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Brachial plexus injury (BPI) with motor neurons (MNs) damage still remain poor recovery in preclinical research and clinical therapy, while cell-based therapy approaches emerged as novel strategies. Previous work of rat skin precursor-derived Schwann cells (SKP–SCs) provided substantial foundation for repairing peripheral nerve injury (PNI). Given that, our present work focused on exploring the repair efficacy and possible mechanisms of SKP-SCs implantation on rat BPI combined with neurorrhaphy post-neurotomy. Results indicated the significant locomotive and sensory function recovery, with improved morphological remodeling of regenerated nerves and angiogenesis, as well as amelioration of target muscles atrophy and motor endplate degeneration. Besides, MNs could restore from oxygen-glucose-deprivation (OGD) injury upon SKP-SCs-sourced secretome treatment, implying the underlying paracrine mechanisms. Moreover, rat cytokine array assay detected 67 cytokines from SKP-SC-secretome, and bioinformatic analyses of screened 32 cytokines presented multiple functional clusters covering diverse cell types, including inflammatory cells, Schwann cells, vascular endothelial cells (VECs), neurons, and SKP-SCs themselves, relating distinct biological processes to nerve regeneration. Especially, a panel of hypoxia-responsive cytokines (HRCK), can participate into multicellular biological process regulation for permissive regeneration milieu, which underscored the benefits of SKP-SCs and sourced secretome, facilitating the chorus of nerve regenerative microenvironment. Furthermore, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor-A (VEGF-A) were outstanding cytokines involved with nerve regenerative microenvironment regulating, with significantly elevated mRNA expression level in hypoxia-responsive SKP-SCs. Altogether, through recapitulating the implanted SKP-SCs and derived secretome as niche sensor and paracrine transmitters respectively, HRCK would be further excavated as molecular underpinning of the neural recuperative mechanizations for efficient cell therapy; meanwhile, the analysis paradigm in this study validated and anticipated the actions and mechanisms of SKP-SCs on traumatic BPI repair, and was beneficial to identify promising bioactive molecule cocktail and signaling targets for cell-free therapy strategy on neural repair and regeneration.

Abstract Objective This study aims to explore ADH4 expression in hepatocellular carcinoma (HCC), its prognostic impact, and its immune correlation to provide novel insights into HCC prognostication and treatment. Methods HCC prognostic marker genes were rigorously selected using GEO database, Lasso regression, GEPIA, Kaplan-Meier and pROC analyses. The expression of interested markers (ADH4, DNASE1L3, RDH16, LCAT, HGFAC) in HCC and adjacent tissues was assessed by Immunohistochemistry (IHC). We observed that ADH4 exhibited low expression levels in liver cancer tissues and high expression levels in normal liver tissues. However, the remaining four genes did not manifest any statistically significant differences between hepatocellular carcinoma (HCC) tissue and adjacent non-cancerous tissue. Consequently, ADH4 became the primary focus of our research. ADH4 expression was validated by signed-rank tests and unpaired Wilcoxon rank sum tests across pan-cancer and HCC datasets. Clinical significance and associations with clinicopathological variables were determined using Kaplan-Meier, logistic regression and Cox analyses on TCGA data. The ADH4-related immune responses were explored by Spearman correlation analysis using TIMER2 data. CD68, CD4, and CD19 protein levels were confirmed by IHC in HCC and non-cancerous tissues. Results ADH4 showed significant downregulation in various cancers, particularly in HCC. Moreover, low ADH4 expression was associated with clinicopathological variables and served as an independent prognostic marker for HCC patients. Additionally, ADH4 affects a variety of biochemical functions and may influence cancer development, prognosis, and treatment by binding to immune cells. Furthermore, at the immune level, the low expression pattern of ADH4 is TME-specific, indicating that ADH4 has the potential to be used as a target for cancer immunotherapy. Conclusion This study highlights the diagnostic, prognostic and immunomodulatory roles of ADH4 in HCC. ADH4 could serve as a valuable biomarker for HCC diagnosis and prognosis, as well as a potential target for immunotherapeutic interventions.

Influenza A virus can infect respiratory tracts and may cause severe illness in humans. Proteins encoded by influenza A virus can interact with cellular factors and dysregulate host biological processes to support viral replication and cause pathogenicity. The influenza viral PA protein is not only a subunit of influenza viral polymerase but also a virulence factor involved in pathogenicity during infection. To explore the role of the influenza virus PA protein in regulating host biological processes, we performed immunoprecipitation and LC‒MS/MS to globally identify cellular factors that interact with the PA proteins of the influenza A H1N1, 2009 pandemic H1N1, and H3N2 viruses. The results demonstrated that proteins located in the mitochondrion, proteasome, and nucleus are associated with the PA protein. We further discovered that the PA protein is partly located in mitochondria by immunofluorescence and mitochondrial fractionation and that overexpression of the PA protein reduces mitochondrial respiration. In addition, our results revealed the interaction between PA and the mitochondrial matrix protein PYCR2 and the antiviral role of PYCR2 during influenza A virus replication. Moreover, we found that the PA protein could also trigger autophagy and disrupt mitochondrial homeostasis. Overall, our research revealed the impacts of the influenza A virus PA protein on mitochondrial function and autophagy.

Therapies for tumors continue to develop, and tumor immunotherapy has emerged as an effective means of controlling tumor progression. Given the limitations of immunotherapy, only some specific patients can benefit from immunotherapy. Since the complex tumor microenvironment is highly influenced by individual variability, immunotherapy will be subjected to different degrees of immune suppression in different tumor microenvironments and thus cannot exert its full effect. In the tumor microenvironment, regulatory T (Treg) cell plays as an immunosuppressive role. Numerous Treg cells infiltrate in indifferent tumor types, resulting in immune escape of tumor tissues, which will have a negative impact on treatment and prognosis. CC chemokine receptor 8 (CCR8) belongs to the CC chemokine receptor family. CCR8 is specifically expressed on Treg cell in the tumor microenvironment and expressed at low level in the surrounding normal tissues and peripheral blood thus it can be a specific marker for Treg cell. CCR8 is a potential therapeutic target and biomarker. This review summarized the research progress of CCR8 in different tumor types in recent years, so as to provide reference for subsequent research.

