Ensartinib in the treatment of anaplastic lymphoma kinase-positive locally advanced or metastatic patients with lung squamous or adenosquamous carcinoma: A real-world, retrospective study.

AIM: To report the efficacy and safety of ensartinib, an anaplastic lymphoma kinase (ALK) inhibitor, in treating patients with ALK-positive advanced lung squamous cell carcinoma (LUSC) or lung adenosquamous carcinoma (LASC) in China. METHODS: This retrospective study analyzed data for 36 advanced-stage patients with ALK-positive LUSC (cohort A) and 13 patients with ALK-positive LASC (cohort B) between December 16, 2020 and December 16, 2021. All patients received once-daily ensartinib 225 mg. Outcome analysis included the demographic characteristics, tumor response, progression-free survival (PFS), and treatment-related adverse events (TRAE). RESULTS: Among the 49 patients, the majority were under 65 years old (73.5%), non-smokers (85.7%), had an Eastern Cooperative Oncology Group Performance Status of 0-1 (77.6%), and were at stage IV (71.4%). All patients were included in the efficacy and safety analysis. Seven PFS events were reported in cohort A while no patients experienced PFS events in cohort B. The median PFS was not estimable for both cohorts. In cohort A, the objective response rate (ORR) was 63.9%, and the disease control rate (DCR) was 83.3%. In the cohort B, the ORR was 76.9% and the DCR was 100.0%. Rash was the only TRAE reported in the cohort A (8.3%) and cohort B (23.1%). No patients had grade 3 or higher TRAE. CONCLUSION: Ensartinib has been tentatively proven favorable efficacy and tolerability in the treatment of patients with ALK-positive advanced LUSC or LASC in the real-world. However, confirmatory studies are still needed in larger sample sizes.

[Establishment of a method for separating macrophage migrasomes].

Objective To establish an efficient method for isolating migrasomes from RAW264.7 macrophages and identifying these isolated migrasomes. Methods Scanning electron microscopy was used to observe the morphological characteristics of migrasomes produced by RAW264.7 cells. A 0.45 µm filter was employed for reverse filtration and elution to isolate the migrasomes. The morphological characteristics of the migrasomes were then observed using transmission electron microscopy. Western blot analysis was performed to determine the expression of characteristic markers of the migrasomes. The RNA carried by the migrasomes was analysed by using LabChip bioanalyzer. Results Scanning electron microscopy revealed that the migrasomes, with membranous structures, were attached to the tip or bifurcation of the retraction fiber formed in the tail of RAW264.7 cells. Transmission electron microscopy showed that the isolated migrasomes had a typical oval vesicle-like structure with wrinkled membrane surfaces. Western blot analysis confirmed the expression of the characteristic markers phosphatidylinositol glycan anchor biosynthesis class K (PIGK), epidermal growth factor domain-specific O-linked N-acetylglucosamine transferase (EOGT) and tetraspanin 4 (TSPAN4) in the migrasomes, while the EV (extracellular vesicle) markers tumor susceptibility gene 101 (TSG101) and Arabidopsis homolog of apoptosis-linked gene 2-interacting protein X (ALIX) were not detected. Furthermore, the isolated migrasomes were found to be rich in small RNA, which were approximately 25-200 nt in length. Conclusion A method for the extraction of well-structured and high quality migrasomes from macrophages is established.

Schistosome egg antigen stimulates the secretion of miR-33-carrying extracellular vesicles from macrophages to promote hepatic stellate cell activation and liver fibrosis in schistosomiasis.

Schistosomiasis is a serious and neglected disease with a high prevalence in tropical and subtropical countries. The primary pathology of hepatic schistosomiasis caused by Schistosoma japonicum (S. japonicum) or Schistosoma mansoni (S. mansoni) infection is egg-induced granuloma and subsequent fibrosis in the liver. Activation of hepatic stellate cells (HSCs) is the central driver of liver fibrosis. Macrophages (Mφ), making up 30% of cells in hepatic granulomas, directly or indirectly regulate HSC activation by paracrine mechanisms, via secreting cytokines or chemokines. Currently, Mφ-derived extracellular vesicles (EVs) are broadly involved in cell communication with adjacent cell populations. However, whether Mφ-derived EVs could target neighboring HSCs to regulate their activation during schistosome infection remains largely unknown. Schistosome egg antigen (SEA) is considered to be the main pathogenic complex mixture involved in liver pathology. Here, we demonstrated that SEA induced Mφ to produce abundant extracellular vesicles, which directly activated HSCs by activating their autocrine TGF-ß1 signaling. Mechanistically, EVs derived from SEA-stimulated Mφ contained increased miR-33, which were transferred into HSCs and subsequently upregulated autocrine TGF-ß1 in HSCs through targeting and downregulating SOCS3 expression, thereby promoting HSC activation. Finally, we validated that EVs derived from SEA-stimulated Mφ utilized enclosed miR-33 to promote HSC activation and liver fibrosis in S. japonicum-infected mice. Overall, our study indicates that Mφ-derived EVs play important roles in the paracrine regulation of HSCs during the progression of hepatic schistosomiasis, representing a potential target for the prevention of liver fibrosis in hepatic schistosomiasis.

