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Background: Prurigo nodularis (PN) as an extremely pruritic and hyperplastic chronic dermatosis induces psychologically and physiologically stressful responses. PN-induced responses in the hypothalamic-pituitary-adrenal (HPA), hypothalamic-pituitary-gonadal (HPG) axes and endocannabinoid system (ECS) are abnormal. Extant studies on the PN’s pathogenesis mostly focused on the PN’s psychological responses. To date, the PN’s physiological responses remain not been fully uncovered yet. Objectives: To investigate the PN-induced physiological responses via the levels of five steroids and two endocannabinoids combined with their ratios in plasma and examine the association between the psychological and physiological responses. Materials and methods: Thirty-six patients with PN, 36 age- and gender-matched healthy controls were recruited. The PN’s psychological symptoms including pruritus severity, pain and life quality were measured with the visual analogue scale, the prurigo score index, numerical rating scale, verbal rating scale and dermatology life quality index. Their concentrations of steroids and endocannabinoids were determined with liquid chromatography-tandem mass spectrometry. Results: Compared to controls, the PN patients showed lower plasma levels in cortisol, cortisone, N-arachidonoyl-ethanolamine (AEA), and the ratio of DHEA to 1-arachydonoyl glycerol (1-AG), which negatively moderately and over correlated with PN’s symptoms, especially with the pruritus severity. Additionally, the PN patients exhibited higher levels in the ratios of testosterone and 1-AG to cortisol, which positively moderately and over correlated with pruritus severity. Thus, the seven biomarkers would be sensitive and reliable biomarkers for assessing the pruritus severity of PN because they met the screening criteria that the biomarkers show intergroup differences and showed moderate or over correlation with the pruritus severity of PN. Conclusions: To the best of our knowledge, this is the first study exploring PN-induced physiological responses. The findigs suggest that alterations in these three endocrine systems may lead to new insights to psychological mechanisms and responses to prurigo nodularis.

Nesfatin-1 is a neuropeptide produced in the hypothalamus. It is known that Nesfatin-1 is involved in food uptake, fat storage, and other metabolic regulation. We hypothesized that Nesfatin-1 may play a role in cardiovascular tissue. Free fatty acids (FFAs) are known to be the risk factor for cardiovascular diseases. FFA-mediated endothelial dysfunction is the critical mechanism of many cardiovascular disorders. The present study explores the protective effects of Nesfatin-1 on FFA-induced endothelial inflammation and the underlying mechanism. We found that significantly increased lactate dehydrogenase release and production of inflammatory factors were observed in FFA-treated human aortic endothelial cells (HAECs), accompanied by the enhanced attachment of U937 monocytes to HAECs and upregulated cell adhesion molecule vascular cell adhesion molecule-1, which were dramatically reversed by the treatment with Nesfatin-1. In addition, the promoted level of nuclear regulator NF-κB p65 and transcriptional function of NF-κB in FFA-treated HAECs were greatly suppressed by HAECs. Growth Factor Independent 1 Transcriptional Repressor 1 (Gfi1), an important negative regulator of NF-κB activity, was significantly downregulated in HAECs by FFAs and was upregulated by Nesfatin-1. Lastly, the inhibitory effects of Nesfatin-1 against FFA-induced NF-κB activation and adhesion of U937 monocytes to HAECs were abolished by the knockdown of Gfi1. In conclusion, our data reveal that Nesfatin-1 inhibited FFA-induced endothelial inflammation mediated by the Gfi1/NF-κB signaling pathway.

Pulmonary fibrosis (PF) is a chronic and progressively fatal disease, but clinically available therapeutic drugs are limited due to efficacy and side effects. The possible mechanism of pulmonary fibrosis includes the damage of alveolar epithelial cells II (AEC2), and activation of immune cells such as macrophages. The ions released from bioceramics have shown the activity in stimulating soft tissue derived cells such as fibroblasts, endothelia cells and epithelia cells, and regulating macrophage polarization. Therefore, this study proposes an “ion therapy” approach based on the active ions of bioceramic materials, and investigates the therapeutic effect of bioactive ions derived from calcium silicate (CS) bioceramics on mouse models of pulmonary fibrosis. We demonstrate that silicate ions significantly reduce pulmonary fibrosis by simultaneously regulating the functions of AEC2 and macrophages. This result suggests potential clinical applications of ion therapy for lung fibrosis., Graphical abstract Image 1, Highlights ● A novel treatment of pulmonary fibrosis based on ion therapy using bioactive ionic solution derived from silicate bioceramics (CS) was demonstrated. ● CS solution can stimulate the alveolar epithelial cells to repair damaged lung tissue. ● CS solution can regulate immune cells to inhibit inflammatory factor secretion and reduce the number of inflammatory cells in lung tissue.

