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Abstract Background Medical device-related pressure injures (MDRPIs) are common in critically ill patients and associated with negative clinical outcomes and elevated healthcare expenses. We aim to estimate worldwide incidence of MDRPI and explore associated factors through systemic review and meta-analysis. Methods The PubMed, Web of Science, Cochrane Library, and Ovid EMBASE databases were systematically queried to identify relevant studies published from Jan 1, 2010 up until June 30, 2024. Studies were included if they provided data on the incidence or prevalence of MDRPI. Random-effect models were utilized to calculate the overall or domain-specific aggregated estimates of MDRPI. A meta-regression analysis was additionally performed to investigate the heterogeneity among studies. Results We included 28 observational studies on 117,624 patients in the meta-analysis. The overall incidence of MDRPI was 19.3% (95% confidence interval (CI) 13.5–25.2%). The incidence of MDRPI in Europe, North America, Asia, South America, and Oceania was 17.3% (95% CI 12.7–21.9%), 3.6% (95% CI 0.0–8.5%), 21.9% (95% CI 14.3–29.6%), 48.3% (95% CI 20.8–75.7%), and 13.0% (95% CI 5.0–21.1%), respectively (p

Abstract Background Osteocytes are critical mechanosensory cells in bone, and mechanically stimulated osteocytes produce exosomes that can induce osteogenesis. MicroRNAs (miRNAs) are important constituents of exosomes, and some miRNAs in osteocytes regulate osteogenic differentiation; previous studies have indicated that some differentially expressed miRNAs in mechanically strained osteocytes likely influence osteoblastic differentiation. Therefore, screening and selection of miRNAs that regulate osteogenic differentiation in exosomes of mechanically stimulated osteocytes are important. Results A mechanical tensile strain of 2500 με at 0.5 Hz 1 h per day for 3 days, elevated prostaglandin E2 (PGE2) and insulin-like growth factor-1 (IGF-1) levels and nitric oxide synthase (NOS) activity of MLO-Y4 osteocytes, and promoted osteogenic differentiation of MC3T3-E1 osteoblasts. Fourteen miRNAs differentially expressed only in MLO-Y4 osteocytes which were stimulated with mechanical tensile strain, were screened, and the miRNAs related to osteogenesis were identified. Four differentially expressed miRNAs (miR-1930-3p, miR-3110-5p, miR-3090-3p, and miR-3058-3p) were found only in mechanically strained osteocytes, and the four miRNAs, eight targeted mRNAs which were differentially expressed only in mechanically strained osteoblasts, were also identified. In addition, the mechanically strained osteocyte-derived exosomes promoted the osteoblastic differentiation of MC3T3-E1 cells in vitro, the exosomes were internalized by osteoblasts, and the up-regulated miR-3110-5p and miR-3058-3p in mechanically strained osteocytes, were both increased in the exosomes, which was verified via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Conclusions In osteocytes, a mechanical tensile strain of 2500 με at 0.5 Hz induced the fourteen differentially expressed miRNAs which probably were in exosomes of osteocytes and involved in osteogenesis. The mechanically strained osteocyte-derived exosomes which contained increased miR-3110-5p and miR-3058-3p (two of the 14 miRNAs), promoted osteoblastic differentiation.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent renal cancers, and the molecular mechanisms underlying its progression are still not fully understood. The expression of CCDC25, a notably underexpressed gene in many tumors, has been understudied in ccRCC. This research aims to explore the role of CCDC25 in ccRCC's clinical outcomes and uncover the molecular pathways influenced by it. Methods A multi-tiered approach was adopted involving bioinformatic analysis, tissue sample evaluation, in vitro and in vivo experiments. CCDC25 expression levels in tumor vs. normal tissues were quantified using Western blot and immunofluorescence studies. Cell proliferation and migration were analyzed using CCK8, EDU, Transwell assays, and wound healing assays. RNA sequencing was performed to elucidate the molecular pathways affected, followed by detailed protein–protein interaction studies and mouse xenograft models. Results CCDC25 was predominantly underexpressed in ccRCC tumors and associated with advanced clinical stages and poor prognosis. Overexpression of CCDC25 in renal cancer cell lines resulted in reduced proliferation and migration. RNA sequencing revealed significant alterations in the Hippo pathway. Overexpression of CCDC25 inhibited the expression of downstream Hippo pathway proteins ITGA3 and CCND1 and promoted YAP phosphorylation. Mechanistic studies showed that CCDC25 interacts with YAP and influences YAP phosphorylation through LATS1. In vivo, CCDC25 overexpression inhibited tumor growth and promoted apoptosis. Conclusion CCDC25 acts as a potential tumor suppressor in ccRCC by inhibiting cell proliferation and migration, potentially through regulating the Hippo signaling pathway. These findings highlight the potential of CCDC25 as a therapeutic target in ccRCC treatment. Graphical Abstract

Abstract Background Kaposiform hemangioendothelioma (KHE) is a rare intermediate vascular tumor with unclear pathogenesis. Recently, three dimensional (3D) cell spheroids and organoids have played an indispensable role in the study of many diseases, such as infantile hemangioma and non-involuting congenital hemangiomas. However, few research on KHE are based on the 3D model. This study aims to evaluate the 3D superiority, the similarity with KHE and the ability of drug evaluation of EOMA spheroids as an in vitro 3D KHE model. Results After two days, relatively uniform morphology and high viability of EOMA spheroids were generated by the rotating cell culture system (RCCS). Through transcriptome analysis, compared with 2D EOMA cells, focal adhesion-related genes such as Itgb4, Flt1, VEGFC, TNXB, LAMA3, VWF, and VEGFD were upregulated in EOMA spheroids. Meanwhile, the EOMA spheroids injected into the subcutaneous showed more obvious KMP than 2D EOMA cells. Furthermore, EOMA spheroids possessed the similar characteristics to the KHE tissues and subcutaneous tumors, such as diagnostic markers (CD31 and LYVE-1), cell proliferation (Ki67), hypoxia (HIF-1α) and cell adhesion (E-cadherin and N-cadherin). Based on the EOMA spheroid model, we discovered that sirolimus, the first-line drug for treating KHE, could inhibit EOMA cell proliferation and downregulate the VEGFC expression. Through the extra addition of VEGFC, the effect of sirolimus on EOMA spheroid could be weakened. Conclusion With a high degree of similarity of the KHE, 3D EOMA spheroids generated by the RCCS can be used as a in vitro model for basic researches of KHE, generating subcutaneous tumors and drug screening.

Abstract Background Necrotizing enterocolitis (NEC) is a multifactorial gastrointestinal disease with high morbidity and mortality among premature infants. However, studies with large samples on the factors of NEC in China have not been reported. This meta-analysis aims to systematically review the literature to explore the influencing factors of necrotizing enterocolitis in premature infants in China and provide a reference for the prevention of NEC. Methods PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database (CBM), Wanfang and VIP databases were systematically searched from inception to February 2023. We used Stata14.0 software to perform the systematic review and meta-analysis. We used fixed or random effects models with combined odds ratios (ORs) and 95% confidence intervals (CIs), and quality was evaluated using the Newcastle‒Ottawa Scale (NOS). Results The total sample was 8616 cases, including 2456 cases in the intervention group and 6160 cases in the control group. It was found that 16 risk factors and 3 protective factors were related to necrotizing enterocolitis in premature infants. Septicemia (OR = 3.91), blood transfusion (OR = 2.41), neonatal asphyxia (OR = 2.46), pneumonia (OR = 6.17), infection (OR = 5.99), congenital heart disease (OR = 4.80), intrahepatic cholestasis of pregnancy (ICP) (OR = 2.71), mechanical ventilation (OR = 1.44), gestational diabetes mellitus (GDM) (OR = 3.08), respiratory distress syndrome (RDS) (OR = 3.28), hypoalbuminemia (OR = 2.80), patent ductus arteriosus (PDA) (OR = 3.10), respiratory failure (OR = 7.51), severe anemia (OR = 2.86), history of antibiotic use (OR = 2.12), and meconium-stained amniotic fluid (MSAF) (OR = 3.14) were risk factors for NEC in preterm infants in China. Breastfeeding (OR = 0.31), oral probiotics (OR = 0.36), and prenatal use of glucocorticoids (OR = 0.38) were protective factors for NEC in preterm infants. Conclusions Septicemia, blood transfusion, neonatal asphyxia, pneumonia, infection, congenital heart disease, ICP, GDM, RDS, hypoproteinemia, PDA, respiratory failure, severe anemia, history of antibiotic use and MSAF will increase the risk of NEC in premature infants, whereas breastfeeding, oral probiotics and prenatal use of glucocorticoids reduce the risk. Due to the quantity and quality of the included literature, the above findings need to be further validated by more high-quality studies.

