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The development of efficient and durable electrocatalysts for the alkaline hydrogen oxidation/evolution reaction is crucial for anion exchange membrane fuel cells/water electrolyzers. However, designing such electrocatalysts poses a challenge due to the need for optimizing various adsorbates. Herein, highly dispersed Ru nanoparticles catalysts is reported encapsulated and supported by defective anatase phase of titanium dioxide (named as Ru NPs/def-TiO 2 (A)) for boosting hydrogen-cycle electrocatalysis with robust anti-CO-poisoning in alkaline conditions. The Ru NPs/def-TiO 2 (A) achieves a high-quality activity of 7.65 A mg Ru -1 , which is 23.2 and 9.5-fold higher than commercial Ru/C and Pt/C in alkaline HOR. Moreover, this catalyst exhibits an outstanding overpotential of 21 mV at 10 mA cm -2 in alkaline HER. Hydrogen underpotential deposition (H upd ) and CO stripping experiments demonstrate that Ru NPs/def-TiO 2 (A) has the optimized H*, OH*, and CO* adsorption strength, enabling the Ru NPs/def-TiO 2 (A) catalyst to display excellent and robust HOR/HER performance under alkaline conditions. Using density functional theory calculations, the enhanced HOR performance mechanism for the Ru NPs/def-TiO 2 (A) catalyst originates from the TiO 2 step face in contact with the Ru nanoparticles, indicating that the kinetics of water formation are considerably more favorable at the Ru NPs/def-TiO 2 (A) interface., (© 2024 Wiley‐VCH GmbH.)

With the advancement of wearable and implantable medical devices, hydrogel flexible bioelectronic devices have attracted significant interest due to exhibiting tissue-like mechanical compliance, biocompatibility, and low electrical resistance. In this study, the development and comprehensive performance evaluation of poly(acrylic acid)/ N,N'-bis(acryloyl) cystamine/ 1-butyl-3-ethenylimidazol-1-ium:bromide (PAA/NB/IL) hydrogels designed for flexible sensor applications are introduced. Engineered through a combination of physical and chemical cross-linking strategies, these hydrogels exhibit strong mechanical properties, high biocompatibility, and effective sensing capabilities. At 95 % strain, the compressive modulus of PAA/NB/IL 100 reach up to 3.66 MPa, with the loading-unloading process showing no significant hysteresis loop, indicating strong mechanical stability and elasticity. An increase in the IL content was observed to enlarge the porosity of the hydrogels, thereby influencing their swelling behavior and sensing functionality. Biocompatibility assessments revealed that the hemolysis rate was below 5 %, ensuring their suitability for biomedical applications. Upon implantation in rats, a minimal acute inflammatory response was observed, comparable to that of the biocompatibility control poly(ethylene glycol) diacrylate (PEGDA). These results suggest that PAA/NB/IL hydrogels hold promise as biomaterials for biosensors, offering a balance of mechanical integrity, physiological compatibility, and sensing sensitivity, thereby facilitating advanced healthcare monitoring solutions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: This work aimed to explore anxiety-associated risk factors in patients diagnosed with ulcerative colitis (UC)., Methods: Clinical data from patients diagnosed with UC and hospitalized at the First Affiliated Hospital of Xi'an Jiaotong University between May 2019 and June 2022 were retrospectively analyzed. A total of 260 patients were included and divided into UC with anxiety (n = 86) and UC without anxiety (n = 174) groups according to the Self-Rating Anxiety Scale score. The quality of life and disease activity in patients with UC were assessed using the Inflammatory Bowel Disease Questionnaire and Mayo Score, respectively. Clinical data, disease characteristics, quality of life, disease activity, and noise exposure were compared between the groups, and factors contributing to anxiety in patients with UC were explored through multivariate logistic regression analysis., Results: No significant difference was found between the groups in terms of disease duration (P = 0.73), distribution of disease (P = 0.86), or medication use (P = 0.86). However, compared to UC patients without anxiety, those with anxiety were older (P < 0.05), predominantly female (P < 0.05), had lower quality of life (P < 0.05), experienced higher disease activity (P < 0.05), and had greater noise exposure (P < 0.05). The quality of life [odds ratio (OR) = 0.558, 95% confidence interval (CI) = 0.348-0.895, P = 0.02] was a protective factor for anxiety in patients with UC. Disease activity (OR = 1.680, 95% CI = 1.103-2.561, P = 0.02) and noise exposure (OR = 2.148, 95% CI = 1.084-4.106, P = 0.01) were significant risk factors for anxiety in patients with UC., Conclusion: Noise exposure and disease activity were associated with an increased risk of anxiety in patients with UC, whereas higher quality of life was protective against anxiety in UC patients., (Copyright © 2024 Noise & Health.)