Migrasomes, a new mode of intercellular communication.

Migrasomes are newly discovered extracellular vesicles (EVs) that are formed in migrating cells and mediate intercellular communication. However, their size, biological generation, cargo packaging, transport, and effects on recipient cells by migrasomes are different from those of other EVs. In addition to mediating organ morphogenesis during zebrafish gastrulation, discarding damaged mitochondria, and lateral transport of mRNA and proteins, growing evidence has demonstrated that migrasomes mediate a variety of pathological processes. In this review, we summarize the discovery, mechanisms of formation, isolation, identification, and mediation of cellular communication in migrasomes. We discuss migrasome-mediated disease processes, such as osteoclast differentiation, proliferative vitreoretinopathy, tumor cell metastasis by PD-L1 transport, immune cell chemotaxis to the site of infection by chemokines, angiogenesis promotion via angiogenic factors by immune cells, and leukemic cells chemotaxis to the site of mesenchymal stromal cells. Moreover, as new EVs, we propose the potential of migrasomes for disease diagnosis and treatment. Video Abstract.

Increased TIM-3 expression in tumor-associated macrophages predicts a poorer prognosis in non-small cell lung cancer: a retrospective cohort study.

Background: T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) is considered a key negative regulator in T-cell-mediated response. However, few studies have been reported on the relationship between TIM-3 expression in tumor-associated macrophages (TAMs) and clinicopathological characteristics of patients. This study evaluated the correlation between the expression of TIM-3 on the surface of TAMs macrophages in tumor matrix and the clinical outcome of patients with non-small cell lung cancer (NSCLC). Methods: The expression of CD68, CD163 and TIM-3 in 248 NSCLC patients who underwent surgery in Zhoushan Hospital from January 2010 to January 2013 was detected by immunohistochemistry (IHC). From the date of operation to the date of death, overall survival (OS) was measured to analyze the relationship between the expression of Tim-3 and the prognosis of NSCLC patients. Results: The study assessed 248 patients with NSCLC. TIM-3 expression in TAMs was more frequently identified in patients with higher carcinoembryonic antigen (CEA) levels, lymph node metastasis, higher grade, high CD68 expression, and high CD163 expression (P<0.05). The OS of the high TIM-3 expression groups was shorter than that of the low TIM-3 expression groups (P=0.01). Patients with high TIM-3 and CD68/CD163 expressions had the worst prognosis, whereas patients with low expressions of both TIM-3 and CD68/CD163 had the best prognosis (P<0.05). In NSCLC, the OS of the high TIM-3 expression groups was shorter than that of the low TIM-3 expression groups (P=0.01). In lung adenocarcinoma, the OS of the high TIM-3 expression groups was shorter than that of the low TIM-3 expression groups(P=0.03). Conclusions: TIM-3 expression in TAMs may be a promising prognostic biomarker for NSCLC or adenocarcinoma. Our results demonstrated that high TIM-3 expression in TAMs was an independent predictor of worse prognosis in patients.

A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles.

Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are extremely promising nanoscale cell-free therapeutic agents. We previously identified that intravenous administration (IV) of human umbilical cord MSC-EVs (hUCMSC-EVs), especially hypoxic hUCMSC-EVs (Hypo-EVs), could suppress allergic airway inflammation and remodeling. Here, we further investigated the therapeutic effects of Hypo-EVs administration by atomizing inhalation (INH), which is a non-invasive and efficient drug delivery method for lung diseases. We found that nebulized Hypo-EVs produced by the atomization system (medical/household air compressor and nebulizer) maintained excellent structural integrity. Nebulized Dir-labeled Hypo-EVs inhaled by mice were mainly restricted to lungs. INH administration of Hypo-EVs significantly reduced the airway inflammatory infiltration, decreased the levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF), declined the content of OVA-specific IgE in serum, attenuated the goblet cell metaplasia, and the expressions of subepithelial collagen-1 and α-smooth muscle actin (α-SMA). Notably, Hypo-EV INH administration was generally more potent than Hypo-EV IV in suppressing IL-13 levels and collagen-1 and α-SMA expressions. RNA sequencing revealed that various biological processes, such as cell adhesion, innate immune response, B cell activation, and extracellular space, were associated with the activity of Hypo-EV INH against asthma mice. In addition, Hypo-EVs could load exogenous miR-146a-5p (miR-146a-5p-EVs). Furthermore, INH administration of miR-146a-5p-EVs resulted in a significantly increased expression of miR-146a-5p mostly in lungs, and offered greater protection against the OVA-induced increase in airway inflammation, subepithelial collagen accumulation and myofibroblast compared with nebulized Hypo-EVs. Overall, nebulized Hypo-EVs effectively attenuated allergic airway inflammation and remodeling, potentially creating a non-invasive route for the use of MSC-EVs in asthma treatment.

Isolation and characterization of extracellular vesicle-like nanoparticles derived from migrasomes.

Migrasomes comprise a recently identified unique type of extracellular vesicle (EV) containing varying numbers of small vesicles. However, the final fate of these small vesicles is still unclear. Here, we report the discovery of EV-like migrasome-derived nanoparticles (MDNPs) that are produced by migrasomes releasing internal vesicles via self-rupture and through a process similar to cell plasma membrane budding. Our results demonstrate that MDNPs have a membrane structure with a typical round-shaped morphology and have the characteristic markers of migrasomes, but do not present the markers of EVs from the cell culture supernatant. More importantly, we also show that MDNPs are loaded with a large number of microRNAs different from those found in migrasomes and EVs. Our results provide evidence that migrasomes can produce EV-like nanoparticles. These findings have important implications for understanding the unknown biological functions of migrasomes.

A retrospective study of ensartinib-treated ALK-positive locally advanced or metastatic NSCLC patients in China.

Aim: This retrospective study aimed to assess the efficacy and safety of ensartinib in Chinese patients with ALK-positive advanced NSCLC in real-world clinical practice. Methods: Clinical data from ALK-positive NSCLC patients treated with ensartinib in China were collected and analyzed. Efficacy end points included objective response rate and progression-free survival. Safety profiles were also evaluated. Results: A total of 682 patients were included in this study. The study demonstrated promising efficacy with an objective response rate of 54.0%, and the median progression-free survival was not estimable. Ensartinib exhibited a manageable safety profile with treatment-related adverse events (TRAEs) consistent with prior clinical trials. The most common TRAE was rash (21.1%) and no TRAE led to death. Conclusion: Ensartinib is active and well tolerated for ALK-positive NSCLC patients in real-world clinical settings.

Targeted therapies have significantly improved outcomes for patients with ALK-positive NSCLC. Ensartinib, a drug which blocks an enzyme in the body called ALK tyrosine kinase, has shown to be efficient and well tolerated in clinical trials. However, real-world evidence is crucial to confirm its effectiveness and safety in diverse patient populations. We analyzed the real-world outcomes of ensartinib treatment in 682 ALK-positive NSCLC patients in China, by looking at past records. The results showed that ensartinib demonstrated positive effects in most patients, meaning it helped in controlling their cancer progression. Side effects affected approximately one quarter of patients and most reported side effects were mild. Rash was the most reported side effect, accounting for about 21%. This study provides valuable insights into the real-world clinical performance of ensartinib, confirming its effectiveness and safety as a treatment option for ALK-positive NSCLC patients.

The influence of firm's feedbacks on user-generated content's linguistic style matching-An explanation based on communication accommodation theory.

