59 (23.1%) in the development cohort and 28 (22.1%) in the validation cohort (P=0.84). Four factors were identified as predictive of intolerable EEN: severe abdominal adhesion, deciliter of blood loss during DS, human serum albumin (Alb) input >40 g during and within 48 hours post-DS, and the visceral fat area (VFA)/total abdominal muscle area index (TAMAI) ratio. The model demonstrated excellent discrimination, with a C-index of 0.79 (95% CI, 0.74-0.87, including internal validation) and robust calibration. In the validation cohort, the nomogram showed strong discrimination (C-index=0.77; 95% CI, 0.64-0.87) and solid calibration. Decision curve analysis affirmed the nomogram's clinical utility. CONCLUSION: This research introduces a nomogram that enables the individualized prediction of intolerable EEN following DS for small intestinal fistula, demonstrating a possible clinical utility.

[Retracted] Tripartite motif 16 suppresses breast cancer stem cell properties through regulation of Gli­1 degradation via the ubiquitin­proteasome pathway.

Following the publication of the above paper, it was drawn to the Editors' attention by a concerned reader that the data obtained from sphere­forming assay experiments shown in Figs. 4C­F and 8B and C, and western blotting data in Figs. 4A and 8A, were strikingly similar to data appearing in different form in other articles by different authors from different research institutes that had already been published, one of which has been retracted. Moreover, a pair of data panels comparing between Fig. 4E and 8C were partly overlapping, such that these data appear to have been derived from the same original source. Owing to the fact that the contentious data in the above article had already been published elsewhere prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 35: 1204­1212, 2016; DOI: 10.3892/or.2015.4437].

Chemical and Geological Properties of Shale Gas: In Situ Desorption of Lower Cambrian Niutitang Shale in the Micangshan Tectonic Zone of South Shaanxi, China.

Shale gas was recently found in the Lower Cambrian Niutitang Formation (LCNF) of the Micangshan tectonic zone of south Shaanxi (MTZSS), but not in commercial quantities. To determine the laws governing the generation, enrichment, and desorption of shale gases in overmatured shale strata in the LCNF of MTZSS, we carried out in situ desorption experiments on nine shale core samples and got 168 desorbed gas samples at different phases of desorption. Also measured were the chemical and carbon isotopic compositions of these desorbed gas samples and the geochemical parameters of the shale core samples. CH4 was the predominant hydrocarbon shale gas identified in the 82.06-98.48% range, suggesting that the gases were mainly dry. The nonhydrocarbon gases found were CO2 and H2. The CH4 content of the desorbed gas samples dropped continuously during desorption, lowering the dryness index to 98.48 and 92.26% of the first and last desorbed shale gas, respectively. The change in the gas ratio during shale gas desorption proved that the adsorbability of the LCNF to the various gases follows the trend H2 > CO2 > C2H6 > CH4 > He. Further, δ13C2H6 and δ13CH4 become heavier during desorption, showing isotopic fractionation arising from the desorption-diffusion coeffect. As the desorption temperature increases, the value of δ13CH4 increases because 12CH4 is more sensitive to temperature than 13CH4, so it is with the ethane. Similar to the LCNF shale gas in other areas of China, the desorbed shale gases are characteristic of carbon isotope reversal (CIR) (δ13CH4 > δ13C2H6). The cracking of the residual soluble organic matter at the high overmaturity stage mixed with the cracking of kerogen at the early stage of maturation, causing CIR. Furthermore, the desorbed gas content was proportionally and inversely related to the CIR degree and final dryness index of the desorbed gas, respectively. Moreover, the carbon isotope fractionation degree of CH4 and δ13C1 of the last desorbed gas correlated positively with the desorbed gas content and the desorbed time of the gas. In conclusion, the four parameters are effective parameters for identifying shale gas sweet spots.

Development and validation of a risk score nomogram model to predict the risk of 5-year all-cause mortality in diabetic patients with hypertension: A study based on NHANES data.