Abstract Background Neuroinflammation may be a potential mechanism of postoperative delirium (POD) in geriatric patients, and hypertonic saline (HS) has immunomodulatory properties. The purpose of this study was to investigate whether HS could reduce the incidence of POD in elderly patients and its effect on neutrophil activation and inflammatory cytokine expression. Methods We studied the effect of pre-infusion of 4 mL/kg 3% hypertonic saline vs. 4 mL/kg 0.9% normal saline on POD in patients undergoing shoulder arthroscopy in a prospective, randomized, double-blind, controlled trial. Neutrophil surface molecules (CD11b, CD66b and CD64) were analyzed by flow cytometry. Circulating concentrations of inflammatory factors IL-1β, IL-6, TNF-α and neurological damage factor S100β were assessed by enzyme immunoassay. The Confusion Assessment Method-Chinese Revision (CAM-CR) was applied for the assessment of POD 1–3 days after surgery. Results The incidence of POD in group H was significantly lower than that in group N (7.14% vs 26.83%, P = 0.036). The expression levels of inflammatory cytokines ( IL-6 and TNF-α) and neutrophil surface markers (CD11b and CD66b) were significantly lower in group H than in group N at 24 h after surgery (P = 0.018, P

Abstract Background Deoxynivalenol (DON), one of the most prevalent mycotoxins, has been found to cause fetal growth retardation in animals. However, limited evidence exists regarding its effects on pregnant women. Methods Maternal urinary concentration of total DON (tDON) and free DON (fDON) in the second trimester was measured using liquid chromatography with tandem mass spectrometry. Provisional daily intake (PDI) of DON was calculated based on tDON concentration. Linear and logistic regression models were used to evaluate the association between DON exposure levels and birth weight, birth length, and the risk of small for gestational age (SGA). Results Among 1538 subjects, the median concentrations of tDON and fDON were 12.1 ng/mL and 5.1 ng/mL, respectively. The PDI values revealed that the median DON intake was 0.7 µg/kg bw, and 35.9% of the total population exceeded the provisional maximum tolerable daily intake (PMTDI) of 1 µg/kg bw. Compared with the lowest tertile, birth weight decreased by 81.11 g (95% CI: -127.00, -35.23) for tDON (P-trend

Abstract Background Liver cancer is a prevalent and deadly form of cancer with high incidence and mortality rates. The PCMT1 protein has been linked to cell anti-apoptosis and tumor metastasis, but its significance in liver hepatocellular carcinoma (LIHC) remains largely unexplored. Methods We conducted a pan-cancer analysis to examine the expression differences of PCMT1. Kaplan–Meier curves were employed to assess the prognostic impact of PCMT1 on LIHC patients, and we investigated the association between PCMT1 and clinical features, which we validated using a GEO therapeutic dataset. Gene enrichment analysis helped identify signaling pathways associated with PCMT1 expression. Moreover, we evaluated the relationship between PCMT1 and immune cell infiltration, as well as the differences in gene mutations between high-expression and low-expression groups. In vitro and in vivo experiments were performed to assess the effect of PCMT1 on tumor cell lines and mouse tumor models, and potential pathways were explored through gene sequencing. Result PCMT1 is highly expressed in most tumors and exhibits a significant association with prognosis in LIHC patients. Pathway enrichment analysis revealed that PCMT1 is involved in cell cycle regulation, immunity, and other processes. Further immune analysis demonstrated that high expression of PCMT1 could reduce tumor-killing immune cell infiltration. In vitro experiments indicated that PCMT1 knockdown could inhibit cancer cell proliferation and migration while promoting apoptosis. In vivo experiments showed that PCMT1 knockdown significantly reduced tumor growth rate, enhanced CD8+T cell infiltration, and increased caspase-3 expression in the tumor area. Gene sequencing suggested that PCMT1 may function through the PI3K–AKT pathway. Conclusion Our findings suggest that PCMT1 acts as a promoter of liver cancer progression and may serve as a novel prognostic indicator and therapeutic target for patients with LIHC.

Abstract Background The chloroplast genome of plants is known for its small size and low mutation and recombination rates, making it a valuable tool in plant phylogeny, molecular evolution, and population genetics studies. Codon usage bias, an important evolutionary feature, provides insights into species evolution, gene function, and the expression of exogenous genes. Coffee, a key crop in the global tropical agricultural economy, trade, and daily life, warrants investigation into its codon usage bias to guide future research, including the selection of efficient heterologous expression systems for coffee genetic transformation. Results Analysis of the codon utilization patterns in the chloroplast genomes of three Coffea species revealed a high degree of similarity among them. All three species exhibited similar base compositions, with high A/T content and low G/C content and a preference for A/T-ending codons. Among the 30 high-frequency codons identified, 96.67% had A/T endings. Fourteen codons were identified as ideal. Multiple mechanisms, including natural selection, were found to influence the codon usage patterns in the three coffee species, as indicated by ENc-GC3s mapping, PR2 analysis, and neutral analysis. Nicotiana tabacum and Saccharomyces cerevisiae have potential value as the heterologous expression host for three species of coffee genes. Conclusion This study highlights the remarkable similarity in codon usage patterns among the three coffee genomes, primarily driven by natural selection. Understanding the gene expression characteristics of coffee and elucidating the laws governing its genetic evolution are facilitated by investigating the codon preferences in these species. The findings can enhance the efficacy of exogenous gene expression and serve as a basis for future studies on coffee evolution.

Abstract Background Great progress has been made in applying immunotherapy to the clinical treatment of tumors. However, many patients with triple-negative breast cancer (TNBC) cannot benefit from immunotherapy due to the immune desert type of TNBC, which is unresponsive to immunotherapy. DMKG, a cell-permeable derivative of α-KG, has shown potential to address this issue. Method We investigated the effects of combining DMKG with radioimmunotherapy on TNBC. We assessed the ability of DMKG to promote tumor cell apoptosis and immunogenic death induced by radiotherapy (RT), as well as its impact on autophagy reduction, antigen and inflammatory factor release, DC cell activation, and infiltration of immune cells in the tumor area. Result Our findings indicated that DMKG significantly promoted tumor cell apoptosis and immunogenic death induced by RT. DMKG also significantly reduced autophagy in tumor cells, resulting in increased release of antigens and inflammatory factors, thereby activating DC cells. Furthermore, DMKG promoted infiltration of CD8 + T cells in the tumor area and reduced the composition of T-regulatory cells after RT, reshaping the tumor immune microenvironment. Both DMKG and RT increased the expression of PD-L1 at immune checkpoints. When combined with anti-PD-L1 drugs (α-PD-L1), they significantly inhibited tumor growth without causing obvious side effects during treatment. Conclusion Our study underscores the potential of pairing DMKG with radioimmunotherapy as an effective strategy for treating TNBC by promoting apoptosis, immunogenic death, and remodeling the tumor immune microenvironment. This combination therapy could offer a promising therapeutic avenue for TNBC patients unresponsive to conventional immunotherapy. Graphical Abstract

Abstract Objectives Patients with vascular anomalies (VAs) who receive oral sirolimus may be at high risk of infectious complications. Antibiotic prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) has been advocated. However, there have been few evidence-based analyses on this topic. This study assessed the effect of prophylactic TMP-SMZ on the incidence of infections in VA patients receiving sirolimus monotherapy. Methods A retrospective, multicenter chart review was performed on all VA patients receiving sirolimus treatment from August, 2013 to January, 2021. Results Before January 2017, 112 patients were treated with sirolimus without antibiotic prophylaxis. In the subsequent period, 195 patients were treated with TMP-SMZ for at least 12 months during sirolimus therapy. The percentage of patients with at least one serious infection during the initial 12 months of sirolimus treatment did not differ between the groups (difference, 1.1%; 95% CI − 7.0–8.0%). We observed no difference in the incidence of individual infection or total adverse events between the groups. The rate of sirolimus discontinuation due to adverse events did not differ significantly between groups. Conclusions We demonstrated that prophylactic TMP-SMZ does not decrease the incidence of infection or improve tolerance in VA patients receiving sirolimus monotherapy.