Developing patches that effectively merge intrinsic deformation characteristics of cardiac with superior tunable mechanical properties remains a crucial biomedical pursuit. Currently used traditional block-shaped or mesh patches, typically incorporating a positive Poisson's ratio, often fall short of matching the deformation characteristics of cardiac tissue satisfactorily, thus often diminishing their repairing capability. By introducing auxeticity into the cardiac patches, this study is trying to present a beneficial approach to address these shortcomings of the traditional patches. The patches, featuring the auxetic effect, offer unparalleled conformity to the cardiac complex mechanical challenges. Initially, scaffolds demonstrating the auxetic effect were designed by merging chiral rotation and concave angle units, followed by integrating scaffolds with a composite hydrogel through thermally triggering, ensuring excellent biocompatibility closely mirroring heart tissue. Tensile tests revealed that auxetic patches possessed superior elasticity and strain capacity exceeding cardiac tissue's physiological activity. Notably, Model III showed an equivalent modulus ratio and Poisson's ratio closely toward cardiac tissue, underscoring its outstanding mechanical potential as cardiac patches. Cyclic tensile loading tests demonstrated that Model III withstood continuous heartbeats, showcasing outstanding cyclic loading and recovery capabilities. Numerical simulations further elucidated the deformation and failure mechanisms of these patches, leading to an exploration of influence on mechanical properties with alternative design parameters, which enabled the customization of mechanical strength and Poisson's ratio. Therefore, this research presents substantial potential for designing cardiac auxetic patches that can emulate the deformation properties of cardiac tissue and possess adjustable mechanical parameters., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

Degradable biomedical elastomers (DBE), characterized by controlled biodegradability, excellent biocompatibility, tailored elasticity, and favorable network design and processability, have become indispensable in tissue repair. This review critically examines the recent advances of biodegradable elastomers for tissue repair, focusing mainly on degradation mechanisms and evaluation, synthesis and crosslinking methods, microstructure design, processing techniques, and tissue repair applications. The review explores the material composition and cross-linking methods of elastomers used in tissue repair, addressing chemistry-related challenges and structural design considerations. In addition, this review focuses on the processing methods of two- and three-dimensional structures of elastomers, and systematically discusses the contribution of processing methods such as solvent casting, electrostatic spinning, and three-/four-dimensional printing of DBE. Furthermore, we describe recent advances in tissue repair using DBE, and include advances achieved in regenerating different tissues, including nerves, tendons, muscle, cardiac, and bone, highlighting their efficacy and versatility. The review concludes by discussing the current challenges in material selection, biodegradation, bioactivation, and manufacturing in tissue repair, and suggests future research directions. This concise yet comprehensive analysis aims to provide valuable insights and technical guidance for advances in DBE for tissue engineering.

Background: Creativity is an essential cognitive ability that plays a crucial role in advanced thinking. While previous research has demonstrated the impact of insomnia on cognitive function, its effects on creativity in Chinese adolescents remain unclear. This study explored the relationship between insomnia (specifically, daytime and nighttime disturbances) and creativity in adolescents. Additionally, it examined the potential mediating effect of the need for cognition on this relationship., Methods: Questionnaires were administered to 302 adolescents to measure their creativity, need for cognition, and insomnia levels using the Williams Creative Tendencies Scale, Need for Cognition Scale, and Bergen Insomnia Scale, respectively. Regression analysis was conducted to examine the direct impact of insomnia on creativity. Furthermore, a mediation model was constructed to investigate the role of the need for cognition in mediating the relationship between insomnia and creativity., Results: The findings of the present study indicated that insomnia had a direct impact on the creativity of adolescents, demonstrating a time-of-day effect. Daytime disturbances were found to have a positive correlation with overall creativity and imagination, whereas no significant direct effect was found between nighttime disturbances and creativity. Further analysis revealed that insomnia, specifically daytime disturbances, might influence creativity by affecting the individual's need for cognition. However, no similar indirect effects were observed for the relationship between nighttime disturbances and creativity., Conclusions: Our findings indicate that adolescents might experience improved creativity as a result of daytime disruptions, and the level of need for cognition could play a crucial role in understanding the link between insomnia and creativity in adolescents., (© 2024. The Author(s).)

Background: Despite its early success, immunotherapy focused on removing T-cell inhibition does not achieve the desired effect in most patients. New strategies that target antigen-driven T-cell activation are needed to improve immunotherapy outcomes. However, a comprehensive analysis of synthetic drivers of T-cells is greatly lacking in lung adenocarcinoma (LUAD) and other types of tumors., Methods: We comprehensively evaluated the patterns of LUAD patients based on T -cell synthetic drivers by unsupervised clustering analysis. A risk model was constructed using Lasso Cox regression analysis. The predicted survival and immunotherapy efficacy of the model was validated by independent cohorts. Finally, single-cell sequencing analysis, and a series of in vitro experiments were conducted to explore the role of lactate dehydrogenase A (LDHA) in the malignant progression of LUAD., Results: Patients in the high-risk group were characterized by survival disadvantage, a "cold" immune phenotype, and by not having benefitted from immunotherapy. LDHA was shown to promote LUAD cell proliferation, cell cycle, invasion, and migration. Secondly, we found that LDHA induced NF-κB pathway activation, tyrosine kinase inhibitor resistance and immunosuppressant microenvironment. Finally, LDHA was found to be highly expressed in fibroblasts, which may be involved in promoting TKI resistance and mediating the immune escape., Conclusion: This study revealed that the T-cell synthetic driver-associated prognostic model developed herein significantly predicted prognosis and immunotherapy efficacy in LUAD. We further investigated the role of LDHA in the malignant phenotype of tumor cells and tumor microenvironment remodeling, providing a promising and novel therapeutic strategy for LUAD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: With the development of medical technology and change of life habits, early-stage lung adenocarcinoma (LUAD) has become more common. This study aimed to systematically analyzed clinicopathological factors associated to the overall survival (OS) of patients with Stage IA LUAD., Methods: A total of 5942 Stage IA LUAD patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier methods and log-rank tests were used to compare the differences in OS. A nomogram constructed based on the Cox regression was evaluated by Concordance index (C index), calibration curve, decision curve analysis (DCA) and area under curve (AUC). And 136 patients were recruited from Shandong Province Hospital for external validation., Results: Cox analysis regression indicated that 12 factors, such as Diagnosis to Treatment Interval (DTI) and Income Level, were independent prognostic factors and were included to establish the nomogram. The C-index of our novel model was 0.702, 0.724 and 0.872 in the training, internal and external validation cohorts, respectively. The 3-year and 5-year survival AUCs and calibration curves showed excellent agreement in each cohort. Some new factors in the SEER database, including DTI and Income Level, were firstly confirmed as independent prognostic factors of Stage IA LUAD patients. The distribution of these factors in the T1a, T1b, and T1c subgroups differed and had different effects on survival., Conclusion: We summarized 12 factors that affect prognosis and constructed a nomogram to predict OS of Stage IA LUAD patients who underwent operation. For the first time, new SEER database parameters, including DTI and Income Level, were proved to be survival-related., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