Background: The present study aimed to develop and validate a prediction nomogram model for 5-year all-cause mortality in diabetic patients with hypertension. Methods: Data were extracted from the National Health and Nutrition Examination Survey (NHANES). A total of 3291 diabetic patients with hypertension in the NHANES cycles for 1999-2014 were selected and randomly assigned at a ratio of 8:2 to the training cohort (n = 2633) and validation cohort (n = 658). Multivariable Cox regression was conducted to establish a visual nomogram model for predicting the risk of 5-year all-cause mortality. Receiver operating characteristic curves and C-indexes were used to evaluate the discriminant ability of the prediction nomogram model for all-cause mortality. Survival curves were created using the Kaplan-Meier method and compared by the log-rank test. Results: The nomogram model included eight independent predictors: age, sex, education status, marital status, smoking, serum albumin, blood urea nitrogen, and previous cardiovascular disease. The C-indexes for the model in the training and validation cohorts were 0.76 (95% confidence interval: 0.73-0.79, p < 0.001) and 0.75 (95% confidence interval: 0.69-0.81, p < 0.001), respectively. The calibration curves indicated that the model had satisfactory consistency in the two cohorts. The risk of all-cause mortality gradually increased as the tertiles of the nomogram model score increased (log-rank test, p < 0.001). Conclusion: The newly developed nomogram model, a readily useable and efficient tool to predict the risk of 5-year all-cause mortality in diabetic patients with hypertension, provides a novel risk stratification method for individualized intervention.

Imbibition Characteristics and Influencing Factors of the Fracturing Fluid in a Tight Sandstone Reservoir.

The strong reservoir heterogeneity and complex microscopic pore structure in the Linxing area make it prone to water block damage during imbibition development. In order to explore the influence of reservoir microscopic characteristics on imbibition efficiency, taking the tight sandstone gas reservoir in the Linxing area of Ordos Basin as an example, the heterogeneity of the tight sandstone reservoir in the study area is characterized in terms of physical and chemical characteristics as well as the microscopic pore structure. Using nuclear magnetic resonance, high-pressure mercury pressure, and other testing methods, spontaneous seepage experiments in real sandstone were carried out to study the distribution law of different pore structures and seepage characteristics at different times and to systematically evaluate the microscopic pore characteristics of dense sandstone reservoirs and the factors affecting seepage and suction. The results show that due to the strong microscopic heterogeneity of tight sandstone, the macroscopic properties cannot directly reflect the microscopic characteristics, and the response to imbibition efficiency is stronger. The pore size is the main controlling factor affecting imbibition, and the contribution rate of the micropore and mesopore mainstream pore size spaces is higher than that of the macropore. Micropores provide imbibition power, and mesopores provide an imbibition interval. High-porosity and high permeability reservoirs are more conducive to imbibition replacement. The intercrystalline pores have a great influence on the imbibition efficiency, and the influence of intergranular pores and dissolution pores on the imbibition cannot be underestimated. The smaller the relative sorting coefficient, interfacial tension, and contact angle, the better the imbibition effect of fracturing fluid. Research results have theoretical guiding significance for spontaneous imbibition to improve oil recovery.

Advanced Electrospinning Technology Applied to Polymer-Based Sensors in Energy and Environmental Applications.

Due to its designable nanostructure and simple and inexpensive preparation process, electrospun nanofibers have important applications in energy collection, wearable sports health detection, environmental pollutant detection, pollutant filtration and degradation, and other fields. In recent years, a series of polymer-based fiber materials have been prepared using this method, and detailed research and discussion have been conducted on the material structure and performance factors. This article summarizes the effects of preparation parameters, environmental factors, a combination of other methods, and surface modification of electrospinning on the properties of composite nanofibers. Meanwhile, the effects of different collection devices and electrospinning preparation parameters on material properties were compared. Subsequently, it summarized the material structure design and specific applications in wearable device power supply, energy collection, environmental pollutant sensing, air quality detection, air pollution particle filtration, and environmental pollutant degradation. We aim to review the latest developments in electrospinning applications to inspire new energy collection, detection, and pollutant treatment equipment, and achieve the commercial promotion of polymer fibers in the fields of energy and environment. Finally, we have identified some unresolved issues in the detection and treatment of environmental issues with electrospun polymer fibers and proposed some suggestions and new ideas for these issues.

Platinum-based neoadjuvant chemotherapy upregulates STING/IFN pathway expression and promotes TILs infiltration in NSCLC.