Abstract Background As the rate of multiple pregnancies increases, delayed interval delivery (DID) is increasingly being implemented to improve perinatal outcomes. But there are no international guidelines for DID in multiple pregnancies. We report a case of DID in a quadruplet pregnancy and review the relevant literature to summarize the management of DID in multiple pregnancies. Case presentation A 22-year-old woman, 22 2/7 weeks' gestation, with quadruplets, was admitted to the hospital for a first cervical cerclage due to cervical dilation. Twenty-five days later, it was found that the cervix was dilated again, so after removing the cervical cerclage, the first quadruplet was delivered vaginally (25 6/7 weeks), and a second cervical cerclage was performed. Four days later, due to re-dilation of the cervix, after removal of the cervical cerclage, the second quadruplet was delivered vaginally (26 3/7 weeks), followed by a third cervical cerclage. Six days later, the pregnancy was terminated by cesarean section due to fetal distress, and the third and fourth quadruplets were delivered (27 2/7 weeks). The patient had no postoperative complications, and all four infants were treated in the neonatal intensive care unit and discharged successfully. Conclusion This case emphasizes that comprehensive management of delayed interval delivery can improve perinatal outcomes in multiple pregnancies, including anti-infection, tocolytic therapy, practice to promote fetal lung, and cervical cerclage.

Abstract Infantile hemangioma (IH) is the most prevalent benign vascular tumor in infants, with distinct disease stages and durations. Despite the fact that the majority of IHs can regress spontaneously, a small percentage can cause disfigurement or even be fatal. The mechanisms underlying the development of IH have not been fully elucidated. Establishing stable and reliable IH models provides a standardized experimental platform for elucidating its pathogenesis, thereby facilitating the development of new drugs and the identification of effective treatments. Common IH models include the cell suspension implantation model, the viral gene transfer model, the tissue block transplantation model, and the most recent three-dimensional (3D) microtumor model. This article summarizes the research progress and clinical utility of various IH models, as well as the benefits and drawbacks of each. Researchers should select distinct IH models based on their individual research objectives to achieve their anticipated experimental objectives, thereby increasing the clinical relevance of their findings.

Abstract Background Non-involuting congenital hemangiomas (NICHs) are fully formed vascular tumors at birth with distinctive clinical, radiologic, and histopathological profiles. In the literature, there is no effective therapy strategy for patients with NICH except surgery. Currently, no cell line or animal model exists for studying the mechanism of NICH and drug validation. We plan to construct a new strategy by constructing NICH organoids for further study. Result Here, we report a novel NICH organoid system construction and optimization process. Both HE and immunohistological staining exactly matched NICH tissue. We further performed transcriptome analysis to elucidate the characteristics of NICH organoids. Both NICH tissue and NICH organoids manifested similar trends in download sites. NICH organoids display novel features to new cells derived from organoids and show spectacular multiplication capacity. In the preliminary verification, we found that cells splitting from NICH organoids were human endothelial cells. Drug validation demonstrated that trametinib, sirolimus, and propranolol showed no inhibitory effects on NICH organoids. Conclusion Our data show that this new NICH-derived organoid faithfully captured the features of this rare vascular tumor. Our study will boost further research on the mechanism of NICH and drug filtering in the future.

Abstract Background The triglyceride-glucose (TyG) index, a simple measure of insulin resistance, is associated with intracranial atherosclerosis (ICAS) and stroke. In hypertensive populations, this association may be pronounced. The aim was to investigate the relationship between TyG and symptomatic intracranial atherosclerosis (sICAS) and recurrence risk in ischemic stroke patients with hypertension. Methods This prospective, multicenter cohort study included patients with acute minor ischemic stroke with a preadmission diagnosis of hypertension from September 2019 to November 2021 with a 3-month follow-up. The presence of sICAS was determined by a combination of clinical manifestations, the location of the infarction, and the corresponding artery with moderate-to-severe stenosis. ICAS burden was determined by the degree and number of ICAS occurrences. Fasting blood glucose (FBG) and triglyceride (TG) were measured to calculate TyG. The main outcome was ischemic stroke recurrence during the 90-day follow-up. Multivariate regression models were used to explore the association of TyG, sICAS, and ICAS burden with stroke recurrence. Results There were 1281 patients with a mean age of 61.6 ± 11.6 years; 70.1% were male, and 26.4% were diagnosed with sICAS. There were 117 patients who experienced stroke recurrence during follow-up. Patients were categorized according to quartiles of TyG. After adjusting for confounders, the risk of sICAS was greater (OR 1.59, 95% CI 1.04–2.43, p = 0.033) and the risk of stroke recurrence was significantly higher (HR 2.02, 95% CI 1.07–3.84, p = 0.025) in the fourth TyG quartile than in the first quartile. The restricted cubic spline (RCS) plot revealed a linear relationship between TyG and sICAS, and the threshold value for TyG was 8.4. Patients were then dichotomized into low and high TyG groups by the threshold. Patients with high TyG combined with sICAS had a higher risk of recurrence (HR 2.54, 95% CI 1.39–4.65) than patients with low TyG without sICAS. An interaction effect on stroke recurrence between TyG and sICAS was found (p = 0.043). Conclusion TyG is a significant risk factor for sICAS in hypertensive patients, and there is a synergistic effect of sICAS and higher TyG on ischemic stroke recurrence. Trial registration number: The study was registered on 16 August 2019 at https://www.chictr.org.cn/showprojen.aspx?proj=41160 (No. ChiCTR1900025214).

Abstract Background The peaberry bean in Arabica coffee has exceptional quality compared to the regular coffee bean. Understanding the molecular mechanism of bean quality is imperative to introduce superior coffee quality traits. Despite high economic importance, the regulatory aspects of bean quality are yet largely unknown in peaberry. A transcriptome analysis was performed by using peaberry and regular coffee beans in this study. Results The result of phenotypic analysis stated a difference in the physical attributes of both coffee beans. In addition, transcriptome analysis revealed low genetic differences. Only 139 differentially expressed genes were detected in which 54 genes exhibited up-regulation and 85 showed down-regulations in peaberry beans compared to regular beans. The majority of differentially expressed genes had functional annotation with cell wall modification, lipid binding, protein binding, oxidoreductase activity, and transmembrane transportation. Many fold lower expression of Ca25840-PMEs1, Ca30827-PMEs2, Ca30828-PMEs3, Ca25839-PMEs4, Ca36469-PGs. and Ca03656-Csl genes annotated with cell wall modification might play a critical role to develop different bean shape patterns in Arabica. The ERECTA family genes Ca15802-ERL1, Ca99619-ERL2, Ca07439-ERL3, Ca97226-ERL4, Ca89747-ERL5, Ca07056-ERL6, Ca01141-ERL7, and Ca32419-ERL8 along lipid metabolic pathway genes Ca06708-ACOX1, Ca29177-ACOX2, Ca01563-ACOX3, Ca34321-CPFA1, and Ca36201-CPFA2 are predicted to regulate different shaped bean development. In addition, flavonoid biosynthesis correlated genes Ca03809-F3H, Ca95013-CYP75A1, and Ca42029-CYP75A2 probably help to generate rarely formed peaberry beans. Conclusion Our results provide molecular insights into the formation of peaberry. The data resources will be important to identify candidate genes correlated with the different bean shape patterns in Arabica.

Abstract Background Sodium formononetin-3ʹ-sulphonate (Sul-F) may alleviate I/R injury in vivo with uncertain mechanism. Endoplasmic reticulum (ER) stress-mediated apoptosis participates in the process of cerebral ischemia‐reperfusion (I/R) injury. Our aim is to figure out the effect of Sul-F on cerebral I/R injury and to verify whether it works through suppressing ER stress-mediated apoptosis. Results The cerebral lesions of middle cerebral artery occlusion (MCAO) model in SD rats were aggravated after 24 h of reperfusion, including impaired neurological function, increased infarct volume, intensified inflammatory response and poor cell morphology. After intervention, the edaravone (EDA, 3 mg/kg) group and Sul-F high-dose (Sul-F-H, 80 mg/kg) group significantly alleviated I/R injury via decreasing neurological score, infarct volume and the serum levels of inflammatory factors (TNF-α, IL-1β and IL-6), as well as alleviating pathological injury. Furthermore, the ER stress level and apoptosis rate were elevated in the ischemic penumbra of MCAO group, and were significantly blocked by EDA and Sul-F-H. In addition, EDA and Sul-F-H significantly down-regulated the ER stress related PERK/eIF2α/ATF4 and IRE1 signal pathways, which led to reduced cell apoptosis rate compared with the MCAO group. Furthermore, there was no difference between the EDA and Sul-F-H group in terms of therapeutic effect on cerebral I/R injury, indicating a therapeutic potential of Sul-F for ischemic stroke. Conclusions Sul-F-H can significantly protects against cerebral I/R injury through inhibiting ER stress-mediated apoptosis in the ischemic penumbra, which might be a novel therapeutic target for ischemic stroke.