Osimertinib is a promising approved third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for treating patients with lung adenocarcinoma (LUAD) harboring EGFR-activating mutations, however, almost all patients develop resistance to Osimertinib eventually limiting the long-term efficacy. Autophagy is a vital cellular recycling process promoting Osimertinib resistance. Identifying accurate and efficient autophagy-regulatory factors is of great significance in reducing Osimertinib resistance. This study identified Cezanne, a member of the ovarian tumor protease (OTU)-deubiquitinating family, as an autophagy regulator. Cezanne was highly expressed in Osimertinib-resistant cells, and Cezanne overexpression promoted Osimertinib resistance, while chloroquine (CQ), an autophagy inhibitor, reverted this process. In the Cezanne-overexpressing cells, autophagy was activated even in the absence of autophagy inducers rapamycin and Earle's Balanced Salt Solution (EBSS). Further study showed that Cezanne stabilized PIK3C3 by deubiquitinating K48-linked ubiquitination at Lysine 322. Surprisingly, as a compensatory mechanism of PI3P generation, PIK3C2A was shown to be upregulated by Cezanne by promoting its transcription in a POLR2A-dependent way. Based on these results, Cezanne also accelerates EGFR recycling which may explain the mechanism mediating Cezanne expression and Osimertinib resistance. In conclusion, this study establishes a new model connecting Cezanne, autophagy, and Osimertinib resistance, opening new avenues to explore the effect of Cezanne and autophagy in LUAD., (© 2023. Cell Death Differentiation Association (ADMC).)

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype., Experimental Design: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and the combined efficacy of IL6 inhibition and anti-PD-1 therapy. Corresponding in vitro studies used EGFR-mutant human cell lines and clinical specimens., Results: We identified that EGFR-mutant tumors which have oncogene-independent acquired resistance to EGFR-TKIs were more mesenchymal and had markedly enhanced IL6 secretion. In EGFR-mutant GEMMs, IL6 depletion enhanced activation of infiltrating natural killer (NK)- and T-cell subpopulations and decreased immunosuppressive regulatory T and Th17 cell populations. Inhibition of IL6 increased NK- and T cell-mediated killing of human osimertinib-resistant EGFR-mutant NSCLC tumor cells in cell culture. IL6 blockade sensitized EGFR-mutant GEMM tumors to PD-1 inhibitors through an increase in tumor-infiltrating IFNγ+ CD8+ T cells., Conclusions: These data indicate that IL6 is upregulated in EGFR-mutant NSCLC tumors with acquired EGFR-TKI resistance and suppressed T- and NK-cell function. IL6 blockade enhanced antitumor immunity and efficacy of anti-PD-1 therapy warranting future clinical combinatorial investigations., (©2023 American Association for Cancer Research.)

