Targeting neutrophil elastase is a promising direction for future cancer treatment.

Neutrophil elastase (NE) is a proteolytic enzyme released extracellular during the formation of neutrophil extracellular traps (NETs) through degranulation. In addition to participating in the body's inflammatory response, NE also plays an important role in cancer. It can promote tumor proliferation, migration, and invasion, induce epithelial-mesenchymal transition (EMT), and change the tumor microenvironment (TME) to promote tumor progression. Concurrently, NE promotes systemic treatment resistance by inducing EMT. However, it can also selectively kill cancer cells and attenuate tumor development. Sivelestat is a specific NE inhibitor that can be used in the perioperative period of esophageal cancer patients to reduce the incidence of postoperative complications after esophagectomy. In addition, the combination of sivelestat and trastuzumab can enhance the efficacy of human epidermal growth factor receptor 2(HER 2) positive breast cancer patients. Meanwhile, targeting the human antibody domains and fragments of NE is also a new way to treat cancer and inflammation-related diseases. This review provides valuable insights into the role of NE in cancer treatment. Additionally, we discuss the challenges associated with the clinical application of sivelestat. By shedding light on the promising potential of NE, this review contributes to the advancement of cancer treatment strategies.

Strategies selection for building e-commerce platforms for agricultural wholesale markets: A tripartite evolutionary game perspective.

The rapid advancement and widespread implementation of digital technology have created opportunities for the e-commerce transformation of agricultural wholesale markets. The building of e-commerce platforms in this process is of utmost importance and should be approached methodically. This article analyzes the interests and behavioral choices of the agricultural wholesale markets, local government, and wholesalers by establishing a tripartite evolutionary game model. It applies replicator dynamics equations to describe the evolutionary strategies of each party. The findings of the study indicate that the behavioral choices of agricultural wholesale markets, local government, and wholesalers are influenced by their initial intentions. Furthermore, there exists a degree of alignment between the choices made by agricultural wholesale markets and wholesalers. The building of e-commerce platforms by agricultural wholesale markets can be facilitated through direct and indirect government subsidies; this also motivates wholesalers to adopt and utilize these platforms. Agricultural wholesale markets may further incentivize wholesalers to utilize their own e-commerce platforms by offering additional benefits. On the other hand, if the agricultural wholesale markets demonstrate strong initial inclinations toward using third-party e-commerce platforms. In this scenario, the local government has the potential to promote the widespread use of these platforms by providing both direct and indirect financial incentives to these markets, as well as actively encouraging wholesalers to participate in them. This study presents policy recommendations for agricultural wholesale markets and local government to support the effective implementation of e-commerce platforms in the agricultural wholesaler markets and facilitate a smooth transition to e-commerce in agricultural wholesale markets.

Neutrophil elastase as a potential biomarker related to the prognosis of gastric cancer and immune cell infiltration in the tumor immune microenvironment.

Exploring biomarkers interrelated the tumor immune microenvironment (TIME) provides novel ideas for predicting the prognosis of gastric cancer (GC) and developing new treatment strategies. We analyzed the differential gene expression levels between the high and low StromalScore and ImmuneScore groups. Neutrophil elastase (ELANE) was evaluated as a potential biomarker by conducting intersection analysis of the protein-protein interaction network and univariate Cox regression analysis. The expression of ELANE was evaluated by immunohistochemistry. Its prognostic value was evaluated using Kaplan-Meier (K-M) survival curves and multivariate Cox regression analysis and its potential biological molecular mechanism was examined by gene set enrichment analysis (GSEA). We applied the CIBERSORT computing method to analyze the relationship between ELANE and tumor immune-infiltrating cells (TIICs). K-M survival curve showed that higher ELANE expression was closely related to shorter overall survival. The Cox regression analysis indicated that the high expression of ELANE was an independent prognostic risk factor in patients with GC. The GSEA revealed that genes in the ELANE high-expression group were involved in the signaling pathways regulating immune response; genes in the ELANE low-expression group were involved in the signaling pathways that regulate metabolism. ELANE might be participate in the change of TIME from immunodominant to metabolically dominant and its expression was closely related to tumor mutation burden and multiple TIICs. ELANE is a potential biomarker for predicting the GC patients' survival and prognosis. It influences the tumor immune cell infiltration in the TIME, and affects the TIME to maintain their immune status.

A novel tool for predicting the risk of central lymph node metastasis in patients with papillary thyroid microcarcinoma: a retrospective cohort study.