Abstract Tacrolimus (Tac) is a common immunosuppressant that used in organ transplantation. However, its therapeutic index is narrow, and it is prone to adverse side effects, along with an increased risk of toxicity, namely, cardio-, nephro-, hepato-, and neurotoxicity. Prior metabolomic investigations involving Tac-driven toxicity primarily focused on changes in individual organs. However, extensive research on multiple matrices is uncommon. Hence, in this research, the authors systemically evaluated Tac-mediated toxicity in major organs, namely, serum, brain, heart, liver, lung, kidney, and intestines, using gas chromatography−mass spectrometry (GC-MS). The authors also employed multivariate analyses, including orthogonal projections to the latent structure (OPLS) and t-test, to screen 8 serum metabolites, namely, D-proline, glycerol, D-fructose, D-glucitol, sulfurous acid, 1-monopalmitin (MG (16:0/0:0/0:0)), glycerol monostearate (MG (0:0/18:0/0:0)), and cholesterol. Metabolic changes within the brain involved alterations in the levels of butanamide, tartronic acid, aminomalonic acid, scyllo-inositol, dihydromorphine, myo-inositol, and 11-octadecenoic acid. Within the heart, the acetone and D-fructose metabolites were altered. In the liver, D-glucitol, L-sorbose, palmitic acid, myo-inositol, and uridine were altered. In the lung, L-lactic acid, L-5-oxoproline, L-threonine, phosphoric acid, phosphorylethanolamine, D-allose, and cholesterol were altered. Lastly, in the kidney, L-valine and D-glucose were altered. Our findings will provide a systematic evaluation of the metabolic alterations in target organs within a Tac-driven toxicity mouse model.

Abstract Background Cardiac damage is the leading cause of death in uremic patients. This study aimed to evaluate the application of non-invasive myocardial work index (NIMWI) by echocardiography in assessing the left ventricular (LV) systolic function in uremic patients. Methods Twenty-six uremic patients and 27 age- and sex-matched healthy volunteers were enrolled in the study. Except for the conventional echocardiographic parameters, the LV myocardial work (MW) parameters including GWI (myocardial global work index), GCW (global constructive work), GWW (global wasted work), and GWE (global work efficiency) were calculated in study participants. Differences in MW parameters between the uremic and normal groups were compared by independent-sample t-test. Receiver operating characteristic (ROC) curves were constructed for MW parameters to detect abnormal LV systolic function in uremic patients. Results Compared with the normal group, GWW was significantly increased and GWE decreased in the uremic group (P

Abstract Background Pantothenate kinase (PANK) is the first and rate-controlling enzymatic step in the only pathway for cellular coenzyme A (CoA) biosynthesis. PANK-associated neurodegeneration (PKAN), formerly known as Hallervorden–Spatz disease, is a rare, life-threatening neurologic disorder that affects the CNS and arises from mutations in the human PANK2 gene. Pantazines, a class of small molecules containing the pantazine moiety, yield promising therapeutic effects in an animal model of brain CoA deficiency. A reliable technique to identify the neurometabolic effects of PANK dysfunction and to monitor therapeutic responses is needed. Methods We applied 1H magnetic resonance spectroscopy as a noninvasive technique to evaluate the therapeutic effects of the newly developed Pantazine BBP-671. Results 1H MRS reliably quantified changes in cerebral metabolites, including glutamate/glutamine, lactate, and N-acetyl aspartate in a neuronal Pank1 and Pank2 double-knockout (SynCre + Pank1,2 dKO) mouse model of brain CoA deficiency. The neuronal SynCre + Pank1,2 dKO mice had distinct decreases in Glx/tCr, NAA/tCr, and lactate/tCr ratios compared to the wildtype matched control mice that increased in response to BBP-671 treatment. Conclusions BBP-671 treatment completely restored glutamate/glutamine levels in the brains of the mouse model, suggesting that these metabolites are promising clinically translatable biomarkers for future therapeutic trials.

Abstract Disordered chromatin remodeling regulation has emerged as an essential driving factor for cancers. Imitation switch (ISWI) family are evolutionarily conserved ATP-dependent chromatin remodeling complexes, which are essential for cellular survival and function through multiple genetic and epigenetic mechanisms. Omics sequencing and a growing number of basic and clinical studies found that ISWI family members displayed widespread gene expression and genetic status abnormalities in human cancer. Their aberrant expression is closely linked to patient outcome and drug response. Functional or componential alteration in ISWI-containing complexes is critical for tumor initiation and development. Furthermore, ISWI-non-coding RNA regulatory networks and some non-coding RNAs derived from exons of ISWI member genes play important roles in tumor progression. Therefore, unveiling the transcriptional regulation mechanism underlying ISWI family sparked a booming interest in finding ISWI-based therapies in cancer. This review aims at describing the current state-of-the-art in the role of ISWI subunits and complexes in tumorigenesis, tumor progression, immunity and drug response, and presenting deep insight into the physiological and pathological implications of the ISWI transcription machinery in cancers.

Abstract Parkinson’s disease (PD) is a multi-system neurodegenerative disorder. Patients with PD often suffer chronic pain. In the present study, we investigated motor, sensory and emotional changes in three different PD mice models. We found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treatment caused significant changes in all measurements. Mechanical hypersensitivity of PD model induced by MPTP peaked at 3 days and persisted for at least 14 days. Using Fos transgenic mice, we found that neurons in the anterior cingulate cortex (ACC) were activated after MPTP treatment. Inhibiting ACC by bilateral microinjection of muscimol significantly reduced mechanical hypersensitivity and anxiety-like responses. By contrast, MPTP induced motor deficit was not affected, indicating ACC activity is mostly responsible for sensory and emotional changes. We also investigated excitatory synaptic transmission and plasticity using brain slices of MPTP treated animals. While L-LTP was blocked or significantly reduced. E-LTP was not significantly affected in slices of MPTP treated animals. LTD induced by repetitive stimulation was not affected. Furthermore, we found that paired-pulse facilitation and spontaneous release of glutamate were also altered in MPTP treated animals, suggesting presynaptic enhancement of excitatory transmission in PD. Our results suggest that ACC synaptic transmission is enhanced in the animal model of PD, and cortical excitation may play important roles in PD related pain and anxiety.

Abstract Objective Iron and steel industry workers are exposed to high levels of inhalable dust particles that contain various elements, including metals, and cause occupational lung diseases. We aim to assess the relationship between occupational dust exposure, systemic inflammation, and spirometric decline in a cohort of Chinese iron and steel workers. Methods We studied 7513 workers who participated in a Health Surveillance program at Wugang Institute for Occupational Health between 2008 and 2017. Time-weighted exposure intensity (TWEI) of dust was quantified based on self-reported dust exposure history, the experience of occupational hygienists, and historical data of dust exposure for workers with certain job titles. A linear mixed-effects model was used for association analyses. Results The average annual change of lung function was − 50.78 ml/year in forced expiratory volume in 1 s (FEV1) and − 34.36 ml/year in forced vital capacity (FVC) in males, and − 39.06 ml/year in FEV1 and − 26.66 ml/year in FVC in females. Higher TWEI prior to baseline was associated with lower longitudinal measurements of FEV1 and FVC but not with their decline rates. Higher WBC and its differential at baseline were associated with lower longitudinal measurements and a more rapid decline of FEV1 and FVC in a dose-dependent monotonically increasing manner. Moreover, the increase of WBC and its differential post-baseline was also associated with a more rapid decline of FEV1 and FVC. Conclusions Our findings support the important role of systemic inflammation in affecting the temporal change of lung function in iron and steel industry workers.