Our previous study found that rat bone marrow–derived neural crest cells (acting as Schwann cell progenitors) have the potential to promote long-distance nerve repair. Cell-based therapy can enhance peripheral nerve repair and regeneration through paracrine bioactive factors and intercellular communication. Nevertheless, the complex contributions of various types of soluble cytokines and extracellular vesicle cargos to the secretome remain unclear. To investigate the role of the secretome and extracellular vesicles in repairing damaged peripheral nerves, we collected conditioned culture medium from hypoxia-pretreated neural crest cells, and found that it significantly promoted the repair of sensory neurons damaged by oxygen-glucose deprivation. The mRNA expression of trophic factors was highly expressed in hypoxia-pretreated neural crest cells. We performed RNA sequencing and bioinformatics analysis and found that miR-21-5p was enriched in hypoxia-pretreated extracellular vesicles of neural crest cells. Subsequently, to further clarify the role of hypoxia-pretreated neural crest cell extracellular vesicles rich in miR-21-5p in axonal growth and regeneration of sensory neurons, we used a microfluidic axonal dissociation model of sensory neurons in vitro, and found that hypoxia-pretreated neural crest cell extracellular vesicles promoted axonal growth and regeneration of sensory neurons, which was greatly dependent on loaded miR-21-5p. Finally, we constructed a miR-21-5p-loaded neural conduit to repair the sciatic nerve defect in rats and found that the motor and sensory functions of injured rat hind limb, as well as muscle tissue morphology of the hind limbs, were obviously restored. These findings suggest that hypoxia-pretreated neural crest extracellular vesicles are natural nanoparticles rich in miRNA-21-5p. miRNA-21-5p is one of the main contributors to promoting nerve regeneration by the neural crest cell secretome. This helps to explain the mechanism of action of the secretome and extracellular vesicles of neural crest cells in repairing damaged peripheral nerves, and also promotes the application of miR-21-5p in tissue engineering regeneration medicine.

Abstract Background Although great progress has been made in anti-cancer therapy, the prognosis of laryngeal squamous cell carcinoma (LSCC) patients remains unsatisfied. Quantities of studies demonstrate that glycolytic reprograming is essential for the progression of cancers, where triosephosphate isomerase 1 (TPI1) serves as a catalytic enzyme. However, the clinicopathological significance and potential biological functions of TPI1 underlying LSCC remains obscure. Methods We collected in-house 82 LSCC tissue specimens and 56 non-tumor tissue specimens. Tissue microarrays (TMA) and immunohistochemical (IHC) experiments were performed. External LSCC microarrays and bulk RNA sequencing data were integrated to evaluate the expression of TPI1. We used a log-rank test and the CIBERSORT algorithm to assess the prognostic value of TPI1 and its association with the LSCC microenvironment. Malignant laryngeal epithelial cells and immune-stromal cells were identified using inferCNV and CellTypist. We conducted a comprehensive analysis to elucidate the molecular functions of TPI1 in LSCC tissue and single cells using Pearson correlation analysis, high dimensional weighted gene co-expression analysis, gene set enrichment analysis, and clustered regularly interspaced short palindromic repeats (CRISPR) screen. We explored intercellular communication patterns between LSCC single cells and immune-stromal cells and predicted several therapeutic agents targeting TPI1. Results Based on the in-house TMA and IHC analysis, TPI1 protein was found to have a strong positive expression in the nucleus of LSCC cells but only weakly positive activity in the cytoplasm of normal laryngeal cells (p

Virtual reality (VR) exercise has been used as a strategy to promote physical health in older adults. Studies have revealed that the effects of exercise interventions vary across age groups. This study aimed to investigate the effects of a 12-week semi-immersion VR-based multicomponent exercise program on the functional fitness of young-old (65–73 years) and middle-old (74–85 years) adults. This study recruited two age groups (young-old adults, n = 49; middle-old adults, n = 37) and randomly assigned them to the experimental (EG) and control (CG) groups. EG participants performed a 75–90-min semi-immersion VR exercise routine twice weekly for 12 weeks, whereas CG participants maintained their original lifestyles without any alterations. The Senior Fitness Test was used to measure functional fitness by assessing upper- and lower-limb flexibility and muscle strength, cardiorespiratory fitness, and balance. EG participants exhibited greater improvements than their CG counterparts in certain functional fitness tests, specifically the Back Scratch, Arm Curl, 2-Minute Step, and 8-Foot Up-and-Go Tests. On comparing the age groups, a difference was exclusively noted in the effects of the Chair Sit-and-Reach Test. In the EG, the intervention significantly improved lower-body flexibility in young-old adults but elicited no such improvement in middle-old adults. Semi-immersion VR exercise improved the functional fitness of young-old and middle-old adults in the EG, with superior results in the former. Elucidating the impact of age-specific exercise interventions on functional capacity will help practitioners design age-specific exercise training content that enhances functional fitness in older adults of different ages.

Objective This study aimed to examine the effects of semi-immersive virtual reality (VR)-based exercise on the quality of life of older adults. Methods It used a randomized controlled trial design. Older adults (mean age: 72.16 ± 4.9 years) were randomly assigned to experimental ( n = 48) and control ( n = 50) groups. The experimental group engaged in semi-immersive VR exercise for 75–90 min, twice a week, for 12 weeks and partook in no other intervention between the end of the exercise intervention and follow-up. Control group members did not participate in any similar program during the intervention or follow-up periods. Both groups completed three assessments: at baseline (pre-test), post-intervention (post-test), and 3 months later (follow-up). Quality of life was assessed using the World Health Organization Quality of Life Instrument-Older Adults Module. Results Generalized estimating equation analyses indicated that the experimental group exhibited significant post-intervention improvements in quality of life in terms of sensory ability, autonomy, social participation/isolation, death and dying domain, and overall quality of life scores. However, none of these significant effects were maintained 3 months after exercise intervention cessation. Conclusions Semi-immersive VR exercise may be a feasible strategy toward enhancing the quality of life of older adults. However, the participants’ quality of life was not maintained upon exercise cessation, indicating that older adults need to be encouraged to exercise regularly to maintain a good quality of life. VR may need to be combined with other modes of intervention in the future to facilitate long-term quality-of-life improvement in older adults.