In virtual brand communities, users and firms continuously use different or similar linguistic styles to communicate with each other. Existing literature has demonstrated that the linguistic style matching (LSM) between the coming users' posts [user-generated content (UGC)] and existing firms' content will influence users' behavior, like promoting users to release more posts. However, little research has been conducted to analyze how firms' feedbacking behaviors influence LSM. To fill the gap, this paper uses Python to measure the LSM between 69,463 posts from 9,777 users and existing firms' generated content in the MIUI community and examines the impact of firms' feedbacks on this LSM. The results show that the firms' feedbacks frequency increased the LSM, but the firms' feedbacks text length decreased the LSM. In addition, users' textual sentiment and the published text length moderate the impact of firms' feedbacks (e.g., frequency, text length) on LSM. Specifically, the users' textual sentiment valence increases the positive effect of firms' feedbacks frequency and weakens the negative effect of firms' feedbacks text length on LSM. The users' produced content text length reduced the positive effect of firms' feedbacks frequency and offset the negative effect of the firms' feedbacks text length on LSM. Further, the effects above are significant for the relatively active users but not for the inactive ones. Based on communication accommodation theory, this paper investigates the impact of firms' feedbacks frequency and text length on subsequent users' posting behaviors, providing an essential reference for guiding firms' virtual brand community management.

Why Are User-Generated Contents So Varied? An Explanation Based on Variety-Seeking Theory and Topic Modeling.

In online communities, such as Twitter, Facebook, or Reddit, millions of pieces of contents are generated by users every day, and these user-generated contents (UGCs) show a great variety of topics discussed that make the online community vivid and attractive. However, the reasons why UGCs show great variety and how a firm can influence this variety was unknown, which had been an obstacle to understanding and managing UGCs' variety. This study fills these two gaps based on variety-seeking theory and topic modeling, which is a technique in machine learning. We extract, quantitatively, the topic of the UGCs using topic modeling and divide UGCs into two types: single topic and multiple topics. The user's tendency to choose the type of UGC is used to measure variety-seeking behavior. We found that users have an intrinsic preference for variety when producing UGCs; the more single topic UGCs were produced in the past, the higher the probability of producing multiple topics UGC and the lower the probability of producing single topic UGC would be in the next, and vice versa. Furthermore, we discussed the effect of language/linguistic style matching (LSM) between firm feedbacks and UGCs on users' variety-seeking tendencies in UGCs' production. This study makes three contributions: (1) broadening variety-seeking theory to new behavior, that is content production behavior, and the results demonstrated that people would show a variety-seeking behavior in producing UGCs. (2) a new feasible method to measure the variety of UGCs by using topic modeling to extract the topics of UGCs and then measure the variety-seeking behavior in producing UGCs by analyzing the choice between single topic and multiple topics. (3) guidance for the firm to alter LSM of feedbacks to influence the variety of UGCs.

Efficacy of Icotinib, an EGFR Tyrosine Kinase Inhibitor in Non-Small Cell Lung Cancer Patients with Exon 19 Deletion and Exon 21 L858R: A Retrospective Analysis in China.

INTRODUCTION: The effect of icotinib on non-small cell lung cancer (NSCLC) patients with EGFR exon 19 deletions (19-Del) or L858R point mutation in exon 21 (21-L858R) remains inconsistent. This study aimed to evaluate the efficacy and safety of icotinib in patients with advanced NSCLC harboring these 2 EGFR mutations. METHODS: We retrospectively assessed the clinical effects of first-line icotinib on advanced NSCLC patients with 2 classic EGFR mutations. Kinase activity assays were used to reaffirm the preclinical efficacy. RESULTS: Among 2,757 patients, 2,365 (86%) harbored 19-Del (1,346/2,757, 49%) or 21-L858R (1,019/2,757, 37%) mutation. Patients with 19-Del had a higher response rate (ORR; 67.8 vs. 62.1%; p = 0.0039) and disease control rate (98.5 vs. 97.2%; p = 0.0223) than those with 21-L858R mutation. The median progression-free survival (PFS) in the 19-Del group (22.3 months, 95% confidence interval [CI]: 21.3-23.4) was significantly longer than that in the 21-L858R group (20.4 months, 95% CI: 19.5-21.7) (p = 0.004). In multivariate analysis, mutation types, clinical stage, and smoking history were significant factors for PFS. Additionally, an in vitro study indicated the 50% inhibitory concentrations (IC50) of icotinib was lower for EGFR 19-Del than 21-L858R. CONCLUSION: These results suggest that EGFR 19-Del confers superior PFS and response to the icotinib treatment compared to 21-L858R.

SJMHE1 Peptide from Schistosoma japonicum Inhibits Asthma in Mice by Regulating Th17/Treg Cell Balance via miR-155.