Abstract Background Breast cancer is the fastest-growing cancer among females and the second leading cause of female death. At present, targeted antibodies combined with hyperthermia locally in tumor has been identified as a potential combination therapy to combat tumors. But in fact, the uniformly deep distribution of photosensitizer in tumor sites is still an urgent problem, which limited the clinical application. We reported an HER2-modified thermosensitive liposome (immunoliposome)-assisted complex by reducing gold nanocluster on the surface (GTSL-CYC-HER2) to obtain a new type of bioplasma resonance structured carrier. The HER2 decoration on the surface enhanced targeting to the breast cancer tumor site and forming irregular, dense, "petal-like" shells of gold nanoclusters. Due to the good photothermal conversion ability under near-infrared light (NIR) irradiation, the thermosensitive liposome released the antitumor Chinese traditional medicine, cyclopamine, accompanied with the degradation of gold clusters into 3–5 nm nanoparticles which can accelerate renal metabolism of the gold clusters. With the help of cyclopamine to degrade the tumor associated matrix, this size-tunable gold wrapped immunoliposome was more likely to penetrate the deeper layers of the tumor, while the presence of gold nanoparticles makes GTSL-CYC-HER2 multimodal imaging feasible. Results The prepared GTSL-CYC-HER2 had a size of 113.5 nm and displayed excellent colloidal stability, photo-thermal conversion ability and NIR-sensitive drug release. These GTSL-CYC-HER2 were taken up selectively by cancer cells in vitro and accumulated at tumour sites in vivo. As for the in vivo experiments, compared to the other groups, under near-infrared laser irradiation, the temperature of GTSL-CYC-HER2 rises rapidly to the phase transition temperature, and released the cyclopamine locally in the tumor. Then, the released cyclopamine destroyed the stroma of the tumor tissue while killing the tumor cells, which in turn increased the penetration of the liposomes in deep tumor tissues. Moreover, the GTSL-CYC-HER2 enhanced the performance of multimodal computed tomography (CT) and photothermal (PT) imaging and enabled chemo-thermal combination therapy. Conclusions This optically controlled biodegradable plasmonic resonance structures not only improves the safety of the inorganic carrier application in vivo, but also greatly improves the anti-tumor efficiency through the visibility of in vivo CT and PT imaging, as well as chemotherapy combined with hyperthermia, and provides a synergistic treatment strategy that can broaden the conventional treatment alone. Graphic Abstract

Abstract Objectives The aim of this study was to evaluate the postoperative analgesia effect of ultrasound-guided single popliteal sciatic nerve block for calcaneal fracture. Methods A total of 120 patients scheduled for unilateral open reduction and internal fixation of calcaneal fracture were enrolled in this prospective randomized study. Patients in group B received ultrasound-guided single popliteal sciatic nerve block after operation, but Patients in group A did not. All patients received patient-controlled intravenous analgesia (PCIA) after operation. The time to initiation of PCIA, the time of first pressing the analgesia pump, duration of analgesia pump use and the total number of times the patient pressed the analgesia pump were recorded. The time of rescue analgesia and the adverse reactions were recorded. Pain magnitude of the patients immediately after discharge from operating room (T1), and at 4th (T2), 8th (T3), 12th (T4), 16th (T5), 24th (T6) and 48th (T7) h after the operation were assessed with visual analog scale (VAS). In addition, patient, surgeon and nurse satisfaction were recorded. Results The VAS scores at T2 ~ T5, the time of rescue analgesia and the adverse reactions, the total number of times the patient pressed the analgesia pump were significantly declined in group B (p

Abstract Background Aroma is one the most crucial inherent quality attributes of fruit. ‘Ruixue’ apples were selected from a cross between ‘Pink Lady’ and ‘Fuji’, a later ripening yellow new cultivar. However, there is little known about the content and composition of aroma compounds in ‘Ruixue’ apples or the genetic characters of ‘Ruixue’ and its parents. In addition, the metabolic pathways for biosynthesis of aroma volatiles and aroma-related genes remain poorly understood. Results Volatile aroma compounds were putatively identified using gas chromatography-mass spectrometry (GC–MS). Our results show that the profile of volatile compounds changes with ripening. Aldehydes were the dominant volatile compounds in early fruit development, with alcohols and esters increasing dramatically during maturation. On the basis of a heatmap dendrogram, these aroma compounds clustered into seven groups. In ripe fruit, esters and terpenoids were the main aroma volatiles in ripening fruit of ‘Pink Lady’ and ‘Fuji’ apples, and they included butyl 2-methylbutanoate; propanoic acid, hexyl ester; propanoic acid, hexyl ester; hexanoic acid, hexyl ester; acetic acid, hexyl ester and (Z, E)-α-farnesene. Interestingly, aldehydes and terpenoids were the dominant volatile aroma compounds in ripening fruit of ‘Ruixue’, and they mainly included hexanal; 2-hexenal; octanal; (E)-2-octenal; nonanal and (Z, E)-α-farnesene. By comparing the transcriptome profiles of ‘Ruixue’ and its parents fruits during development, we identified a large number of aroma-related genes related to the fatty acid, isoleucine and sesquiterpenoid metabolism pathways and transcription factors that may volatile regulate biosynthesis. Conclusions Our initial study facilitates a better understanding of the volatile compounds that affect fruit flavour as well as the mechanisms underlying differences in flavour between ‘Ruixue’ and its parents.

Abstract Objective To determine whether revision laparoscopic Kasai portoenterostomy (RLKPE) is a viable treatment option for patients with biliary atresia (BA) who had undergone initially successful laparoscopic Kasai portoenterostomy (ILKPE). Methods The medical records of 312 patients with nonsyndromic BA who had undergone ILKPE between May 2009 and May 2017 were retrospectively reviewed. The patients were divided into three groups according to their outcomes after ILKPE: group A: 25 patients who had undergone RLKPE; group B: 203 patients who had undergone ILKPE and required no further surgical intervention; group C: 84 patients with failed ILKPE who had either died or required liver transplantation for survival. The 3-year and 5-year survival with native liver (SNL) rates were compared between groups A and B and between groups A and C. Among the 25 patients in group A, the perioperative data of RLKPE were compared with those of ILKPE. Results Of the 312 patients who had undergone ILKPE, 228 reached the normal bilirubin concentration range within 6 months postoperatively. Among them, 25 patients with a sudden cessation of bile flow had undergone RLKPE. Adequate biliary drainage, as evidenced by normalized conjugated bilirubin levels, was achieved in 80% of patients who had undergone RLKPE. The perioperative variables, including the operative time, blood loss, rate of conversion to open surgery and complications of RLKPE, were not significantly different between RLKPE and ILKPE. The 3-year and 5-year SNL rates in patients after RLKPE were 64.0% and 52.0%, respectively, which were not significantly different from the corresponding rates of 86.2% and 73.9%, respectively, in patients after unrevised ILKPE (P > 0.05). Conclusion Our data demonstrated that RPLKE is a viable and effective treatment option in patients with sudden cessation of bile drainage after ILKPE. RPLKE can delay the need for liver transplantation, yielding encouraging medium-term patient outcomes.

Abstract Background Muscle stem cells (MuSCs) are absolutely required for the formation, repair, and regeneration of skeletal muscle tissue. Increasing evidence demonstrated that tissue stem cells, especially mesenchymal stem cells (MSCs), can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory properties. Human mesenchymal stem cells (hMSCs) treated with interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) were reported to possess anti-inflammatory functions by producing TNF-stimulated gene 6 (TSG-6). However, whether human muscle stem cells (hMuSCs) also possess TSG-6 mediated anti-inflammatory functions has not been explored. Methods The ulcerative colitis mouse model was established by subjecting mice to dextran sulfate sodium (DSS) in drinking water for 7 days. hMuSCs were pretreated with IFN-γ and TNF-α for 48 h and were then transplanted intravenously at day 2 of DSS administration. Body weights were monitored daily. Indoleamine 2,3-dioxygenase (IDO) and TSG-6 in hMuSCs were knocked down with short hairpin RNA (shRNA) and small interfering RNA (siRNA), respectively. Colon tissues were collected for length measurement and histopathological examination. The serum level of IL-6 in mice was measured by enzyme-linked immunosorbent assay (ELISA). Real-time PCR and Western blot analysis were performed to evaluate gene expression. Results hMuSCs treated with inflammatory factors significantly ameliorated inflammatory bowel disease (IBD) symptoms. IDO and TSG-6 were greatly upregulated and required for the beneficial effects of hMuSCs on IBD. Mechanistically, the tryptophan metabolites, kynurenine (KYN) or kynurenic acid (KYNA) produced by IDO, augmented the expression of TSG-6 through activating their common receptor aryl hydrocarbon receptor (AHR). Conclusion Inflammatory cytokines-treated hMuSCs can alleviate DSS-induced colitis through IDO-mediated TSG-6 production.