INTRODUCTION: Central lymph node status in papillary thyroid microcarcinoma (PTMC) plays an important role in treatment decision-making clinically, however, it is not easy to predict central lymph node metastasis (CLNM). The present work focused on finding the more rational alternative for evaluating central lymph node status while identifying influencing factors to construct a model to predict CLNM incidence. METHODS: In this study, we retrospectively analyzed the typical sonographic and clinicopathologic features of 546 PTMC patients who underwent surgery, among which, the data of 382 patients were recruited in the training cohort and that of 164 patients in the validation cohort. Based on the outcome of the training cohort, significant influencing factors were further identified through univariate analysis and were considered as independent variables in multivariable logistic regression analysis and incorporated in and presented with a nomogram. RESULTS: In total, six independent predictors, including the age, sex, tumor size, multifocality, capsular invasion, Hashimotos thyroiditis were entered into the nomogram. Both internal validation and external validation revealed the favorable discrimination of our as-constructed nomogram. Calibration curves exhibited high consistency. As suggested by decision-curve analyses, the as-constructed nomogram might be applied in clinic. Besides, the model also distinguished patients according to risk stratification. CONCLUSIONS: The novel nomogram containing remarkable influencing factors for CLNM cases was established in the present work. The nomogram can assist clinicians in clinical decision-making.

AG1478 Elicits a Novel Anti-Influenza Function via an EGFR-Independent, GBF1-Dependent Pathway.

Current options for preventing or treating influenza are still limited, and new treatments for influenza viral infection are urgently needed. In the present study, we serendipitously found that a small-molecule inhibitor (AG1478), previously used for epidermal growth factor receptor (EGFR) inhibition, demonstrated a potent activity against influenza both in vitro and in vivo. Surprisingly, the antiviral effect of AG1478 was not mediated by its EGFR inhibitory activity, as influenza virus was insensitive to EGFR blockade by other EGFR inhibitors or by siRNA knockdown of EGFR. Its antiviral activity was also interferon independent as demonstrated by a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) knockout approach. Instead, AG1478 was found to target the Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 (GBF1)-ADP-ribosylation factor 1 (ARF1) system by reversibly inhibiting GBF1 activity and disrupting its Golgi-cytoplasmic trafficking. Compared to known GBF1 inhibitors, AG1478 demonstrated lower cellular toxicity and better preservation of Golgi structure. Furthermore, GBF1 was found to interact with a specific set of viral proteins including M1, NP, and PA. Additionally, the alternation of GBF1 distribution induced by AG1478 treatment disrupted these interactions. Because targeting host factors, instead of the viral component, imposes a higher barrier for developing resistance, GBF1 modulation may be an effective approach to treat influenza infection.

Novel Mouse Models of Fungal Asthma.

Alternaria alternata is a ubiquitous fungus and a major allergen associated with the development of asthma. Inhalation of intact spores is the primary cause of human exposure to fungal allergen. However, allergen-rich cultured fungal filtrates are oftentimes used in the current models of fungal sensitization that do not fully reflect real-life exposures. Thus, establishing novel spore exposure models is imperative. In this study, we established novel fungal exposure models of both adult and neonate to live spores. We examined pathophysiological changes in the spore models as compared to the non-exposure controls and also to the conventional filtrate models. While both Alternaria filtrate- and spore-exposed adult BALB/c mice developed elevated airway hyperresponsiveness (AHR), filtrates induced a greater IgE mediated response and higher broncholavage eosinophils than spores. In contrast, the mice exposed to Alternaria spores had higher numbers of neutrophils. Both exposures induced comparable levels of lung tissue inflammation and mucous cell metaplasia (MCM). In the neonatal model, exposure to Alternaria spores resulted in a significant increase of AHR in both adult and neonatal mice. Increased levels of IgE in both neonatal and adult mice exposed to spores was associated with increased eosinophilia in the treatment groups. Adult demonstrated increased numbers of lymphocytes that was paralleled by increased IgG1 production. Both adults and neonates demonstrated similarly increased eosinophilia, IgE, tissue inflammation and MCM.

Microbial community dissimilarity for source tracking with application in forensic studies.