PURPOSE: Helminths and their products can regulate immune response and offer new strategies to control and alleviate inflammation, including asthma. We previously found that a peptide named as SJMHE1 from Schistosoma japonicum can suppress asthma in mice. This study mainly investigated the molecular mechanism of SJMHE1 in inhibiting asthma inflammation. METHODS: SJMHE1 was administered to mice with OVA-induced asthma via subcutaneous injection, and its effects were detected by testing the airway inflammation of mice. The Th cell distribution was analyzed by flow cytometry. Th-related transcription factor and cytokine expression in the lungs of mice were analyzed using quantitative real-time PCR (qRT-PCR). The expression of miR-155 and levels of phosphorylated STAT3 and STAT5 were also determined after SJMHE1 treatment in mice by qRT-PCR and Western blot analysis. The in vitro mouse CD4+ T cells were transfected with lentivirus containing overexpressed or inhibited miR-155, and the proportion of Th17, Treg cells, CD4+p-STAT3+, and CD4+p-STAT5+ cells were analyzed by flow cytometry. RESULTS: SJMHE1 ameliorated the airway inflammation of asthmatic mice, upregulated the proportion of Th1 and Treg cells, and the expression of Th1 and Treg-related transcription factor and cytokines. Simultaneously, SJMHE1 treatment reduced the percentage of Th2 and Th17 cells and the expression of Th2 and Th17-related transcription factor and cytokines. SJMHE1 treatment decreased the expression of miR-155 and p-STAT3 but increased p-STAT5 expression. In vitro, the percentage of Th17 and CD4+p-STAT3+ cells increased in CD4+ T cells transfected over-expression of miR-155, but SJMHE1 inhibited the miR-155-mediated increase of Th17 cells. Furthermore, SJMHE1 increased the proportion of Treg and CD4+p-STAT5+ cells after transfected over-expression or inhibition of miR-155. CONCLUSION: SJMHE1 regulated the balance of Th17 and Treg cells by modulating the activation of STAT3 and STAT5 via miR-155 in asthma. SJMHE1 might be a promising treatment for asthma.

Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles Promote the Proliferation of Schwann Cells by Regulating the PI3K/AKT Signaling Pathway via Transferring miR-21.

As an alternative mesenchymal stem cell- (MSC-) based therapy, MSC-derived extracellular vesicles (EVs) have shown promise in the field of regenerative medicine. We previously found that human umbilical cord mesenchymal stem cell-derived EVs (hUCMSC-EVs) improved functional recovery and nerve regeneration in a rat model of sciatic nerve transection. However, the underlying mechanisms are poorly understood. Here, we demonstrated for the first time that hUCMSC-EVs promoted the proliferation of Schwann cells by activating the PI3K/AKT signaling pathway. Furthermore, we showed that hUCMSC-EVs mediated Schwann cell proliferation via transfer of miR-21. Our findings highlight a novel mechanism of hUCMSC-EVs in treating peripheral nerve injury and suggest that hUCMSC-EVs may be an attractive option for clinical application in the treatment of peripheral nerve injury.

Schistosoma japonicum peptide SJMHE1 inhibits acute and chronic colitis induced by dextran sulfate sodium in mice.

BACKGROUND: Harnessing helminth-based immunoregulation is a novel therapeutic strategy for many immune dysfunction disorders, including inflammatory bowel diseases (IBDs). We previously identified a small molecule peptide from Schistosoma japonicum and named it SJMHE1. SJMHE1 can suppress delayed-type hypersensitivity, collagen-induced arthritis and asthma in mice. In this study, we assessed the effects of SJMHE1 on dextran sulfate sodium (DSS)-induced acute and chronic colitis. METHODS: Acute and chronic colitis were induced in C57BL/6 mice by DSS, following which the mice were injected with an emulsifier SJMHE1 or phosphate-buffered saline. The mice were then examined for body weight loss, disease activity index, colon length, histopathological changes, cytokine expression and helper T (Th) cell subset distribution. RESULTS: SJMHE1 treatment significantly suppressed DSS-induced acute and chronic colitis, improved disease activity and pathological damage to the colon and modulated the expression of pro-inflammatory and anti-inflammatory cytokines in splenocytes and the colon. In addition, SJMHE1 treatment reduced the percentage of Th1 and Th17 cells and increased the percentage of Th2 and regulatory T (Treg) cells in the splenocytes and mesenteric lymph nodes of mice with acute colitis. Similarly, SJMHE1 treatment upregulated the expression of interleukin-10 (IL-10) mRNA, downregulated the expression of IL-17 mRNA and modulated the Th cell balance in mice with chronic colitis. CONCLUSIONS: Our data show that SJMHE1 provided protection against acute and chronic colitis by restoring the immune balance. As a small molecule, SJMHE1 might be a novel agent for the treatment of IBDs without immunogenicity concerns.