Several recent studies have used virtual reality (VR)-based exercise to enhance functional fitness in older adults. However, most of these studies exclusively focused on short-term intervention outcomes. Therefore, this study aimed to determine the effect of VR-based exercise on older adults’ retention of functional fitness after intervention and at follow-up.This study was a randomized controlled trial wherein older adults (mean age: 72.16 ± 4.9 years) were assigned to experimental ( n = 48) and control ( n = 50) groups. Experimental group participants engaged in VR exercise sessions for 75 to 90 minutes biweekly over 12 weeks. Control group participants did not participate in the intervention. Functional fitness was assessed using the Senior Fitness Test. Functional fitness changes were compared using a generalized estimating equation. Pre-, post-, and follow-up tests were conducted at weeks 1, 13, and 24, respectively. After VR-based training, the experimental group performed better in functional fitness tests, including upper body flexibility, lower body flexibility, upper body strength, cardiorespiratory fitness, balance, and agility, than the control group immediately after the intervention. Improvements in lower body flexibility, upper body strength, cardiorespiratory fitness, balance, and agility persisted in the experimental group for up to 12 weeks. This study demonstrates that VR-based training potentially improves community-dwelling older adults’ functional fitness. Its findings may support the future development of novel exercise technologies and serve as a reference for the implementation of physical health promotion strategies for older adults.

Abstract Chronic hepatitis C virus (HCV) infection is an important public health issue. However, knowledge on how the virus remodels the metabolic and immune response toward hepatic pathologic environment is limited. The transcriptomic and multiple evidences reveal that the HCV core protein–intestine‐specific homeobox (ISX) axis promotes a spectrum of metabolic, fibrogenic, and immune modulators (e.g., kynurenine, PD‐L1, and B7‐2), regulating HCV‐infection relevant pathogenic phenotype in vitro and in vivo. In a transgenic mice model, the HCV core protein–ISX axis enhance metabolic disturbance (particularly lipid and glucose metabolism) and immune suppression, and finally, chronic liver fibrosis in a high‐fat diet (HFD)‐induced disease model. Mechanistically, cells with HCV JFH‐1 replicons upregulate ISX and, consequently, the expressions of metabolic, fibrosis progenitor, and immune modulators via core protein‐induced nuclear factor‐κB signaling. Conversely, cells with specific ISX shRNAi inhibit HCV core protein‐induced metabolic disturbance and immune suppression. Clinically, the HCV core level is significantly correlated with ISX, IDOs, PD‐L1, and B7‐2 levels in HCC patients with HCV infection. Therefore, it highlights the significance of HCV core protein–ISX axis as an important mechanism in the development of HCV‐induced chronic liver disease and can be a specific therapeutic target clinically.

BackgroundFew studies assess cord blood biomarkers to predict prenatal exposure to di(2-ethylhexyl) phthalate (DEHP) on the development of allergic diseases later in childhood. IL-33 has been indicated to play an important role in allergic diseases. We evaluated the association of prenatal DEHP exposure and IL-33 in cord blood on the development of allergic diseases. We also investigated the mechanism of DEHP in human lung epithelial cells and asthma animal models.Methods66 pregnant women were recruited, and their children followed when they were aged 3 years. Maternal urinary DEHP metabolites were determined using liquid chromatography-electrospray-ionization-tandem mass spectrometry. The effect of DEHP on IL-33 production was investigated in human lung epithelial cells and club cell-specific aryl hydrocarbon receptor (AhR) deficiency mice. ELISA and RT-PCR, respectively, measured the IL-33 cytokine concentration and mRNA expression.ResultsThe concentrations of maternal urinary DEHP metabolites and serum IL-33 in cord blood with childhood allergy were significantly higher than those in the non-childhood allergy group. DEHP and MEHP could induce IL-33 production and reverse by AhR antagonist and flavonoids in vitro. Enhanced ovalbumin-induced IL-4 and IL-33 production in bronchoalveolar lavage fluid (BALF) by DEHP exposure and suppressed in club cell-specific AhR null mice. Kaempferol has significantly reversed the DEHP effect in the asthma animal model.ConclusionsCord blood IL-33 level was correlated to childhood allergy and associated with maternal DEHP exposure. IL-33 might be a potential target to assess the development of DEHP-related childhood allergic disease. Flavonoids might be the natural antidotes for DEHP.

Acute lymphoblastic leukaemia (ALL) is the most prevalent cancer in children, and excessive iron buildup resulting from blood transfusions and chemotherapy potentially has a negative impact on treatment outcomes and prognosis in patients with ALL. Therefore, initiating early iron chelation therapy during ALL treatment is a logical approach. Ideally, the selected iron chelator should also possess anti-leukaemia properties. The aim of the present study was to explore the potential impact and underlying mechanism of deferasirox (DFX) in ALL therapy. This study proved that DFX, an iron chelator, is capable of inducing leukaemia cell death through ferroptosis, which is achievable by increasing the expression of acetylated nuclear factor erythroid 2-related factor 2 (NRF2). More specifically, NRF2 acetylation on Lys599 was facilitated by acetyltransferase-p300/CBP. These findings indicate that DFX could serve as a potent adjunctive medication for patients with ALL. Moreover, DFX may offer dual benefits in ALL treatment, functioning as both an iron chelator and NRF2-modulating agent. Further research and clinical trials are necessary to fully elucidate the therapeutic potential of DFX in patients with ALL and incorporate it into treatment protocols.