Objectives: To evaluate the effects of platinum-based neoadjuvant chemotherapy (NACT) on the STING/IFN pathway and tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC), as well as clinicopathological factors affecting patient survival. Materials and methods: A total of 68 patients aged 34-77 years with NSCLC who received neoadjuvant chemotherapy and surgical treatment from March 2012 to February 2019 were reviewed, and the clinical pathological data and paired tissue specimens before and after NACT were collected. Immunohistochemistry and immunofluorescence were used to detect the protein levels of STING, PD-L1 and IFN-ß, and the infiltration density of CD3+ TILs and CD8+TILs. The correlation between the expression of STING, PD-L1, IFN-ß and the infiltration density of CD3+ TILs and CD8+ TILs as well as the clinicopathological characteristics before and after NACT was analyzed. The relationship between the related indexes, clinicopathological features and prognosis was also discussed. Results: NACT increased the expression of STING, IFN-ß and PD-L1 in tumor cells, and the infiltration of CD3+ and CD8+ TILs. In addition, ypTNM stage, ypN stage, changes in CD3+ TILs and in PD-L1 were associated with DFS (disease-free survival). CD3+ TILs changes and ypN stage were associated with OS (overall survival). Notably, ypN stage and CD3+ TILs changes were independent prognostic factors for DFS and OS. Conclusion: NACT stimulates STING/IFN-ß pathway, promotes infiltration of CD3+ and CD8+ TILs, triggers innate and adaptive immunity, and also upregulates PD-L1, which complemented the rationale for neoadjuvant chemotherapy in combination with immunotherapy. In addition, DFS was longer in patients with ypTNM I, ypN0-1, and elevated CD3+TILs after NACT. Patients with ypN0 and elevated CD3+ TILs after NACT had better OS benefits.

Alectinib continuation beyond progression in ALK-positive non-small cell lung cancer with alectinib-refractory.

Background: Alectinib, a next-generation anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI), has demonstrated noteworthy efficacy in the treatment of non-small cell lung cancer (NSCLC). Unfortunately, 53.3% of untreated patients receiving first-line treatment with alectinib developed resistance to alectinib. However, despite the widespread use of alectinib, studies on the efficacy and safety of continuing alectinib with other necessary therapies after progression of alectinib and possible population of benefit are still limited. Methods: This retrospective cohort study included fifteen patients with ALK-positive NSCLC from nine institutions in China who experienced disease progression after first- or second-line treatment and continued to receive alectinib treatment between 2019 and 2022. This study aimed to evaluate the median progression-free survival (mPFS), objective response rate (ORR), median overall survival (mOS), and adverse events (AEs) of continuing alectinib combined with other therapies after the emergence of drug resistance. Results: Among fifteen patients eligible for this study, all patients started continuing treatment with alectinib after oligoprogression or central nervous system (CNS) progression. The mPFS for the whole cohort receiving continuing alectinib with other necessary therapies was 8 months [95% confidence interval (CI): 4 to not applicable (NA)], with an ORR of 46.7%. The mOS was not reached. During continuing alectinib treatment, only one patient experienced grade 2 elevation of aspartate aminotransferase (AST) and serum glutamic-oxaloacetic transaminase (SGOT). Conclusions: The continuation of alectinib treatment combined with other necessary therapies demonstrates favorable response and safety in patients with ALK-positive NSCLC who experienced oligoprogression or CNS progression following alectinib in first- or second-line therapy. Instead of immediately switching to another ALK-TKI, continuing alectinib combined with other necessary therapies may offer greater survival benefits to the patients.

Functional characterization of a geranylgeranyl diphosphate synthase in the leaf beetle Monolepta hieroglyphica.

Geranylgeranyl diphosphate synthase (GGPPS) as the short-chain prenyltransferases for catalyzing the formation of the acyclic precursor (E)-GGPP has been extensively investigated in mammals, plants, and microbes, but its functional plasticity is poorly understood in insect species. Here, a single GGPPS in leaf beetle Monolepta hieroglyphica, MhieGGPPS, was functionally investigated. Phylogenetic analysis showed that MhieGGPPS was clustered in one clade with homologs and had six conserved motifs. Molecular docking results indicated that binding sites of dimethylallyl diphosphate (DMAPP), (E)-geranyl pyrophosphate (GPP), and (E)-farnesyl pyrophosphate (FPP) were in the chain-length determination region of MhieGGPPS, respectively. In vitro, recombiant MhieGGPPS could catalyze the formation of (E)-geranylgeraniol against different combinations of substrates including isopentenyl pyrophosphate (IPP)/DMAPP, IPP/(E)-GPP, and IPP/(E)-FPP, suggesting that MhieGGPPS could not only use (E)-FPP but also (E)-GPP and DMAPP as the allylic cosubstrates. In kinetic analysis, the (E)-FPP was most tightly bound to MhieGGPPS than that of others. It was proposed that MhieGGPPS as a multifunctional enzyme is differentiated from the other GGPPSs in the animals and plants, which only accepted (E)-FPP as the allylic cosubstrate. These findings provide valuable insights into understanding the functional plasticity of GGPPS in M. hieroglyphica and the novel biosynthesis mechanism in the isoprenoid pathway.