Abstract Breast cancer is the first killer leading to female death, and tumor metastasis is one of the important factors leading to the death of patients, but the specific mechanism of breast cancer metastasis is not very clear at present. Our study showed that overexpression of TIMELESS could significantly inhibit the invasion and metastasis of breast cancer cells ZR-75-30 and the assembly of F-actin protein. On the contrary, knockdown of TIMELESS promoted the invasion and metastasis of breast cancer cells. Further study revealed that TIMELESS overexpression decreased the mRNA and protein levels of MMP9. Furthermore, TIMELESS could interact with p65, leading to repress the association of p65 and its acetyltransferase CBP and down-regulating the acetylation level of p65, which inhibited the activation of NF-κB signal pathway. In conclusion, our research showed that TIMELESS may repress the invasion and metastasis of breast cancer cells via inhibiting the acetylation of p65, inhibiting the activation of NF-κB, thus down-regulating the expression of MMP9, and then inhibiting the invasion and metastasis of breast cancer cells.

Abstract Background Fibrosarcomatous dermatofibrosarcoma protuberans (FS-DFSP) is a form of tumor progression of dermatofibrosarcoma protuberans (DFSP) with an increased risk of metastasis and recurrence. Few studies have compared the clinicopathological features of FS-DFSP and conventional DFSP (C-DFSP). Objectives To better understand the epidemiological and clinicopathological characteristics of FS-DFSP. Methods We conducted a cohort study of 221 patients diagnosed with DFSP and built a recognition model with a back-propagation (BP) neural network for FS-DFSP. Results Twenty-six patients with FS-DFSP and 195 patients with C-DFSP were included. There were no differences between FS-DFSP and C-DFSP regarding age at presentation, age at diagnosis, sex, size at diagnosis, size at presentation, and tumor growth. The negative ratio of CD34 in FS-DFSP (11.5%) was significantly lower than that in C-DFSP (5.1%) (P = 0.005). The average Ki-67 index of FS-DFSP (18.1%) cases was significantly higher than that of C-DFSP (8.1%) cases (P

Abstract Background The population of plants is a crucial indicator in plant phenotyping and agricultural production, such as growth status monitoring, yield estimation, and grain depot management. To enhance the production efficiency and liberate labor force, many automated counting methods have been proposed, in which computer vision-based approaches show great potentials due to the feasibility of high-throughput processing and low cost. In particular, with the success of deep learning, more and more deeper learning-based approaches are introduced to deal with agriculture automation. Since different detection- and regression-based counting models have distinct characteristics, how to choose an appropriate model given the target task at hand remains unexplored and is important for practitioners. Results Targeting in-field maize tassels as a representative case study, the goal of this work is to present a comprehensive benchmark of state-of-the-art object detection and object counting methods, including Faster R-CNN, YOLOv3, FaceBoxes, RetinaNet, and the leading counting model of maize tassels—TasselNet. We create a Maize Tassel Detection Counting (MTDC) dataset by supplementing bounding box annotations to the Maize Tassels Counting (MTC) dataset to allow the training of detection models. We investigate key factors effecting the practical applications of the models, such as convergence behavior, scale robustness, speed-accuracy trade-off, as well as parameter sensitivity. Based on our benchmark, we summarise the advantages and limitations of each method and suggest several possible directions to improve current detection- and regression-based counting approaches to benefit next-generation intelligent agriculture. Conclusions Current state-of-the-art detection- and regression-based counting approaches can all achieve a relatively high degree of accuracy when dealing with in-field maize tassels, with at least 0.85 $$R^2$$ R 2 values and 28.2% rRMSE error. While detection-based methods are more robust than regression-based methods in scale variations and can infer extra information (e.g., object positions and sizes), the latter ones have significantly faster convergence behaviors and inference speed. To choose an appropriate in-filed plant counting method, accuracy, robustness, speed and some other algorithm-specific factors should be taken into account with the same priority. This work sheds light on different aspects of existing detection and counting approaches and provides guidance on how to tackle in-field plant counting. The MTDC dataset is made available at https://git.io/MTDC

Abstract Background The high prevalence of early childhood caries (ECC) is widespread around the world, and oral health education (OHE) plays a vital role in preventing ECC. Numerous studies on ECC risk factor assessment have assisted us in enriching the content of OHE. The objective of this study was to further assess independent risk factors for ECC at different ages to provide evidence and insights for OHE. Methods Children aged 3–5 years old (N = 1301) in Shandong Province were enrolled in this cross-sectional study. Data about oral health status and caregivers’ oral health knowledge, attitude, and practice (KAP) were extracted from the 4th National Oral Health Survey of China. The associations between ECC prevalence and various KAP variables were tested with chi-square tests, bivariate analysis and multivariable logistic regression analyses. Results The ECC prevalence in Shandong Province was 64.6%, and the dmft mean was 3.15. The independent variables with an increased risk for ECC were age, feeding method within 6 months of birth, bedtime sugar frequency, experience of toothache over the past year and dental visits (P

Abstract Herein, a novel phototheranostic nanocomplex that is self-assembled from bovine serum albumin (BSA) and indocyanine green (ICG) is developed for enhanced near-infrared (NIR) fluorescence imaging, which benefits the guidance on in vivo cancer photothermal therapy (PTT). The study confirms that the binding of ICG with the bind sits on the albumin will result in improved hydrolytic stability and high photoluminescence quantum yield (PLQY). The ICG loading ratio in the nanocomplex is optimized and confirms the loading ratio of 0.5% ICG to be the optimal content. The optimized ICG–BSA nanocomplex (ICG–BSA NC) possesses a higher PLQY of 16.8% than that of free ICG (2.7%). The high PLQY and efficient passive targeting ability of ICG–BSA NC help improve its in vivo tumor accumulation and NIR fluorescence imaging significantly. Under laser irradiation, efficient PTT with obvious tumor growth suppression on a triple negative breast tumor model can be observed in the ICG–BSA NC treated group.

Abstract Background Global climate change is predicted to force the bathymetric migrations of shallow-water marine invertebrates. Hydrostatic pressure is proposed to be one of the major environmental factors limiting the vertical distribution of extant marine invertebrates. However, the high-pressure acclimation mechanisms are not yet fully understood. Results In this study, the shallow-water sea cucumber Apostichopus japonicus was incubated at 15 and 25 MPa at 15 °C for 24 h, and subjected to comparative transcriptome analysis. Nine samples were sequenced and assembled into 553,507 unigenes with a N50 length of 1204 bp. Three groups of differentially expressed genes (DEGs) were identified according to their gene expression patterns, including 38 linearly related DEGs whose expression patterns were linearly correlated with hydrostatic pressure, 244 pressure-sensitive DEGs which were up-regulated at both 15 and 25 MPa, and 257 high-pressure-induced DEGs which were up-regulated at 25 MPa but not up-regulated at 15 MPa. Conclusions Our results indicated that the genes and biological processes involving high-pressure acclimation are similar to those related to deep-sea adaptation. In addition to representative biological processes involving deep-sea adaptation (such as antioxidation, immune response, genetic information processing, and DNA repair), two biological processes, namely, ubiquitination and endocytosis, which can collaborate with each other and regulate the elimination of misfolded proteins, also responded to high-pressure exposure in our study. The up-regulation of these two processes suggested that high hydrostatic pressure would lead to the increase of misfolded protein synthesis, and this may result in the death of shallow-water sea cucumber under high-pressure exposure.