Effective therapeutic strategies are needed for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations that acquire resistance to EGFR tyrosine kinase inhibitors (TKIs) mediated by epithelial-to-mesenchymal transition (EMT). We investigate cell surface proteins that could be targeted by antibody-based or adoptive cell therapy approaches and identify CD70 as being highly upregulated in EMT-associated resistance. Moreover, CD70 upregulation is an early event in the evolution of resistance and occurs in drug-tolerant persister cells (DTPCs). CD70 promotes cell survival and invasiveness, and stimulation of CD70 triggers signal transduction pathways known to be re-activated with acquired TKI resistance. Anti-CD70 antibody drug conjugates (ADCs) and CD70-targeting chimeric antigen receptor (CAR) T cell and CAR NK cells show potent activity against EGFR TKI-resistant cells and DTPCs. These results identify CD70 as a therapeutic target for EGFR mutant tumors with acquired EGFR TKI resistance that merits clinical investigation., Competing Interests: Declaration of interests J.V.H. serves on advisory committees for DAVA Oncology, Regeneron, BerGenBio, Jazz Pharmaceuticals, Curio Science, Immunocore, AstraZeneca, EMD Serono, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation Medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion, and Chugai Pharmaceuticals; receives research support from Takeda, AstraZeneca, Boehringer-Ingelheim, and Spectrum; and receives royalties and licensing fees from Spectrum Pharmaceuticals. D.L.G. serves as an advisor/consultant for Sanofi, GlaxoSmithKline, Janssen Research & Development, Ribon Therapeutics, Mitobridge, Eli Lilly, Menarini, and Napa Therapeutics and receives research funding from Janssen Research & Development, Takeda, AstraZeneca, Mitobridge, Ribon Therapeutics, NGM Biopharmaceuticals, Boehringer Ingelheim, and Mirati Therapeutics. S.S.K. reports research support from Boehringer Ingelheim, Janssen, MiNA Therapeutics, MiRXES, and Taiho Therapeutics and honoraria from Boehringer Ingelheim, Bristol Meyers Squibb, AstraZeneca, Chugai Pharmaceutical, and Takeda Pharmaceuticals, all outside of the submitted work. X.L. receives consulting/advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Eli Lilly, Boehringer Ingelheim, Hengrui Therapeutics, Janssen, Blueprint Medicines, Sensei Biotherapeutics, and AbbVie and received research funding from Eli Lilly, EMD Serono, Regeneron, and Boehringer Ingelheim. M.B.N. and J.P.R. receive royalties and licensing fees from Spectrum Pharmaceuticals. M.B.N. and J.V.H. have filed a patent for CD70 targeting in EGFR TKI-resistant NSCLC (17/611,019). J.P.R. is currently a full-time employee and shareholder of AstraZeneca. Y.Y.E. discloses research support from AstraZeneca, Takeda, Eli Lilly, Xcovery, Tuning Point Therapeutics, BluPrint, and Elevation Oncology; an advisory role for AstraZeneca, Eli Lilly, Takeda, Spectrum, Bristol Myers Squibb, and Turning Point; and accommodation expenses from Eli Lilly. H.U. receives research support from Takeda Pharmaceuticals and Boehringer Ingelheim. S.H. receives consulting fees from AstraZeneca and Boehringer Ingelheim and speaker fees from Qiagen., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: This study investigates the effects and mechanisms of intestinal microbiota transplantation on cerebral ischemia reperfusion injury in aged mice., Methods: We constructed a middle cerebral artery occlusion model after fecal microbiota transplantation from young C57 mice to aged C57 mice for 30 consecutive days via enema. The neurological deficit score, cerebral infarction volume, fecal flora composition, and IL-17 levels in the colon, brain, and serum were evaluated in young mice, aged mice, and aged mice that received fecal microbiota transplantation. Moreover, we administered rIL-17A through caudal vein injection to verify its effect on cerebral ischemia reperfusion injury in aged mice., Results: We find that aged mice exhibited larger cerebral infarction volume and more severe neurological deficit than young mice after middle cerebral artery occlusion. Bacteroidetes increased and firmicutes decreased significantly in the feces of aged mice after microbiota transplantation. Furthermore, the transplanted mice showed improved neurological function and reduced infarction volume after middle cerebral artery occlusion compared with the control aged mice. We also find that the neuroprotective effect of the microbiota transplantation was reversed by pre-treatment of rIL-17A., Conclusion: In summary, intestinal microbiota transplantation can alleviate cerebral ischemia reperfusion injury in aged mice by restoring their microbiota environment and inhibiting IL-17 in the gut, serum, and brain tissue., (© 2022 John Wiley & Sons Ltd.)