Abstract For past two decades, p53 has been claimed as the primary sensor initiating apoptosis. Under severe cellular stress, p53 transcriptional activity activates BH3-only proteins such as Bim, Puma, or Noxa to nullify the inhibitory effects of anti-apoptotic proteins on pro-apoptotic proteins for mitochondrial outer membrane permeabilization. Cellular stress determines the expression level of p53, and the amount of p53 corresponds to the magnitude of apoptosis. However, our studies indicated that Bim and Puma are not the target genes of p53 in three cancer models, prostate cancer, glioblastoma, and osteosarcoma. Bim counteracted with Bcl-xl to activate apoptosis independently of p53 in response to doxorubicin-induced severe DNA damage in prostate cancer. Moreover, the transcriptional activity of p53 was more related to cell cycle arrest other than apoptosis for responding to DNA damage stress generated by doxorubicin in prostate cancer and glioblastoma. A proteasome inhibitor that causes protein turnover dysfunction, bortezomib, produced apoptosis in a p53-independent manner in glioblastoma and osteosarcoma. p53 in terms of both protein level and nuclear localization in combining doxorubicin with bortezomib treatment was obviously lower than when using DOX alone, inversely correlated with the magnitude of apoptosis in glioblastoma. Using a BH3-mimetic, ABT-263, to treat doxorubicin-sensitive p53-wild type and doxorubicin-resistant p53-null osteosarcoma cells demonstrated only limited apoptotic response. The combination of doxorubicin or bortezomib with ABT-263 generated a synergistic outcome of apoptosis in both p53-wild type and p53-null osteosarcoma cells. Together, this suggested that p53 might have no role in doxorubicin-induced apoptosis in prostate cancer, glioblastoma and osteosarcoma. The effects of ABT-263 in single and combination treatment of osteosarcoma or prostate cancer indicated a dual control to regulate apoptosis in response to severe cellular stress. Whether our findings only apply in these three types of cancers or extend to other cancer types remains to be explored.

Abstract In this paper, we calculate the vector, axial-vector and tensor form factors of $$P\rightarrow T$$ P → T transition within the standard light-front (SLF) and covariant light-front (CLF) quark models (QMs). The self-consistency and Lorentz covariance of CLF QM with two types of correspondence schemes are investigated. The zero-mode effects and the spurious $$\omega $$ ω -dependent contributions to the form factors of $$P\rightarrow T$$ P → T transition are analyzed. Employing a self-consistent CLF QM, we present our numerical predictions for the vector, axial-vector and tensor form factors of $$c\rightarrow (q,s)$$ c → ( q , s ) ( $$q=u,d$$ q = u , d ) induced $$D \rightarrow (a_2,K^*_2)$$ D → ( a 2 , K 2 ∗ ) , $$D_s \rightarrow (K^*_2,f'_{2})$$ D s → ( K 2 ∗ , f 2 ′ ) , $$\eta _c(1S) \rightarrow (D^*_2,D^*_{s2})$$ η c ( 1 S ) → ( D 2 ∗ , D s 2 ∗ ) , $$ B_c \rightarrow (B^*_2,B^*_{s2})$$ B c → ( B 2 ∗ , B s 2 ∗ ) transitions and $$b\rightarrow (q,s,c)$$ b → ( q , s , c ) induced $$B \rightarrow (a_2,K^*_2,D^*_2)$$ B → ( a 2 , K 2 ∗ , D 2 ∗ ) , $$B_s \rightarrow (K^*_2,f'_2,D^*_{s2})$$ B s → ( K 2 ∗ , f 2 ′ , D s 2 ∗ ) , $$B_c \rightarrow (D^*_2,D^*_{s2},\chi _{c2}(1P))$$ B c → ( D 2 ∗ , D s 2 ∗ , χ c 2 ( 1 P ) ) , $$\eta _b(1S) \rightarrow (B^*_2,B^*_{s2})$$ η b ( 1 S ) → ( B 2 ∗ , B s 2 ∗ ) transitions. Finally, in order to test the obtained form factors, the semileptonic $$B\rightarrow {\bar{D}}_2^*(2460)\ell ^+\nu _\ell $$ B → D ¯ 2 ∗ ( 2460 ) ℓ + ν ℓ ( $$\ell =e,\mu $$ ℓ = e , μ ) and $${\bar{D}}_2^*(2460)\tau ^+\nu _{\tau }$$ D ¯ 2 ∗ ( 2460 ) τ + ν τ decays are studied. It is expected that our results for the form factors of $$P\rightarrow T$$ P → T transition can be applied further to the relevant phenomenological studies of meson decays.

Objective: Previous studies have shown the correlations between serum ferritin and non-alcoholic fatty liver disease (NAFLD) or diabetes. However, this relationship remains unclear in patients with type 2 diabetes (T2DM) with NAFLD. Therefore, this study aimed to elaborate the relationship between serum ferritin levels and NAFLD in middle-aged and older patients with T2DM and further explored the biomarkers for NAFLD in T2DM. Methods: A total of 805 middle-aged and older patients with T2DM were divided into NAFLD and non-NAFLD groups, and their serum ferritin levels were compared. Next, NAFLD group were divided into five subgroups according to the qu intile levels of serum ferritin, and the differences in the constituent ratios of NAFLD were analyzed. A logistic regression analysis was performed to determine the risk factors for NAFLD in patients with T2DM. Results: The serum ferritin levels were significantly higher in T2DM pati ents with NAFLD (168.47 (103.78, 248.00) ng/mL) than in the non-NAFLD patients (121.19 (76.97, 208.39) ng/mL). The constituent ratios of NAFLD were significantly highe r in the F5 and F4 groups than in the F2 or F1 groups (22.70 and 22.70% vs. 15.90 and 16.90%, respectively; P < 0.05). Binary logistic regression analysis showed that serum ferritin (P = 0.001) was an independent risk factor for NAFLD in patients with T2DM. Conclusions: Serum ferritin levels were significantly increased in T2DM with NAFLD, and the constituent ratios of NAFLD increased gradually along with the increased levels of serum ferritin. Thus, serum ferritin is an independent risk factor for NAFLD in patients with T2DM.

Abstract Apical-basal cell polarity and lumen formation are essential features of many epithelial tissues, which are disrupted in diseases like cancer. Here, we describe a proteomics-based screen to identify proteins involved in lumen formation in three-dimensional spheroid cultures. We established a suspension-based culture method suitable for generating polarized cysts in sufficient quantities for proteomic analysis. Using this approach, we identified several known and unknown proteins proximally associated with PAR6B, an apical protein involved in lumen formation. Functional analyses of candidates identified PARD3B (a homolog of PARD3), RALB, and HRNR as regulators of lumen formation. We also identified PTPN14 as a component of the Par-complex that is required for fidelity of apical-basal polarity. Cells transformed with KRASG12V exhibit lumen collapse/filling concomitant with disruption of the Par-complex and down-regulation of PTPN14. Enforced expression of PTPN14 maintained the lumen and restricted the transformed phenotype in KRASG12V-expressing cells. This represents an applicable approach to explore protein–protein interactions in three-dimensional culture and to identify proteins important for lumen maintenance in normal and oncogene-expressing cells.