Abstract Background The use of oral (PO) antibiotics following a course of certain intravenous (IV) antibiotics is proposed in order to avoid the complications of IV medications and to decrease the cost. However, the efficacy and safety of sequential IV/PO antibiotics is unclear and requires further study. Methods The databases, including PubMed, EMBASE and Cochrane Library, were searched. Studies comparing outcomes in patients with perforated appendicitis receiving sequential IV/PO and PO antibiotics therapy were screened. The Newcastle-Ottawa Scale (NOS) and the Jadad score were used to evaluate the quality of the cohort and the randomized controlled portions of the trial, respectively. Statistical heterogeneity was assessed using the I 2 value. A fixed or random-effect model was applied according to the I 2 value. Results Five controlled studies including a total of 580 patients were evaluated. The pooled estimates revealed that sequential IV/PO antibiotic therapy did not increase the risk of complications, with a risk ratio (RR) of 0.97 (95% CI 0.51–1.83, P = 0.93) for postoperative abscess, 1.04 (95% CI 0.25–4.36, P = 0.96) for wound infection and 0.62 (95% CI 0.33–1.16, P = 0.13) for readmission. Conclusions Our study demonstrates that sequential IV/PO antibiotic therapy is noninferior to IV antibiotic therapy regarding postoperative abscess, wound infection and readmission.

Abstract Background Enzymatic hydrolysis of lignocellulose by fungi is a key step in global carbon cycle and biomass utilization. Cellulolytic enzyme production is tightly controlled at a transcriptional level. Here, we investigated the roles of different histone lysine methylation modifications in regulating cellulolytic enzyme gene expression, as histone lysine methylation is an important process of chromatin regulation associated with gene transcription. Results PoSet1 and PoSet2 in Penicillium oxalicum, orthologs of Set1 and Set2 in budding yeast, were associated with the methylation of histone H3 lysine 4 (H3K4) and lysine 36 (H3K36). Cellulolytic enzyme production was extensively upregulated by the disruption of PoSet2, but was significantly downregulated by the disruption of PoSet1. We revealed that the activation of cellulolytic enzyme genes was accompanied by the increase of H3K4me3 signal, as well as the decrease of H3K36me1 and H3K36me3 signal on specific gene loci. The repression of cellulolytic enzyme genes was accompanied by the absence of global H3K4me1 and H3K4me2. An increase in the H3K4me3 signal by Poset2 disruption was eliminated by the further disruption of Poset1 and accompanied by the repressed cellulolytic enzyme genes. The active or repressed genes were not always associated with transcription factors. Conclusion H3K4 methylation is an active marker of cellulolytic enzyme production, whereas H3K36 methylation is a marker of repression. A crosstalk occurs between H3K36 and H3K4 methylation, and PoSet2 negatively regulates cellulolytic enzyme production by antagonizing the PoSet1-H3K4me3 pathway. The balance of H3K4 and H3K36 methylation is required for the normal transcription of cellulolytic enzyme genes. These results extend our previous understanding that cellulolytic enzyme gene transcription is primarily controlled by transcription factors.

Abstract Background Metastasis is an important factor in the poor prognosis of breast cancer. As an important core clock protein, brain and muscle arnt-like 1 (BMAL1) is closely related to tumorigenesis. However, the molecular mechanisms that mediate the role of BMAL1 in invasion and metastasis remain largely unknown. In this study, we investigated the BMAL1 may take a crucial effect in the progression of breast cancer cells. Methods BMAL1 and MMP9 expression was measured in breast cell lines. Transwell and scratch wound-healing assays were used to detect the movement of cells and MTT assays and clonal formation assays were used to assess cells’ proliferation. The effects of BMAL1 on the MMP9/NF-κB pathway were examined by western blotting, co-immunoprecipitation and mammalian two-hybrid. Results In our study, it showed that cell migration and invasion were significantly enhanced when overexpressed BMAL1. Functionally, overexpression BMAL1 significantly increased the mRNA and protein level of matrix metalloproteinase9 (MMP9) and improved the activity of MMP9. Moreover, BMAL1 activated the NF-κB signaling pathway by increasing the phosphorylation of IκB and promoted human MMP9 promoter activity by interacting with NF-kB p65, leading to increased expression of MMP9. When overexpressed BMAL1, CBP (CREB binding protein) was recruited to enhance the activity of p65 and further activate the NF-κB signaling pathway to regulate the expression of its downstream target genes, including MMP9, TNFα, uPA and IL8, and then promote the invasion and metastasis of breast cancer cells. Conclusions This study confirmed a new mechanism by which BMAL1 up-regulated MMP9 expression to increase breast cancer metastasis, to provide research support for the prevention and treatment of breast cancer.

Abstract Background Mechanical loading is an essential factor for bone formation. A previous study indicated that mechanical tensile strain of 2500 microstrain (με) at 0.5 Hz for 8 h promoted osteogenesis and corresponding mechanoresponsive microRNAs (miRs) were identified in osteoblasts. However, in osteocytes, it has not been identified which miRs respond to the mechanical strain, and it is not fully understood how the mechanoresponsive miRs regulate osteoblast differentiation. Methods Mouse MLO-Y4 osteocytes were applied to the same mechanical tensile strain in vitro. Using molecular and biochemical methods, IGF-1 (insulin-like growth factor-1), PGE2 (prostaglandin E2), OPG (osteoprotegerin) and NOS (nitric oxide synthase) activities of the cells were assayed. MiR microarray and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were applied to select and validate differentially expressed miRs, and the target genes of these miRs were then predicted. MC3T3-E1 osteoblasts were stimulated by the mechanical tensile strain, and the miR-29b-3p expression was detected with miR microarray and RT-qPCR. Additionally, the effect of miR-29b-3p on IFG-1 secretion of osteocytes and the influence of conditioned medium of osteocytes transfected with miR-29b-3p on osteoblast differentiation were investigated. Results The mechanical strain increased secretions of IGF-1 and PGE2, elevated OPG expression and NOS activities, and resulted in altered expression of the ten miRs, and possible target genes for these differentially expressed miRs were revealed through bioinformatics. Among the ten miRs, miR-29b-3p were down-regulated, and miR-29b-3p overexpression decreased the IGF-1 secretion of osteocytes. The mechanical strain did not change expression of osteoblasts’ miR-29b-3p. In addition, the conditioned medium of mechanically strained osteocytes promoted osteoblast differentiation, and the conditioned medium of osteocytes transfected with miR-29b-3p mimic inhibited osteoblast differentiation. Conclusions In osteocytes (but not osteoblasts), miR-29b-3p was responsive to the mechanical tensile strain and regulated osteoblast differentiation via regulating IGF-1 secretion of mechanically strained osteocytes.

Abstract Background Long noncoding RNAs (lncRNAs) have emerged as playing crucial roles in abiotic stress responsive regulation, however, the mechanism of lncRNAs underlying drought-tolerance remains largely unknown in cassava, an important tropical and sub-tropical root crop of remarkable drought tolerance. Results In this study, a total of 833 high-confidence lncRNAs, including 652 intergenic and 181 anti-sense lncRNAs, were identified in cassava leaves and root using strand-specific RNA-seq technology, of which 124 were drought-responsive. Trans-regulatory co-expression network revealed that lncRNAs exhibited tissue-specific expression patterns and they preferred to function differently in distinct tissues: e.g., cell-related metabolism, cell wall, and RNA regulation of transcription in folded leaf (FL); degradation of major carbohydrate (CHO) metabolism, calvin cycle and light reaction, light signaling, and tetrapyrrole synthesis in full expanded leaf (FEL); synthesis of major CHO metabolism, nitrogen-metabolism, photosynthesis, and redox in bottom leaf (BL); and hormone metabolism, secondary metabolism, calcium signaling, and abiotic stress in root (RT). In addition, 27 lncRNA-mRNA pairs referred to cis-acting regulation were identified, and these lncRNAs regulated the expression of their neighboring genes mainly through hormone metabolism, RNA regulation of transcription, and signaling of receptor kinase. Besides, 11 lncRNAs were identified acting as putative target mimics of known miRNAs in cassava. Finally, five drought-responsive lncRNAs and 13 co-expressed genes involved in trans-acting, cis-acting, or target mimic regulation were selected and confirmed by qRT-PCR. Conclusions These findings provide a comprehensive view of cassava lncRNAs in response to drought stress, which will enable in-depth functional analysis in the future.