Microbial source-tracking is a useful tool for trace evidence analysis in Forensics. Community-wide massively parallel sequencing profiles can bypass the need for satellite microbes or marker sets, which are unreliable when handling unstable samples. We propose a novel method utilizing Aitchison distance to select important suspects/sources, and then integrate it with existing algorithms in source tracking to estimate the proportions of microbial sample coming from important suspects/sources. A series of comprehensive simulation studies show that the proposed method is capable of accurate selection and therefore improves the performance of current methods such as Bayesian SourceTracker and FEAST in the presence of noise microbial sources.

Flight and Walking Performance of Dark Black Chafer Beetle Holotrichia parallela (Coleoptera: Scarabaeidae) in the Presence of Known Hosts and Attractive Nonhost Plants.

Holotrichia parallela damages seriously on peanut (Arachis hypogaea) pods. Elucidation of its flight and walking performance in the presence of different plants may provide an insight in its host selection process and an explanation to its strong olfactory preference to an attractive nonhost, castor bean (Ricinus communis). We determined the relationships among flight performance, mate choice, and body weight of H. parallela beetles, and then investigated their flight and walking patterns in the presence of known hosts and attractive nonhost plants using a flight mill and a locomotion compensator, respectively. Body weights were not related to mating success, regardless of sex. The flight proportion of selected females drastically decreased compared with nonselected females, nonselected males, and selected males. Within mated males, heavier individuals exhibited poorer flight performance than lighter ones. In flight bioassay, peanut showed an arrestment effect on virgin females. For walking activity factors (distance, time, and speed), the host plants velvetleaf (Abutilon theophrasti) and Siberian elm (Ulmus pumila) elicited the strongest responses in females and males, respectively. Interestingly, the most preferred adult host, Siberian elm, and the nonhost, castor bean, elicited the highest values of two orientation factors (orientation and upwind length) in females. The chemical similarity hypothesis, which states that feeding or oviposition of insects mistakenly on nonhost can be traced to their chemical similarity to actual hosts, could explain the attraction of H. parallela to castor bean.

Fatal Attraction: Ricinus communis Provides an Attractive but Risky Mating Site for Holotrichia parallela Beetles.

The castor bean, Ricinus communis L., is a non-host plant for the large black chafer, Holotrichia parallela Motschulsky (Coleoptera: Scarabaeidae). In laboratory bioassays we found that this plant was no less attractive than the main host plant (peanut, Arachis hypogaea) and three food plant species: velvetleaf (Abutilon theophrasti), the glossy privet (Ligustrum lucidum), and the Siberian elm (Ulmus pumila). In field trapping experiments a Soxhlet extract of castor bean leaves caught more beetles than the optimal sex lure blend [(R)-(-)-linalool and (L)-isoleucine methyl ester blended in a ratio of 1:4], compared at equal doses (500 µl), and laboratory bioassays indicated that a castor bean plant could enhance the attractiveness of different blend ratios of sex lures. Olfactometer bioassays showed that males prefer volatiles emitted from different combinations of castor bean plant extracts and a signaling female over a female alone. In the presence of castor bean plants copulation rates of H. parallela were highest among all test environments both in laboratory bioassays (60%) and in field tests (70%). This study, combined with our previous observation of the feeding behavior of H. parallela adults on castor bean leaves, suggests that castor bean plants may provide an attractive but risky mating site for H. parallela beetles. The enhancement of male mate-location and copulation rate in the presence of castor bean plants can balance its paralytic effects on H. parallela after intake of potential toxins contained in its leaves.

Experience-based mediation of feeding and oviposition behaviors in the cotton bollworm: Helicoverpa armigera (Lepidoptera: Noctuidae).

Experience is well known to affect sensory-guided behaviors in many herbivorous insects. Here, we investigated the effects of natural feeding experiences of Helicoverpa armigera larvae on subsequent preferences of larval approaching and feeding, as well as the effect of host-contacting experiences of mated females on subsequent ovipositional preference. The results show that the extent of experience-induced preference, expressed by statistical analysis, depended on the plant species paired with the experienced host plant. Larval feeding preference was much easier to be induced by natural feeding experience than larval approaching preference. Naïve larvae, reared on artificial diet, exhibited clear host-ranking order as follows: tobacco ≥ cotton > tomato > hot pepper. Feeding experiences on hot pepper and tobacco could always induce positive feeding preference, while those on cotton often induced negative effect, suggesting that the direction of host plant experience-induced preference is not related to innate feeding preference. Inexperienced female adults ranked tobacco as the most preferred ovipositional host plant, and this innate preference could be masked or weakened but could not be reversed by host-contacting experience after emergence.