Background: This study is part of a larger research effort to explore the molecular mechanism of hepatocellular carcinoma, reduce drug resistance and seek new targets., Objective: The objective of this study is to investigate the effect and mechanism of fibroblast growth factor receptor inhibitor AZD4547 on Sorafenib-resistant hepatoma cells., Methods: First, we constructed a Sorafenib-resistant hepatoma cell line Huh7R. Different groups of Huh7R cells were treated with Sorafenib, AZD4547, Sorafenib combined with AZD4547, and normal saline. The cell viability was detected by Cell Counting Kit-8. Then Fibroblast growth factor receptor and Toll-like receptor 4 were detected by Western blot, as well as the LC3 II/I, Beclin1, and P62. In addition, we used the autophagy inhibitor 3-methyladenine to identify the mechanism of AZD4547 combined with Sorafenib for inducing Sorafenib-resistant hepatoma cell death., Results: We find that AZD4547 combined with Sorafenib significantly inhibited the viability of Sorafenib-resistant hepatoma cell Huh7R. As for its mechanism, AZD4547 was able to inhibit fibroblast growth factor receptor activity, promote autophagy and regulate immunity. AZD4547 increased LC3 II/I, Beclin1, and Toll-like receptor 4 proteins, and decreased P62 protein level in Huh7R cells significantly when given in combination with sorafenib. Furthermore, 3-methyladenine inhibited autophagy and reversed the killing effect of the combination of AZD4547 and Sorafenib on Huh7R cells., Conclusion: The inhibition of fibroblast growth factor receptor activity by AZD4547 can significantly enhance autophagy and immune response, as well as promote the death of Sorafenib-resistant hepatoma cells., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Circular RNAs (circRNAs) have been shown to modulate gene expression and participate in the development of multiple malignancies. The purpose of this study was to investigate the role of circ&#95;0008039 in breast cancer (BC). The expression of circ&#95;0008039, miR-140-3p, and spindle and kinetochore-associated protein 2 (SKA2) was detected by qRT-PCR. Cell viability, colony formation, migration, and invasion were evaluated using methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay, colony formation assay, and transwell assay, respectively. Glucose consumption and lactate production were measured using commercial kits. Protein levels of hexokinase II (HK2) and SKA2 were determined by western blot. The interaction between miR-140-3p and circ&#95;0008039 or SKA2 was verified by dual-luciferase reporter assay. Finally, a mouse xenograft model was established to investigate the roles of circ&#95;0008039 in BC in vivo. We found that circ&#95;0008039 and SKA2 were upregulated in BC tissues and cells, while miR-140-3p was downregulated. Knockdown of circ&#95;0008039 suppressed BC cell proliferation, migration, invasion, and glycolysis. Moreover, miR-140-3p could bind to circ&#95;0008039 and its inhibition reversed the inhibitory effect of circ&#95;0008039 interference on proliferation, migration, invasion, and glycolysis in BC cells. SKA2 was verified as a direct target of miR-140-3p and its overexpression partially inhibited the suppressive effect of miR-140-3p restoration in BC cells. Additionally, circ&#95;0008039 positively regulated SKA2 expression by sponging miR-140-3p. Consistently, silencing circ&#95;0008039 restrained tumor growth via increasing miR-140-3p and decreasing SKA2. In conclusion, circ&#95;0008039 downregulation suppressed BC cell proliferation, migration, invasion, and glycolysis partially through regulating the miR-140-3p/SKA2 axis, providing an important theoretical basis for treatment of BC., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Cancer-associated fibroblasts (CAFs) are an essential component in the tumor microenvironment and have been reported to contribute to tumor progression through many mechanisms; however, the detailed mechanism underlying the immune-suppression effect of CAFs is not clearly defined. In this study, human breast cancer-derived CAFs were cultured, and CAF-derived exosomes in a culture medium were isolated. Using a miRNA profiles assay, we identify a significantly higher level of microRNA-92 isolated in CAFs exosomes. After treatment by CAF-derived exosomes, breast cancer cells express higher programmed cell death receptor ligand 1 (PD-L1), accompanied with increased miR-92 expression. Increased PD-L1 expression, which was induced by CAF-derived exosomes, significantly promotes apoptosis and impaired proliferation of T cells. The underlying mechanism of this effect was studied, proliferation and migration of breast cancer cells were increased after the transfection of miR-92, LATS2 was recognized as a target gene of miR-92, and further confirmed by a luciferase assay. Immunoprecipitation showed that LATS2 can interact with YAP1, chromatin immunoprecipitation confirmed that after nuclear translocation YAP1 could bind to the enhancer region of PD-L1 to promotes transcription activity. Furthermore, the animal study confirmed that CAFs significantly promoted tumor progression and impaired the function of tumor-infiltrated immune cells in vivo . Our data revealed a novel mechanism that can induce immune suppression in the tumor microenvironment., (Copyright © 2020 Dou, Ren, Han, Xu, Ge, Gu and Wang.)

Background: Triple-negative breast cancer (TNBC) is a clinically aggressive subtype of breast cancer with a bad prognosis. Chemotherapy is still the standard of care for TNBC treatment. Circular RNAs (CircRNAs) have been recently discovered to be closely involved in the initiation and development of human cancers. Herein, we focus our attention on the functions and underlying mechanisms of circUBE2D2 in TNBC progression and chemoresistance., Methods: The expression of circUBE2D2, miR-512-3p, and cell division cycle associated 3 (CDCA3) mRNA were determined by qRT-PCR. CCK-8, colony formation, transwell and flow cytometry assays were performed to detect cell proliferation, migration, invasion and apoptosis. Western blot assay was utilized to measure the protein level of CDCA3. RNA pull-down, luciferase reporter and RIP experiments were employed to examine the possible regulatory mechanism of circUBE2D2., Results: CircUBE2D2 expression was elevated in TNBC tissues and cells. TNBC patients with high circUBE2D2 expression are inclined to present advanced TNM stage, lymph node metastasis and adverse prognosis. Knockdown of circUBE2D2 repressed cell proliferation, migration and invasion in vitro, and impeded tumor growth in vivo. Moreover, silencing of circUBE2D2 reduced doxorubicin resistance of TNBC cells. In-depth mechanism analysis revealed that circUBE2D2 served as a miRNA sponge to protect CDCA3 from the attack of miR-512-3p. Additionally, the tumor-suppressive effect induced by circUBE2D2 depletion was greatly impaired upon miR512-3p down-regulation or CDCA3 overexpression. Also, depletion of circUBE2D2 decreased the resistance to doxorubicin through regulating miR-512-3p/CDCA3 axis., Conclusion: CircUBE2D2 promoted TNBC progression and doxorubicin resistance through acting as a sponge of miR-512-3p to up-regulate CDCA3 expression. Targeting circUBE2D2 combine with doxorubicin might be exploited as a novel therapy for TNBC., Competing Interests: Competing interestThe authors have no conflict of interest to declare., (© The Author(s) 2020.)