Abstract Background The transanastomotic feeding tube (TAFT) is widely used around the world in patients with esophageal atresia (EA). However, the safety of the use of TAFT is still unknown and remains to be clarified. Methods The following electronic databases were searched: PubMed, EMBASE and Cochrane. Studies comparing outcomes in patients with the use of TAFT (TAFT+) and patients without the use of TAFT (TAFT-) were scrutinized. The quality of included studies was evaluated with the Newcastle–Ottawa scale score. Statistical heterogeneity was assessed using the I 2 value. A fixed or random-effect model was applied. Results Four retrospective controlled studies involving 455 patients were included. The pooled estimates showed that the use of TAFT significantly increased the risk of stricture, with a risk ratio (RR) of 1.83 (95% CI 1.30–2.58; P = 0.0005). The meta-analyses of other postoperative complications did not show significant differences between TAFT+ and TAFT- group, with a RR of 1.65 (95% CI 0.93–2.93; P = 0.09) for anastomotic leakage, 0.91 (95% CI 0.34–2.44; P = 0.85) for sepsis, 1.89 (95% CI 0.22–16.20; P = 0.56) for tracheomalacia, 0.50 (95% CI 0.13–1.93; P = 0.31) for gastroesophageal reflux, 1.29 (95% CI 0.28–5.92; P = 0.74) for wound infection, and 0.97 (95% CI 0.03–36.75; p = 0.99) for pneumonia. Conclusions This study demonstrates that the use of TAFT in patients with EA significantly increases the risk of stricture. However, TAFT is not associated with other complications, including anastomotic leakage, sepsis, tracheomalacia, gastroesophageal reflux, wound infection and pneumonia.

Abstract Background Calcineurin (CaN) having a high expression in hippocampal neurons is closely related to apoptosis. Pretreatment with nimodipine can lower the apoptosis rate of hippocampal neuron to reduce the incidence of postoperative cognitive dysfunction (POCD). However, the relationship between cerebral protective effect of pretreatment with nimodipine and CaN is controversial in the literature. The aim of this study is to evaluate the relationship between neuroprotective effect of nimodipine and CaN on POCD in aged rats. Methods Ninety-six 18-month-old male Sprague-Dawley rats were randomly assigned into 4 groups (n = 24 each): control group (Group C), nimodipine group (Group N), surgery group (Group S) and nimodipine + surgery group (Group N + S). In Group N and Group N + S, nimodipine 1 mg/kg was intraperitoneally injected, while the equal volume of normal saline was given instead in Group S. 30 min later, Group N and Group C inhaled pure oxygen for 2 h, and Group S and N + S inhaled 3% sevoflurane for 2 h when exploratory laparotomy was performed. Morris water maze test was performed on 1 day before operation and 1, 3 and 7 days after operation. After the end of Morris water maze test at 1 day before operation and 1 and 7 days after operation, 8 rats were sacrificed, brains were removed and hippocampal tissues were obtained for detection of apoptosis in hippocampal neurons, cytoplasmic calcium ([Ca2+]i), and hippocampal CaN and caspase-3 expression. Results Compared with the 1st day before operation, the escape latency, apoptosis rate, [Ca2+]i, expression of CaN and caspase-3 increased significantly, but the frequency of crossing the original platform decreased dramatically in Group S and N + S(P

Abstract Background Our previous study showed that during in vitro experiments changes in calcium concentration were associated with apoptosis. We presumed that the calcium ion might play a role as intermediate messenger for apoptosis-related genes. No such evidence has been reported in the literature. Here, we investigate the effect of calcium ionophore A23187 on the apoptosis of rat hepatic stellate cells (HSCs) stimulated by transforming growth factor-β1 (TGF-β1) to explore the mechanism of apoptosis through the endoplasmic reticulum stress pathway. Methods The apoptotic rate was determined using flow cytometry. The changes in Ca2+ level in HSCs were examined with laser confocal microscopy. The expressions of caspase-12 GRP78 and caspase-9 were assayed via western blot. Results The respective apoptosis rates for the blank group, the TGF-β1 group and the TGF-β1 + low, medium and high dose calcium ionophore A23187 groups were 3.40 ± 0.10%, 1.76 ± 0.12%, 5.86 ± 0.31%, 11.20 ± 0.48% and 15.08 ± 0.75%, with significant differences between the groups (p

Abstract Background Infantile hemangioma (IH) is the most common vascular tumor in children. It is controversial whether IHs has effects on the quality of life (QOL) in patients of whom IH poses no threat or potential for complication. Thus, we conducted this study to evaluate the q QOL in patients with IH and find the predictors of poor QOL. Methods The PedsQL 4.0 Genetic Core Scales and the PedsQL family information form were administered to parents of children with IH and healthy children both younger than 2-year-old. The quality-of-life instrument for IH (IH-QOL) and the PedsQL 4.0 family impact module were administered to parents of children with IH. We compared the PedsQL 4.0 Genetic Core Scales (GCIS) scores of the two groups. Multiple step-wise regression analysis was used to determine factors that influenced QOL in children with IH and their parents. Results Except for physical symptom, we found no significant difference in GCIS between patient group and healthy group (P = 0.409). The internal reliability of IH-QOL was excellent with the Cronbach’s alpha coefficient for summary scores being 0.76. Multiple step-wise regression analysis showed that the predictors of poor IH-QOL total scores were hemangioma size, location, and mother’s education level. The predictors of poor FIM total scores were hemangioma location and father’s education level. The predictors of poor GCIS total scores were children’s age, hemangioma location and father’s education level. Conclusion The findings support the feasibility and reliability of the Chinese version of IH-QOL to evaluate the QOL in children with IH and their parents. Hemangioma size, location and education level of mother are important impact factors for QOL in children with IH and their parents.

Abstract Background Postoperative delirium (POD) is a common disorder in the elderly patients, and neuroinflammation is the possible underlying mechanism. This study is designed to determine whether or not hypertonic saline (HS) pre-injection can alleviate POD in aged patients. Methods This prospective study recruited 120 geriatric patients who underwent hip surgery. The patients were randomly divided into two groups: control group (NS group) and HS group. Patients in the NS group were pre-injected with 4 mL/kg isotonic saline, and those in the HS group were pre-injected with 4 mL/kg 7.5% HS. All 120 patients were then subjected to general anesthesia. Blood samples were extracted to detect the concentration of inflammatory factors, namely, IL-1β, IL-6, IL-10, and TNF-α, and the nerve injury factor S100β. Flow cytometry was used to detect the number of monocytes in peripheral venous blood and evaluate the relationship of inflammation to delirium. The nursing delirium screening scale (Nu-DESC) was used to determine cognitive function 1 to 3 days postoperatively. Results Analysis using random-effect multivariable logistic regression indicated that HS administration before anesthesia was associated with a low risk of POD (odds ratio [OR], 0.13; 95% CI, 0.04 to 0.41; P = 0.001) and few CD14 + CD16+ monocytes (β = − 0.61; 95% CI, − 0.74 to − 0.48; P = 0.000) the following day. When the association between HS and delirium was controlled for CD14 + CD16+ monocytes, the effect size became nonsignificant (odds ratio [OR], 0.86; 95% CI, 0.14 to 5.33; P = 0.874). TNF-α was significantly associated with POD (odds ratio [OR], 1.10; 95% CI, 1.05 to 1.16; P = 0.000). However, IL-1β, IL-6, IL-10, and S100β were not significantly related to POD. Conclusion HS can alleviate POD in geriatric patients and may inhibit the secretion of inflammatory factors by monocytes.

Abstract Purpose Immune checkpoint inhibitors (ICIs)-associated myocarditis was a rare yet severe complication observed in individuals undergoing immunotherapy. This study investigated the immune status and characteristics of patients diagnosed with ICIs- associated myocarditis. Methods A total of seven patients diagnosed with ICIs-associated myocarditis were included in the study, while five tumor patients without myocarditis were recruited as reference controls. Additionally, 30 healthy individuals were recruited as blank controls. Biochemical indices, electrocardiogram, and echocardiography measurements were obtained both prior to and following the occurrence of myocarditis. High-throughput sequencing of T cell receptor (TCR) was employed to assess the diversity and distribution characteristics of TCR CDR3 length, as well as the diversity of variable (V) and joining (J) genes of T lymphocytes in peripheral blood. Results In the seven patients with ICIs-associated myocarditis, Troponin T (TNT) levels exhibited a significant increase following myocarditis, while other parameters such as brain natriuretic peptide (BNP), QTc interval, and left ventricular ejection fraction (LVEF) did not show any significant differences. Through sequencing, it was observed that the diversity and uniformity of CDR3 in the ICIs-associated myocarditis patients were significantly diminished. Additionally, the distribution of CDR3 nucleotides deviated from normality, and variations in the utilization of V and J gene segments. Conclusion The reconstitution of the TCR immune repertoire may play a pivotal role in the recognition of antigens in patients with ICIs-associated myocarditis.