Schistosoma japonicum-derived peptide SJMHE1 promotes peripheral nerve repair through a macrophage-dependent mechanism.

Peripheral nerve injury, a disease that affects 1 million people worldwide every year, occurs when peripheral nerves are destroyed by injury, systemic illness, infection, or an inherited disorder. Indeed, repair of damaged peripheral nerves is predominantly mediated by type 2 immune responses. Given that helminth parasites induce type 2 immune responses in hosts, we wondered whether helminths or helminth-derived molecules might have the potential to improve peripheral nerve repair. Here, we demonstrated that schistosome-derived SJMHE1 promoted peripheral myelin growth and functional regeneration via a macrophage-dependent mechanism and simultaneously increased the induction of M2 macrophages. Our findings highlight the therapeutic potential of schistosome-derived SJMHE1 for improving peripheral nerve repair.

The role of platelet to mean platelet volume ratio in the identification of adult-onset still's disease from sepsis.

OBJECTIVES: Inflammatory factors exert a significant role in the development of adult-onset Still's disease (AOSD) and sepsis. Although platelet counts and platelet parameters have long served as indicators for inflammatory diseases, their role in the differential diagnosis between adult-onset stills disease and sepsis remains unclear. We designed this retrospective study to explore whether the platelet to mean platelet volume (MPV) ratio (PMR) can help to distinguish AOSD from sepsis. METHODS: A total of 110 AOSD patients and 84 sepsis patients were enrolled in the study. Seventy-three AOSD patients and 56 sepsis patients between January 2010 and June 2017 were enrolled in the test cohort to analyze PMR values, which was then validated in the validation cohort (37 AOSD patients and 28 sepsis patients between June 2017 and December 2019). RESULTS: The values of PMR were significantly higher in AOSD patients than in sepsis patients (test cohort, validation cohort, and entire cohort), In the test cohort, logistic regression analysis showed that PMR was an independent risk factor of AOSD (odds ratios [OR]: 9.22, 95% confidence interval [CI] 2.15-39.46, p=0.003). Further receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve was 0.735 (95% CI 0.631-0.839, p<0.001) for PMR alone and 0.925 (95% CI 0.869-0.980, p<0.001) for the combination of PMR and serum ferritin. Consistently, the validation cohort exhibited analogous results. CONCLUSIONS: PMR could be used as a single indicator or a complementary indicator to distinguish AOSD from sepsis.

A semi-analytical model for the modal density of periodic mediums based on the symplectic method.

In this paper, a semi-analytical approach is provided for the modal density of periodic mediums based on the symplectic method. For two-dimensional periodic mediums with a plate component and one-dimensional periodic mediums with a beam component and truss component, the symplectic method is introduced to describe the conditions of continuity and periodicity of the unit cell. And then by virtue of the adjoint symplectic orthogonal relations, an eigenproblem is first established for the dispersion relation of the periodic mediums. The group velocity is then obtained semi-analytically by differentiating the eigenproblem with respect to frequency. Since the expressions of the kinematic and the kinetic variables of the unit cell involved in derivation processes are expressed in terms of symplectic analytical waves, the modal density of periodic mediums can be obtained with high efficiency and with high accuracy. Numerical examples including two-dimensional periodic mediums with a plate component and one-dimensional periodic mediums with a beam component and truss component are provided. The comparison of the present results with the results obtained from the finite element model confirms the effectiveness of the proposed method.

Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice.