Background: Most secondary transmission of COVID-19 is occurring in a hospital setting. To decrease person-to-person contact, health care providers have built many isolation wards. However, out-of-hospital professionals cannot access patient information, which has greatly reduced the efficiency of treatment; it is inconvenient for health care professionals to issue a case discussion with professionals from other wards. This article mainly introduces a mobile telehealth system (MTS) applied to facilitate patient information presentation and case discussion. Materials and Methods: The MTS searches patient information, which is stored in hospital intranet, and uses five modules to display patient information. By a request/response module and a real-time interaction module, we successfully conducted case discussions. In addition, we took measures in three areas to prevent patient information leakage. Results: The system uses mobile collaboration technology to present patient information and support case discussion. MTS was officially launched for 37 days, during which it has been used 3,061 times. Conclusions: The building of the MTS not only provides convenience and benefit for health care professionals, but also reduces person-to-person contact.

Background/aims: High-resolution anorectal manometry (HRAM) has been considered a first-line diagnostic tool for functional defecation disorder. However, clinical studies on HRAM used in constipation patients are very limited and few studies have reported the characteristics of anorectal pressure in Chinese patients. The aim of this study is to investigate the characteristics of motility data in a cohort of Chinese patients with functional constipation., Methods: A total of 82 consecutive patients with functional constipation who underwent a standardized HRAM were retrospectively enrolled in this study. The functional defecation disorder was classified into Rao's types., Results: The mean age of 82 patients was 51 years (range, 16-83 years). Indications for anorectal manometry were functional constipation for all patients. The mean resting pressure was 69.2 ± 21.2 mmHg (range, 24.5-126.9 mmHg). The mean maximum squeezing pressure was 198.4 ± 75.6 mmHg (range, 54.2-476.9 mmHg). The mean length of the anal high pressure zone was 3.4 ± 1.0 cm (range, 0.6-4.9 cm). Sixty (73.2%) patients were diagnosed as functional defecation disorder. In attempted defecation, type I was most common (n = 24), followed by type II (n = 12), type III (n = 11), and type IV (n = 13) that were present on HRAM according to Rao's classification. In all 60 patients with functional defecation disorder, 37 were women and 23 were men. Men were significantly more likely than women to have functional defecation disorder (92.0% vs 64.9%, P = 0.014)., Conclusion: HRAM could be used as a test for the diagnosis of functional defecation disorder and functional defecation disorder is common in Chinese patients with functional constipation.

Background: Different levels of telemedicine systems have been built across China. To share high-quality medical resources and conduct centralized management of telemedicine systems, a regional telemedicine system (RTS) (such as a provincial level system) has been developed to integrate with small-scale telemedicine systems. Although the established systems offer integration services, they are tightly coupled systems, and not easily integrated with new systems. Meanwhile, with the increasing of input/output, it is difficult for them to run with high scalability, considering the cost of architecture redesign and further development. This article presents the design and implementation of regional integration system through a study in Henan, China, mainly aimed to integrate with heterogeneous small-scale telemedicine systems and provide high efficiency., Methods: A provincial telemedicine system and some city-level telemedicine systems have already been established. The provincial system has been built to act as a regional integration system to connect city-level systems. Adopting message-based technology, the provincial system achieves high availability and high scalability, respectively, through LevelDB + ZooKeeper and multicast., Results: The system achieved the centralized management of established telemedicine systems without restructuring their framework, improving high availability of RTS when one ActiveMQ service node in a group failed, and it did not negatively influence normal business logic when adding a new service node. At the same time, two "Master" state ActiveMQ service nodes provided services simultaneously, which enable the RTS to achieve high scalability., Conclusions: The message-based regional integration system enriched the RTS with high availability, easy extensibility, and provided a convenient way to integrate new small-scale telemedicine systems.

Background and Aims: Rifaximin is a minimally absorbed antibiotic, which has shown efficacy in irritable bowel syndrome (IBS) patients. However, the mechanism on how it effects in IBS is still incompletely defined. In this study, Trichinella spiralis-infected post-infectious (PI) IBS mouse model was used, to assess the action of rifaximin on visceral hypersensitivity, barrier function, gut inflammation, and microbiota., Methods: Post-infectious IBS model was established by T. spiralis infection in mice. Rifaximin were administered to PI-IBS mice for seven consecutive days. The abdominal withdrawal reflex and threshold of colorectal distention were employed to evaluate visceral sensitivity. Smooth muscle contractile response was recorded in the organ bath. Intestinal permeability was measured by Ussing chamber. Expression of tight junction protein and cytokines were measured by Western blotting. Ilumina miseq platform was used to analyze bacterial 16S ribosomal RNA., Results: Post-infectious IBS mice treated with rifaximin exhibited decreased abdominal withdrawal reflex score, increased threshold, reduced contractile response, and intestinal permeability. Rifaximin also suppressed the expression of interleukin-12 and interleukin-17 and promoted the expression of the major tight junction protein occludin. Furthermore, rifaximin did not change the composition and diversity, and the study reavealed that rifaximin had a tiny effect on the relative abundance of Lactobacillus and Bifidobacterium in this PI-IBS model., Conclusions: Rifaximin alleviated visceral hypersensitivity, recovered intestinal barrier function, and inhibited low-grade inflammation in colon and ileum of PI-IBS mouse model. Moreover, rifaximin exerts anti-inflammatory effects with only a minimal effect on the overall composition and diversity of the gut microbiota in this model., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