Abstract Apoptosis induced by doxorubicin, bortezomib, or paclitaxel, targeting DNA, 26S proteasome, and microtubules respectively, was assessed in two osteosarcoma cells, p53 wild-type U2OS and p53-null MG63 cells. Doxorubicin-induced apoptosis only occurred in U2OS, not in MG63. In contrast, bortezomib and paclitaxel could drive U2OS or MG63 toward apoptosis effectively, suggesting that apoptosis induced by bortezomib or paclitaxel is p53-independent. The expressions of Bcl2 family members such as Bcl2, Bcl-xl, and Puma could be seen in U2OS and MG63 cells with or without doxorubicin, bortezomib, or paclitaxel treatment. In contrast, another member, Bim, only could be observed in U2OS, not in MG63, under the same conditions. Bim knockdown did not affect the doxorubicin-induced apoptosis in U2OS, suggested that a BH3-only protein other than Bim might participate in apoptosis induced by doxorubicin. Using a BH3-mimetic, ABT-263, to inhibit Bcl2 or Bcl-xl produced a limited apoptotic response in U2OS and MG63 cells, suggesting that this BH3-mimetic cannot activate the Bax/Bak pathway efficiently. Significantly, ABT-263 enhanced doxorubicin- and bortezomib-induced apoptosis synergistically in U2OS and MG63 cells. These results implied that the severe cellular stress caused by doxorubicin or bortezomib might be mediated through a dual process to control apoptosis. Respectively, doxorubicin or bortezomib activates a BH3-only protein in one way and corresponding unknown factors in another way to affect mitochondrial outer membrane permeability, resulting in apoptosis. The combination of doxorubicin with ABT-263 could produce synergistic apoptosis in MG63 cells, which lack p53, suggesting that p53 has no role in doxorubicin-induced apoptosis in osteosarcoma. In addition, ABT-263 enhanced paclitaxel to induce moderate levels of apoptosis.

ObjectiveThis study aimed to investigate the role of ficolin-2 (FCN2) in the development and course of hepatocellular carcinoma (HCC) and to contribute to the evolution of innovative HCC therapeutics.MethodsOncomine, GEPIA (Gene Expression Profiling Interactive Analysis), TISIDB (Tumor Immune System Interactions and Drug Bank database), UALCAN (University of Alabama at Birmingham Cancer data analysis portal), UCSC (University of California, Santa Cruz), R package, the Kaplan–Meier technique, Cox regression analysis, LinkedOmics, Pearson’s correlation, and a nomogram were used to investigate the prognostic value of FCN2 in HCC. Co-expressed genes were screened. A protein–protein interaction network was created using the STRING database. Finally, immunohistochemistry was performed to establish the expression of FCN2 in HCC tissues. A pan-cancer study centered on HCC-related molecular analysis was also conducted to look for a link between FCN2 and immune infiltration, immune modulators, and chemokine receptors.ResultsIn HCC tissues, the expression of FCN2 was observed to be lower than that in normal tissues. This was connected to the HCC marker alpha-fetoprotein, showing that FCN2 is involved in the development and progression of cancer. FCN2 may act through Staphylococcus aureus infection, lectins, and other pathways. Furthermore, at the immune level, the expression of FCN2 in HCC was associated with some immune cell infiltration, immunomodulators, and chemokine receptors.ConclusionFCN2 may be an immune checkpoint inhibitor for HCC, creating a breakthrough in the treatment of HCC.

Abstract Epigenetic regulation is important for cancer tumor metastasis and progression, including lung and liver cancer. However, the mechanism of epigenetic regulation in liver cancer leaves much to be discussed. According to a previous study, p300/CBP‐associated factor (PCAF) mediated epithelial–mesenchymal transition (EMT) and promotes cancer metastasis by recruiting intestine‐specific homeobox (ISX) and bromodomain‐containing protein 4 (BRD4) in lung cancer. To figure out whether the three genes are also expressed in patients with hepatocellular carcinoma (HCC) or not, and their correlation with patients’ outcome, BRD4, PCAF, and ISX messenger RNA (mRNA) expression levels in 377 patients with HCC were investigated using quantitative polymerase chain reaction and confocal fluorescence imaging. The correlation of the gene expression (PCAF, ISX, and BRD4) in liver cancer is also being investigated. Here, we show that the mRNA expression of PCAF, BRD4, and ISX in 377 paired specimens from patients with HCC, and the adjacent normal tissues exhibited a tumor‐specific expression pattern, highly correlated with disease pathogenesis, patient survival time, progression stage, and poor prognosis. The results show that ISX and BRD4 can potentially be a target for improving the survival rate.

Abstract Background Diabetic nephropathy (DN) is a leading cause of renal failure, whereas the effective and early diagnostic biomarkers are still lacking. Methods Fourteen cytokines and chemokines mRNA were detected in urinary extracellular vesicles (EVs) from the screening cohort including 4 healthy controls (HC), 4 diabetes mellitus (DM) and 4 biopsy-proven DN patients, and was validated in another 16 HC and 15 DM and 28 DN patients. Correlation analysis was performed between the candidate biomarkers and clinic parameters as well as kidney histological changes. The findings were also confirmed in DN rat model with single injection of STZ. Results The number of small EVs secreted in urine was increased in DN patients compared to DM patients and healthy controls, with expression of AQP1 (a marker of proximal tubules) and AQP2 (a marker of distal/collecting tubules). Small EVs derived CCL21 mRNA increased significantly in DN patients and correlated with level of proteinuria and eGFR. Interestingly, elevated CCL21 mRNA from urine small EVs was observed in DN patients with normal renal function and could discriminate early DN patients from DM more efficiently compared to eGFR and proteinuria. CCL21 also showed an accurate diagnostic ability in distinguishing incipient from overt DN. Histologically, CCL21 mRNA expression increased progressively with the deterioration of tubulointerstitial inflammation and showed the highest level in nodular sclerosis group (class III) in DN patients. Remarkable infiltration of CD3 positive T cells including both CD4 and CD8 positive T cell population were observed in DN patients with high-CCL21 expression. Besides, accumulation of CD3 positive T cells correlated with level of urinary small EVs derived CCL21 and co-localized with CCL21 in the tubulointerstitium in DN patients. Finally, the correlation of CCL21 expression in renal cortex and urinary small EVs was confirmed in STZ-induced DN rat model. Conclusions Urinary small EVs derived CCL21 mRNA may serve as early biomarker for identifying DN linked with pathogenesis. CCL21 mRNA mediated T cell infiltration may constitute the key mechanism of chronic inflammation in DN.