ZNF283, a Krüppel-associated box zinc finger protein, inhibits RNA synthesis of porcine reproductive and respiratory syndrome virus by interacting with Nsp9 and Nsp10.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a viral pathogen with substantial economic implications for the global swine industry. The existing vaccination strategies and antiviral drugs offer limited protection. Replication of the viral RNA genome encompasses a complex series of steps, wherein a replication complex is assembled from various components derived from both viral and cellular sources, as well as from the viral genomic RNA template. In this study, we found that ZNF283, a Krüppel-associated box (KRAB) containing zinc finger protein, was upregulated in PRRSV-infected Marc-145 cells and porcine alveolar macrophages and that ZNF283 inhibited PRRSV replication and RNA synthesis. We also found that ZNF283 interacts with the viral proteins Nsp9, an RNA-dependent RNA polymerase, and Nsp10, a helicase. The main regions involved in the interaction between ZNF283 and Nsp9 were determined to be the KRAB domain of ZNF283 and amino acids 178-449 of Nsp9. The KRAB domain of ZNF283 plays a role in facilitating Nsp10 binding. In addition, ZNF283 may have an affinity for the 3' untranslated region of PRRSV. These findings suggest that ZNF283 is an antiviral factor that inhibits PRRSV infection and extend our understanding of the interactions between KRAB-containing zinc finger proteins and viruses.

S100A4 reprofiles lipid metabolism in mast cells via RAGE and PPAR-γ signaling pathway.

S100A4 is implicated in metabolic reprogramming across various cell types and is known to propel the progression of numerous diseases including allergies. Nonetheless, the influence of S100A4 on mast cell metabolic reprogramming during allergic disorders remains unexplored. Utilizing a mast cell line (C57), cells were treated with recombinant mouse S100A4 protein, with or without a PPAR-γ agonist (ROSI) or a RAGE inhibitor (FPS-ZM1). Subsequent assessments were conducted for mast cell activation and lipid metabolism. S100A4 induced mast cell activation and the release of inflammatory mediators, concurrently altering molecules involved in lipid metabolism and glycolysis over time. Furthermore, S100A4 stimulation resulted in cellular oxidative stress and mitochondrial dysfunction. Alterations in the levels of pivotal molecules within the RAGE/Src/JAK2/STAT3/PPAR-γ and NF-κB signaling pathways were noted during this stimulation, which were partially counteracted by ROSI or FPS-ZMI. Additionally, a trend of metabolic alterations was identified in patients with allergic asthma who exhibited elevated serum S100A4 levels. Correlation analysis unveiled a positive association between serum S100A4 and serum IgE, implying an indirect association with asthma. Collectively, our findings suggest that S100A4 regulates the lipid-metabolic reprogramming of mast cells, potentially via the RAGE and PPAR-γ-involved signaling pathway, offering a novel perspective in the disease management in patients with allergic disorders.

Hybrid Whale Optimization with a Firefly Algorithm for Function Optimization and Mobile Robot Path Planning.

With the wide application of mobile robots, mobile robot path planning (MRPP) has attracted the attention of scholars, and many metaheuristic algorithms have been used to solve MRPP. Swarm-based algorithms are suitable for solving MRPP due to their population-based computational approach. Hence, this paper utilizes the Whale Optimization Algorithm (WOA) to address the problem, aiming to improve the solution accuracy. Whale optimization algorithm (WOA) is an algorithm that imitates whale foraging behavior, and the firefly algorithm (FA) is an algorithm that imitates firefly behavior. This paper proposes a hybrid firefly-whale optimization algorithm (FWOA) based on multi-population and opposite-based learning using the above algorithms. This algorithm can quickly find the optimal path in the complex mobile robot working environment and can balance exploitation and exploration. In order to verify the FWOA's performance, 23 benchmark functions have been used to test the FWOA, and they are used to optimize the MRPP. The FWOA is compared with ten other classical metaheuristic algorithms. The results clearly highlight the remarkable performance of the Whale Optimization Algorithm (WOA) in terms of convergence speed and exploration capability, surpassing other algorithms. Consequently, when compared to the most advanced metaheuristic algorithm, FWOA proves to be a strong competitor.