The corticotropin-releasing factor (CRF) family is involved in modulating gastrointestinal motility, sensitivity and inflammation. CRF signalling exerts an important role in inflammatory bowel disease (IBD), predominantly by activating CRF receptors. The aim of the present study was to investigate the function of CRF receptor 1 (CRF‑R1) in the development of mucosal inflammation induced by dextran sulphate sodium (DSS) and the underlying mechanism. Consecutive administration of CRF or CP154526 was used to activate or block the CRF‑R1 in DSS‑treated mice. Colonic inflammation was evaluated by determining the Disease Activity Index (DAI) and histology score. CRF‑R1 expression was proportional to the DAI, the histology score and the number of macrophages. Activation of CRF‑R1 aggravated mucosal inflammation by activating nuclear factor (NF)‑κB and subsequently increasing the expression levels of tumour necrosis factor (TNF)‑α and interleukin (IL)‑6. Inhibition of CRF‑R1 decreased the expression level of CRF‑R1, macrophage infiltration, NF‑κB activation, and TNF‑α and IL‑6 expression levels, ultimately alleviating the mucosal inflammation. Thus, CRF‑R1 expression was proportional to the severity of DSS‑induced colitis. Activation of CRF‑R1 increased the DAI and histological scores of the colons from DSS‑treated mice by promoting M1 macrophage polarization, demonstrated as increased NF‑κB activation, and TNF‑α and IL‑6 release. These results provide evidence of the pro‑inflammatory role of CRF‑R1 in a DSS‑induced ulcerative colitis (UC) model and a possible underlying mechanism, which may facilitate the elucidation of potential treatment approaches for UC.

Background: HOX antisense transcript RNA (HOTAIR) is a 2148 nt long, intergenic, non-coding RNA molecule, which is reported to be highly expressed in many types of cancers. This meta-analysis summarizes its expression in cancer., Methods: We searched all eligible papers on the prognostic impact of HOTAIR in cancer from inception to 30 September 2015 in PubMed, CBMdisc, and the CNKI database. Only full texts were included. Revman 5.3 was used for meta-analysis., Results: A total of 11 studies of 1010 cases were included in the meta-analysis. HOTAIR expression was higher in: cancer tissues in than adjacent or normal tissues (odds ratio [OR] 37.52, 95% confidence interval [CI] 18.94-74.31; P  < 0.00001); in cancer tissues with lymph node metastasis than in those without lymph node metastasis (OR 3.37, 95% CI 2.36-4.82; P  < 0.00001); and in histological grades II-III than in histological gradeI(OR 0.47, 95% CI 0.29-0.75; P  = 0.002)., Conclusion: This study shows that HOTAIR may play an important role in cancer occurrence and development, but whether it is a marker of cancer diagnosis and reliable prognosis remains to be confirmed. More rigorous design and meticulous quality epidemiological studies are required., (© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Despite the robotic surgery is widely applied, sleeve lobectomy for lung cancer using the Da Vinci surgical system is still less performed. We described a sleeve lobectomy for adenocarcinoma located at the left lower lobe using the Da Vinci surgical system., Case Presentation: A case of 57-year old female referred to our hospital. Computed tomography scan showed an occupation located at the left lower lobe and adenocarcinoma project from the lobe bronchus was diagnosed by bronchoscope examination. A sleeve lobectomy was performed using the Da Vinci surgical system and the postoperative recovery was uneventful., Conclusions: Robotic thoracic surgery is feasible to perform sleeve lobectomy inspite of inadequate experience.

Despite the lobectomy in video-assisted thoracic surgery (VATS) is widely applied, in VATS the resection of benign lymphadenopathy is still less performed because of less importance in affecting the prognosis. We report our surgery procedure of benign lymphadenopathy in lobectomy with benign pulmonary disease performed in a two-port approach. A 50-year-old male was operated on by the thoracoscopic approach through two-port incision. And the postoperative recovery was uneventful with no complications occurred., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

We describe a novel technique of totally robotic-assisted non-circumferential tracheal resection and running anastomosis with coverage of anastomosis with anterior mediastinal fat flap. A 71-year-old female presented with cough and CT scan revealed a mass at the intra-thoracic trachea. A complete robotic-assisted tracheal resection and anastomosis was performed. The postoperative course was uneventful. The final pathologic examination confirmed the diagnosis of primary tracheal leiomyoma.

Chemoradiation-resistant cancers limit treatment efficacy and safety. We show here the cancer cell-specific, on-demand intracellular amplification of chemotherapy and chemoradiation therapy via gold nanoparticle- and laser pulse-induced mechanical intracellular impact. Cancer aggressiveness promotes the clustering of drug nanocarriers and gold nanoparticles in cancer cells. This cluster, upon exposure to a laser pulse, generates a plasmonic nanobubble, the mechanical explosion that destroys the host cancer cell or ejects the drug into its cytoplasm by disrupting the liposome and endosome. The same cluster locally amplifies external X-rays. Intracellular synergy of the mechanical impact of plasmonic nanobubble, ejected drug and amplified X-rays improves the efficacy of standard chemoradiation in resistant and aggressive head and neck cancer by 100-fold in vitro and 17-fold in vivo, reduces the effective entry doses of drugs and X-rays to 2-6% of their clinical doses and efficiently spares normal cells. The developed quadrapeutics technology combines four clinically validated components and transforms a standard macrotherapy into an intracellular on-demand theranostic microtreatment with radically amplified therapeutic efficacy and specificity.