Epithelial cells that organise into structures that contain a lumen are polarised. Here, the authors show that the short intracellular domain of transmembrane protein CD13 is required to capture endosomes at the apical site and is required for the polarisation of cells.

Abstract Background Falls among older adults are a serious public health problem. Many studies indicate that positive functional fitness performance decreases the risk of falls. A limited amount of previous study has investigated the association between broad functional fitness and the fall risk. This study examines the associations between functional fitness and the risk of falling among community-dwelling older adults. Methods Three waves of cross-sectional data were collected from 2017 to 2019 in Taipei City, Taiwan. Six hundred sixty-five participants aged ≥65 years were randomly recruited from 12 districts of Taipei. Eight functional fitness tests (i.e., back scratch, chair-sit and-reach, 8-ft up-and-go, 30-s sit-to-stand, 30-s arm curl, 30-s single-leg stance, 2-min step, and hand grip strength tests) were performed to record the physical performance of older subjects. A Chinese version of the fall-risk questionnaire (FRQ) was used to calculate the fall risk scores. Linear regression and logistic regression were utilized to estimate the relationships of each functional fitness and fall risk. Result The results showed that 37.45% of older adults had a high risk of falling. It was found for each functional fitness that performance was linearly associated with the risk of falling. Moreover, older adults with low-performance levels in all functional fitness except back-scratching were more likely to have a higher risk of falling. Conclusions Our study indicated that functional fitness performance appears to provide valid predictive guidance for reducing the risk of falling among the older population.

To understand the role of architectural environment on metabolic plasticity of cancer cells, Al Masri et al. compare the metabolic activities of cancer cells grown in 2D vs 3D. They find that cells cultivated in 2D are highly glycolytic and dependent on glucose and glutamine for growth, while cells cultivated in 3D have extensive metabolic plasticity, and are able to maintain growth even in glucose or amino acid depleted environment.

Abstract Background To investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors. Methods The BrdU assay, Annexin-V/PI assay, TRAP staining and immunofluorescence were performed to explore the effect of LA on the proliferation, apoptosis and differentiation of OC precursors in vitro and in vivo. Flow cytometry was performed to sort primary osteoclast precursors and CD4(+) T cells and to analyze the change in the expression of target proteins in osteoclast precursors. A recruitment assay was used to test how LA and Cadhein-11 regulate the recruitment of OC precursors. RT-PCR and Western blotting were performed to analyze the changes in the mRNA and protein expression of genes related to the PI3K-AKT pathway and profibrotic genes. Safranin O-fast green staining, H&E staining and TRAP staining were performed to analyze the severity of bone resorption and accumulation of osteoclasts. Results LA promoted the expression of CXCL10 and Cadherin-11 in CD115(+) precursors through the PI3K-AKT pathway. We found that CXCL10 and Cadherin-11 were regulated by the activation of CREB and mTOR, respectively. LA-induced overexpression of CXCL10 in CD115(+) precursors indirectly promoted the differentiation of osteoclast precursors through the recruitment of CD4(+) T cells, and the crosstalk between these two cells promoted bone resorption in bone metastasis from CRC. On the other hand, Cadherin-11 mediated the adhesion between osteoclast precursors and upregulated the production of specific collagens, especially Collagen 5, which facilitated fibrotic changes in the tumor microenvironment. Blockade of the PI3K-AKT pathway efficiently prevented the progression of bone metastasis caused by lactate. Conclusion LA promoted metastatic niche formation in the tumor microenvironment through the PI3K-AKT pathway. Our study provides new insight into the role of LA in the progression of bone metastasis from CRC. Video Abstract

Abstract Background This study aims to analyze the effect of the body mass index (BMI) on E2, P and LH values in females who received intrauterine insemination (IUI) treatment on human chorionic gonadotropin (HCG) day. Methods A total of 2319 cycles of IUI-assisted pregnancy treatment were selected in our hospital. Based on the BMI, female infertility patients are divided into three groups: normal weight group, overweight and obese group. Results For patients with natural cycles and ≤ 35 years old, there were 440, 178 and 197 cases in the three groups, respectively. For patients with natural cycles and > 35 years old, there were 90, 83 and 81 cycles in the three groups, respectively. For patients with induced ovulation cycle and ≤ 35 years old, there were 425, 203 and 516 cases in the three groups, respectively. For patients with induced ovulation cycle and > 35 years old, there were 26, 26 and 54 cases in the three groups, respectively. Conclusion When a patient is ≤35 years old, the BMI affects the E2, LH and P values on the day of artificial insemination. However, the BMI is negatively correlated with E2, LH and P in IUI on HCG day. After controlling for age and assisted pregnancy, the correlation analysis revealed that the BMI is negatively correlated with hormone E2 and LH. The higher the BMI was, the lower the levels of hormones E2, LH and P became. However, in the present study, the BMI did not significantly improve the clinical pregnancy rate of patients who received IUI.

This research demonstrates the preparation of composite membranes containing graphene oxide (GO) and investigates the separation mechanisms of various salts and bovine serum albumin (BSA) solutions. A microporous polyvinylidene fluoride–polyacrylic acid–GO (PVDF-PAA-GO) separation layer was fabricated on non-woven support. The GO-incorporating composite resulted in enlarged pore size (0.16 μm) compared with the control membrane (0.12 μm). The zeta potential of the GO composite was reduced to –31 from –19 mV. The resulting membranes with and without GO were examined for water permeability and rejection efficiency with single salt and BSA solutions. Using the non-woven/PVDF-PAA composite, the permeance values were 88–190 kg/m2hMPa, and the salt rejection coefficients were 9–28% for Na2SO4, MgCl2, MgSO4, and NaCl solutions. These salt removals were based on the Donnan exclusion mechanism considering the ion radii and membrane pore size. Incorporating GO into the separation layer exhibited limited impacts on the filtration of salt solutions, but significantly reduced BSA membrane adhesion and increased permeance. The negatively charged protein reached almost complete removal (98.4%) from the highly negatively charged GO-containing membrane. The GO additive improved the anti-fouling property of the composite membrane and enhanced BSA separation from the salt solution.