BACKGROUND: As one of the main functional forms of mesenchymal stem cells (MSCs), MSC-derived extracellular vesicles (MSC-EVs) have shown an alternative therapeutic option in experimental models of allergic asthma. Oxygen concentration plays an important role in the self-renewal, proliferation, and EV release of MSCs and a recent study found that the anti-asthma effect of MSCs was enhanced by culture in hypoxic conditions. However, the potential of hypoxic MSC-derived EVs (Hypo-EVs) in asthma is still unknown. METHODS: BALB/c female mice were sensitized and challenged with ovalbumin (OVA), and each group received PBS, normoxic human umbilical cord MSC-EVs (Nor-EVs), or Hypo-EVs weekly. After treatment, the animals were euthanized, and their lungs and bronchoalveolar lavage fluid (BALF) were collected. With the use of hematoxylin and eosin (HE), periodic acid-Schiff (PAS) and Masson's trichrome staining, enzyme-linked immune sorbent assay (ELISA), Western blot analysis, and real-time PCR, the inflammation and collagen fiber content of airways and lung parenchyma were investigated. RESULTS: Hypoxic environment can promote human umbilical cord MSCs (hUCMSCs) to release more EVs. In OVA animals, the administration of Nor-EVs or Hypo-EVs significantly ameliorated the BALF total cells, eosinophils, and pro-inflammatory mediators (IL-4 and IL-13) in asthmatic mice. Moreover, Hypo-EVs were generally more potent than Nor-EVs in suppressing airway inflammation in asthmatic mice. Compared with Nor-EVs, Hypo-EVs further prevented mouse chronic allergic airway remodeling, concomitant with the decreased expression of pro-fibrogenic markers α-smooth muscle actin (α-SMA), collagen-1, and TGF-ß1-p-smad2/3 signaling pathway. In vitro, Hypo-EVs decreased the expression of p-smad2/3, α-SMA, and collagen-1 in HLF-1 cells (human lung fibroblasts) stimulated by TGF-ß1. In addition, we showed that miR-146a-5p was enriched in Hypo-EVs compared with that in Nor-EVs, and Hypo-EV administration unregulated the miR-146a-5p expression both in asthma mice lung tissues and in TGF-ß1-treated HLF-1. More importantly, decreased miR-146a-5p expression in Hypo-EVs impaired Hypo-EV-mediated lung protection in OVA mice. CONCLUSION: Our findings provided the first evidence that hypoxic hUCMSC-derived EVs attenuated allergic airway inflammation and airway remodeling in chronic asthma mice, potentially creating new avenues for the treatment of asthma.

The role of platelet to mean platelet volume ratio in the identification of adult-onset still's disease from sepsis

OBJECTIVES: Inflammatory factors exert a significant role in the development of adult-onset Still's disease (AOSD) and sepsis. Although platelet counts and platelet parameters have long served as indicators for inflammatory diseases, their role in the differential diagnosis between adult-onset stilĺs disease and sepsis remains unclear. We designed this retrospective study to explore whether the platelet to mean platelet volume (MPV) ratio (PMR) can help to distinguish AOSD from sepsis. METHODS: A total of 110 AOSD patients and 84 sepsis patients were enrolled in the study. Seventy-three AOSD patients and 56 sepsis patients between January 2010 and June 2017 were enrolled in the test cohort to analyze PMR values, which was then validated in the validation cohort (37 AOSD patients and 28 sepsis patients between June 2017 and December 2019). RESULTS: The values of PMR were significantly higher in AOSD patients than in sepsis patients (test cohort, validation cohort, and entire cohort), In the test cohort, logistic regression analysis showed that PMR was an independent risk factor of AOSD (odds ratios [OR]: 9.22, 95% confidence interval [CI] 2.15-39.46, p=0.003). Further receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve was 0.735 (95% CI 0.631-0.839, p<0.001) for PMR alone and 0.925 (95% CI 0.869-0.980, p<0.001) for the combination of PMR and serum ferritin. Consistently, the validation cohort exhibited analogous results. CONCLUSIONS: PMR could be used as a single indicator or a complementary indicator to distinguish AOSD from sepsis.

[Pharmacology and Clinical Evaluation of Ensartinib Hydrochloride Capsule].

Lung cancer is one of the most common malignancies with the highest incidence rate and mortality rate worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85%. Only 5% NSCLC patients are anaplastic lymphoma kinase (ALK) rearrangement positive NSCLC, but the prognosis of these patients is poor, and treatment is urgent. Ensartinib (X-396), a next-generation ALK tyrosine kinase inhibitor (ALK-TKI), has shown greater potency on inhibiting ALK activity and controlling brain metastases than crizotinib, which is indicated for the treatment of crizotinib-resistant, ALK-positive NSCLC patients. Several phase I to III clinical trials included both healthy volunteers and NSCLC patients have been conducted both in China and abroad. In this review, we briefly summarized the results of these trials, and preliminary efficacy, safety, pharmacology and pharmacokinetics/pharmacodynamics of ensartinib were discussed.