The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment.

The limited specificity of nanoparticle (NP) uptake by target cells associated with a disease is one of the principal challenges of nanomedicine. Using the threshold mechanism of plasmonic nanobubble (PNB) generation and enhanced accumulation and clustering of gold nanoparticles in target cells, we increased the specificity of PNB generation and detection in target versus non-target cells by more than one order of magnitude compared to the specificity of NP uptake by the same cells. This improved cellular specificity of PNBs was demonstrated in six different cell models representing diverse molecular targets such as epidermal growth factor receptor, CD3 receptor, prostate specific membrane antigen and mucin molecule MUC1. Thus PNBs may be a universal method and nano-agent that overcome the problem of non-specific uptake of NPs by non-target cells and improve the specificity of NP-based diagnostics, therapeutics and theranostics at the cell level.

Lung cancer is the leading cause of cancer death in both men and women in the United States, with a low 5-year survival rate despite improved treatment strategies. These data underscore the great need for effective chemoprevention of this cancer. Mutations and activation of KRAS occur frequently in, and are thought to be a primary driver of the development of, non-small cell lung cancers (NSCLC) of the adenocarcinoma subtype. In this study, we developed a new approach for the chemoprevention of NSCLC involving specific targeting of apoptosis in mutant KRAS cells. This approach is based on a synthetic lethal interaction among TNF-related apoptosis-inducing ligand (TRAIL), the second mitochondria-derived activator of caspase Smac/DIABLO (Smac), and KRAS. Mutational activation of KRAS modulated the expression of TRAIL receptors by upregulating death receptors and downregulating decoy receptors. Furthermore, oncogenic KRAS repressed cellular FADD-like interleukin 1β-converting enzyme (FLICE)-like inhibitory protein (c-FLIP) expression through activation of Erk/mitogen-activated protein kinase (MAPK)-mediated activation of c-Myc. Smac overcame KRAS-induced cell-survival signaling by antagonizing X-linked inhibitor of apoptosis protein (XIAP). Therefore, the combination of TRAIL and a small molecule mimic of Smac induced apoptosis specifically in mutant KRAS cells without harming normal cells. We further showed that short-term, intermittent in vivo treatment with TRAIL and Smac mimic induced apoptosis in tumor cells and reduced tumor burden in a murine model of KRAS-induced lung cancer. These results reflect the potential benefit of a selective therapeutic approach for the chemoprevention of NSCLC.

Cancer chemoprevention uses natural, synthetic, or biological substances to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer. It holds promise for overcoming problems associated with the treatment of late-stage cancers. However, the broad application of chemoprevention is compromised at present by limited effectiveness and potential toxicity. To overcome these challenges, here we developed a new chemoprevention approach that specifically targets premalignant tumour cells for apoptosis. We show that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of beta-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activation of c-Myc, and that all-trans-retinyl acetate (RAc) independently upregulates tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, we show that short-term and non-continuous TRAIL and RAc treatment induce apoptosis specifically in intestinal polyps, strongly inhibit tumour growth, and prolong survival in multiple intestinal neoplasms C57BL/6J-Apc(Min)/J (Apc(Min)) mice. With our approach, we further demonstrate that TRAIL and RAc induce significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.

Activation of NFkappaB is frequently associated with human malignancies. The involvement of NFkappaB is in part attributed to its ability to activate various genes promoting cell survival. This property contributes to aggressive tumor growth and resistance to chemotherapy and radiation in cancer treatment. Various reports have shown that inhibition of NFkappaB promotes apoptosis and suppress tumor growth. However, NFkappaB has many important cellular functions and targeting NFkappaB directly may lead to severe side effects. Thus, developing strategies with low cytotoxicity to overcome NKkappaB-mediated cell survival is critical to improve cancer therapy. In this report, we described an approach using TRAIL/ Apo2L (TNF-related apoptosis-inducing ligand TRAIL or Apo2 ligand) and a Smac analog to overcome and bypass NFkappaB activation in cancer treatment. We have shown that a panel of head and neck squamous cell carcinoma (HNSCC) cell lines are highly resistant to TRAIL-induced apoptosis due to activation of NFkappaB-mediated cell survival pathways, and that inhibition of NFkappaB renders HNSCC cells sensitive to TRAIL. We further show that TRAIL and a small molecule mimic of Smac overcome and bypass NFkappaB activation in inducing cancer cell death. Since this treatment has no effect on NFkappaB activation and TRAIL offers tumor selectivity, cotreatment of TRAIL and Smac provides a strategy with potentially low toxicity to overcome NFkappaB activation in cancer cells, which has potential therapeutic benefit.

Tumor necrosis factor (TNFalpha) receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-kappaB and the kinase, JNK. While activation of caspase 8 is required for TNFalpha-induced apoptosis, and induction of NF-kappaB inhibits cell death, the precise function of JNK activation in TNFalpha signaling is not clearly understood. Here, we report that TNFalpha-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation of jBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP1 complex. We propose that the JNK pathway described here is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. Further, our findings define a mechanism for crosstalk between intrinsic and extrinsic cell death pathways.