Background: The aim of this study was to determine the effect of Facebook remote live-streaming-guided exercise on the functional fitness of community-dwelling older adults.Method: This study used a non-randomized controlled design with single-blinding (outcome assessors). Older adults (mean age = 70.36 ± 4.51 years) were assigned to either the experimental group (n = 39) or the control group (n = 34). The experimental group participated in a 75-min Facebook remote live-streaming-guided exercise routine twice a week for 8 weeks at home, whereas the control group maintained their original lifestyle without any intervention. Functional fitness was assessed using the Senior Fitness Test, which assessed upper and lower limb flexibility and muscle strength, cardiorespiratory fitness, and balance. The test was administered before and after the intervention.Results: The results revealed that an 8-week Facebook remote live-streaming-guided exercise intervention increased lower limb flexibility and muscle strength and cardiorespiratory fitness in community-dwelling older adults.Conclusion: The current findings suggest that a home-based exercise program using the Facebook platform may be a feasible method to broadly improve the functional fitness of community-dwelling older adults.

Objective(s): The aim of this study was to conduct a meta-analysis to assess the clinical safety of ceftolozane-tazobactam for the treatment of acute bacterial infections in adult patients. Methods: The PubMed, Embase, and Cochrane databases were searched from their inception until May 2020 for relevant randomized controlled trials (RCTs). Only RCTs evaluating the risk of adverse events (AEs) for ceftolozane-tazobactam and comparative treatments for acute bacterial infections in adult patients were included. Results: Overall, four RCTs including a total of 2924 patients (1475 in the ceftolozane-tazobactam group and 1449 in the control group) were included in the meta-analysis. The rate of treatment-emergent AEs was 51.3% (748/1458) in the ceftolozane-tazobactam group, which was comparable to the control group, 49.9% [714/1430; odd’s ratio (OR), 1.06; 95% confidence interval (CI), 0.91–1.25; I 2 = 0%]. In addition, no difference was observed between the ceftolozane-tazobactam and control groups in terms of the risk of serious AEs (OR, 1.22; 95% CI, 0.93–1.61; I 2 = 15.5%) and the risk of discontinuing the study drug due to AEs (OR, 0.85; 95% CI, 0.55–1.33; I 2 = 0%). The rate of all-cause mortality did not significantly differ between the ceftolozane-tazobactam and control groups (OR, 1.11; 95% CI, 0.82–1.50; I 2 = 0%). The only exception was the risk of Clostridiodes difficile ( C. difficile ) colitis, where ceftolozane-tazobactam treatment was associated with a significantly higher risk compared with the control group [0.72% (10/1376) versus 0.14% (2/1391), OR, 3.84; 95% CI, 1.23–11.97; I 2 = 0%]. Conclusion: Ceftolozane-tazobactam treatment is as tolerable as comparative treatment options for acute bacterial infections in adult patients, however it has an increased risk of C. difficile infection. As a novel broad-spectrum antibiotic, ceftolozane-tazobactam could be a safe therapeutic option for use in common clinical practice. Plain language summary The safety of ceftolozane-tazobactam (an antibiotics) for the treatment of acute bacterial infections Objective(s): Ceftolozane-tazobactam is an effective antibiotic for the treatment of acute bacterial infections. This study conducts a meta-analysis to assess the clinical safety (side effects) of ceftolozane-tazobactam for the treatment of acute bacterial infections in adult patients compared with other drugs. Methods: We extracted data from four randomized controlled trials, including a total of 2924 patients (1475 in the ceftolozane-tazobactam group and 1449 in the control group). Results: The rate of treatment related adverse events (AEs) was similar in the ceftolozane-tazobactam group (51.3%) and control group (49.9%). There was also no difference in risk of serious adverse events, the risk of discontinuing the study drug due to AEs, and all-cause mortality. The only exception was the risk of Clostridiodes difficile colitis (a cause of antibiotic-associated diarrhea), where ceftolozane-tazobactam treatment was associated with a significantly higher risk compared with the control group. Conclusion: In conclusion, as a novel broad-spectrum antibiotic, ceftolozane-tazobactam could be a safe therapeutic option for use in clinical practice.

Abstract In this paper, we calculate the matrix element and form factors of vector-to- vector (V I → V II ) transition within the standard light-front (SLF) and covariant light- front (CLF) quark models (QMs), and investigate the self-consistency and Lorentz covari- ance of the CLF QM within two types of correspondences between the manifest covariant Bethe-Salpeter approach and the LF approach. The zero-mode and valence contributions to the form factors of V I → V II transition in the CLF QM and their relation to the SLF results are analyzed, and the main conclusions obtained via the decay constants of vector and axial-vector mesons and the form factors of P → V transition in the previous works are confirmed again. Furthermore, we present our numerical predictions for the form factors of c → (q, s) (q = u, d) induced D * → (K * , ρ), D ∗ → (ϕ, K * ), J/Ψ → D s ∗ D ∗ $$ \left({D}_s^{\ast },{D}^{\ast}\right) $$ , B c ∗ → B s ∗ B ∗ $$ {B}_c^{\ast}\to \left({B}_s^{\ast },{B}^{\ast}\right) $$ transitions and b → (c, s, q) induced B ∗ → (D ∗, K ∗, ρ), B s ∗ → D s ∗ ϕ K ∗ $$ {B}_s^{\ast}\to \left({D}_s^{\ast },\phi, {K}^{\ast}\right) $$ , B c ∗ → J / Ψ D s ∗ D ∗ , ϒ 1 S → B c ∗ B s ∗ B ∗ $$ {B}_c^{\ast}\to \left(J/\varPsi, {D}_s^{\ast },{D}^{\ast}\right),\varUpsilon (1S)\to \left({B}_c^{\ast },{B}_s^{\ast },{B}^{\ast}\right) $$ the relevant phenomenological studies of meson decays.

Abstract Background The morbidity of knee arthritis is increasing among aged people and total knee arthroplasty has been its mainstream treatment to date. Postoperative rehabilitation is an important part of the procedure. However, the intense pain during the functional exercise involved has always been a challenge for both patients and health care professionals. The aim of this study is to test the analgesic effect of a mixture of nitrous oxide/oxygeb (1:1) inhalation for patients who are doing functional exercise 1 month after total knee arthroplasty. Methods/design This double-blind, randomized, placebo-controlled study will be implemented in the Rehabilitation Department in the General Hospital of Ningxia Medical University. Patients aged between 50 and 75 years who underwent a primary unilateral total knee arthroplasty are eligible for inclusion. The key exclusion criteria include: epilepsy, pulmonary embolism, intestinal obstruction, aerothorax. The treatment group (A) will receive a pre-prepared nitrous oxide/oxygen mixture plus conventional treatment (no analgesics), and the control group (B) will receive oxygen plus conventional treatment (no analgesics). Patients, physicians, therapists, and data collectors are all blind to the experiment. Assessments will be taken immediately after functional exercise begins (T0), 5 min (T1) after functional exercise begins, and 5 min after functional exercise has finished (T2). Patients will be randomly allocated between a treatment group (A) and a control group (B) in a ratio of 1:1. Primary outcome, including pain severity in the procedure, will be taken for each group. Secondary outcomes include blood pressure, heart rate, oxygen saturation, side effects, knee joint range of motion, Knee Society Score (KSS), rescue analgesia need, and satisfaction from both therapists and patients. Discussion This study will focus on exploring a fast and efficient analgesic for patients who are doing functional exercise after total knee arthroplasty. Our previous studies suggested that the prefixed nitrous oxide/oxygen mixture was an efficacious analgesic for the management of burn-dressing pain and breakthrough cancer pain. The results of this study should provide a more in-depth insight into the effects of this analgesic method. If this treatment proves successful, it could be implemented widely for patients doing functional exercise in the rehabilitation department. Trial registration ChiCTR-INR-17012891. Registered on 6 October 2017.

Abstract We investigate the self-consistency and Lorentz covariance of the covariant light-front quark model (CLF QM) via the matrix elements and form factors ($${{\mathcal {F}}}=g$$ F=g , $$a_{\pm }$$ a± and f) of $$P\rightarrow V$$ P→V transition. Two types of correspondence schemes between the manifest covariant Bethe–Salpeter approach and the light-front quark model are studied. We find that, for $$a_{-}(q^2)$$ a-(q2) and $$f(q^2)$$ f(q2) , the CLF results obtained via $$\lambda =0$$ λ=0 and ± polarization states of vector meson within the traditional type-I correspondence scheme are inconsistent with each other; and moreover, the strict covariance of the matrix element is violated due to the nonvanishing spurious contributions associated with noncovariance. We further show that such two problems have the same origin and can be resolved simultaneously by employing the type-II correspondence scheme, which advocates an additional replacement $$M\rightarrow M_0$$ M→M0 relative to the traditional type-I scheme; meanwhile, the results of $${{\mathcal {F}}}(q^2)$$ F(q2) in the standard light-front quark model (SLF QM) are exactly the same as the valence contributions and equal to numerally the full results in the CLF QM, i.e., $$[{{\mathcal {F}}}]_{\mathrm{SLF}}=[{{\mathcal {F}}}]_{\mathrm{val.}}\doteq [{{\mathcal {F}}}]_\mathrm{full}$$ [F]SLF=[F]val.≐[F]full . The numerical results for some $$P\rightarrow V$$ P→V transitions are updated within the type-II scheme. Above findings confirm the conclusion obtained via the decay constants of vector and axial-vector mesons in the previous works.

Abstract Background Endolithic microbes in coral skeletons are known to be a nutrient source for the coral host. In addition to aerobic endolithic algae and Cyanobacteria, which are usually described in the various corals and form a green layer beneath coral tissues, the anaerobic photoautotrophic green sulfur bacteria (GSB) Prosthecochloris is dominant in the skeleton of Isopora palifera. However, due to inherent challenges in studying anaerobic microbes in coral skeleton, the reason for its niche preference and function are largely unknown. Results This study characterized a diverse and dynamic community of endolithic microbes shaped by the availability of light and oxygen. In addition, anaerobic bacteria isolated from the coral skeleton were cultured for the first time to experimentally clarify the role of these GSB. This characterization includes GSB’s abundance, genetic and genomic profiles, organelle structure, and specific metabolic functions and activity. Our results explain the advantages endolithic GSB receive from living in coral skeletons, the potential metabolic role of a clade of coral-associated Prosthecochloris (CAP) in the skeleton, and the nitrogen fixation ability of CAP. Conclusion We suggest that the endolithic microbial community in coral skeletons is diverse and dynamic and that light and oxygen are two crucial factors for shaping it. This study is the first to demonstrate the ability of nitrogen uptake by specific coral-associated endolithic bacteria and shed light on the role of endolithic bacteria in coral skeletons.

Objective To investigate the relationship between peroxisome proliferator-activated receptor gamma (PPARγ) mRNA, serum adiponectin (ADP) and lipids in paediatric patients with Kawasaki disease (KD). Methods This prospective study enrolled paediatric patients with KD and grouped them according to the presence or absence of coronary artery lesions (CAL). A group of healthy age-matched children were recruited as the control group. The levels of PPARγ mRNA, serum ADP and lipids were compared between the groups. Receiver operating characteristic (ROC) curve analysis was undertaken to determine if the PPARγ mRNA level could be used as a predictive biomarker of CAL prognosis. Results The study enrolled 42 patients with KD (18 with CAL [CAL group] and 24 without CAL [NCAL group]) and 20 age-matched controls. PPARγ mRNA levels in patients with KD were significantly higher than those in the controls; but significantly lower in the CAL group than the NCAL group. ROC curve analysis demonstrated that the PPARγ mRNA level provided good predictive accuracy for the prognosis of CAL. There was no association between PPARγ, ADP and lipid levels. Conclusion There was dyslipidaemia in children with KD, but there was no correlation with PPARγ and ADP. PPARγ may be a predictor of CAL in patients with KD with good predictive accuracy.

Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show that Drosophila Girdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination from GIRDIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration of GIRDIN expression is associated with poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.