The human gut harbors a dense and highly diverse microbiota of approximately 1,000 bacterial species. The interaction between the host and gut bacteria strongly influences human health. Numerous evidence suggest that intestinal flora imbalance is closely associated with the development and treatment of liver diseases, including acute liver injury and chronic liver diseases (cirrhosis, autoimmune liver disease, and fatty liver). Therefore, regulating the gut microbiota is expected to be a new method for the adjuvant treatment of liver diseases. Fecal microbiota transplantation (FMT) is defined as the transplantation of gut microbiota from healthy donors to sick patients via the upper or lower gastrointestinal route to restore the normal intestinal balance. In this study, we briefly review the current research on the gut microbiota and its link to liver diseases and then summarize the evidence to elucidate the clinical application and development of FMT in liver disease treatment.

Objectives To investigate the diagnostic performance of single-source dual-energy computed tomography (DECT) based on gemstone spectral imaging technology (including Discovery CT750HD and Revolution CT) in patients with suspected feet/ankles gouty arthritis, and evaluate the urate deposition with a novel semi-quantitative DECT scoring system. Methods A total of 196 patients were consecutively included. Feet and ankles were evaluated in all patients by single-source DECT scan. The 2015 EULAR/ACR criteria were used as the reference for the diagnosis of gout. The sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of DECT for the diagnosis of gout in the early (≤1 year), middle (1–3 years), and late (> 3 years) disease durations were calculated. Besides, a novel semi-quantitative DECT scoring system was assessed for the measurement of urate deposition, and the correlation between the scores and the clinical and serological data were also evaluated. Moreover, the influences of artifacts on the diagnostic performance of DECT were also determined. Results The sensitivity, specificity, and AUC of DECT in 196 patients were 38.10, 96.43%, and 0.673 in the early-stage group; 62.96, 100.00%, and 0.815 in the middle-stage group; and 77.55, 87.50%, and 0.825 in the late-stage group, respectively. The overall diagnostic accuracies in the AUC of DECT (Discovery CT750HD and Revolution CT) in the middle and late stages of gout were higher than that in the early stage of gout. Besides, the monosodium urate crystals were deposited on the first metatarsophalangeal joints and ankles/midfeet. Age, the presence of tophus, bone erosion, and disease duration considerably affected the total urate score. No statistical difference in the positive detection of nail artifact, skin artifact, vascular calcification, and noise artifact was found between the case and control groups. Conclusion DECT (Discovery CT750HD and Revolution CT) showed promising diagnostic accuracy for the detection of urate crystal deposition in gout but had limited diagnostic sensitivity for short-stage gout. Longer disease duration, the presence of tophus, and bone erosion were associated with the urate crystal score system. The artifacts do not remarkably affect the diagnostic performance of DECT in gout.

OBJECTIVE: The aim of the present study was to compare three ventilatory techniques for reducing PaCO2in patients with severe acute distress syndrome treated with permissive hypercapnia.MATERIALS AND METHODS: In a group of six patients with severe acute distress syndrome who developed permissive hypercapnia with protective techniques ofmechanical ventilation, three ventilatory strategies were compared: expiratory washout alone, optimized mechanical ventilation, defined as an increase in respiratory frequency associated with a reduction of the instrumental dead space, and the combination of both methods. In all strategies, inspiratory plateau airway pressure was kept constant by setting the extrinsic positive end-expiratory pressure.RESULTS: Expiratory washout and optimized mechanical ventilation had similar effects on CO2 elimination. A further decrease in PaCO2 was observed when bothmethods were combined. Extrinsic positive end-expiratory pressure had to be reduced during expiratory washout, whereas it remained unchanged during optimized mechanical ventilation alone.CONCLUSIONS: In patients with severe acute distress syndrome, who need lower plateau airway pressures in order to avoid overdistention, therefore developinghypercapnia, the increasing respiratory rate and reducing instrumental dead space are as efficient as expiratory washout to reduce PaCO2 and, when used incombination, both techniques have additive effects and result in PaCO2 levels close to normal values., OBJETIVO: O objetivo deste estudo foi comparar três técnicas ventilatórias para reduzir pressão arterial de CO2 em pacientes com insuficiência respiratória agudasevera e em hipercapnia permissiva.MATERIAIS E MÉTODOS: Em um grupo de seis pacientes com insuficiência respiratória aguda severa que desenvolveram hipercapnia permissiva com técnicas protetoras de ventilação mecânica, três estratégias ventilatórias foram comparadas: lavagem panexpiratória isolada, ventilação otimizada (definida como aumento na freqüência respiratória associado à redução do espaço morto instrumental) e a combinação de ambos os métodos. Em todas as técnicas a pressão de platô inspiratória foi mantida constante por ajuste da pressão expiratória final positiva extrínseca.RESULTADOS: A lavagem pan-expiratória e a ventilação otimizada tiveram efeitos similares na eliminação de CO2, sendo que um decréscimo adicional na pressãoarterial de CO2 foi observado quando ambos os métodos foram combinados. A pressão expiratória final positiva extrínseca teve de ser reduzida quando a lavagem pan-expiratória foi usada, mas permaneceu inalterada durante a ventilação otimizada isolada.CONCLUSÕES: Nos pacientes com insuficiência respiratória aguda severa, que necessitam de pressões de platô mais baixas para evitar hiperdistensão, e que em decorrência disso desenvolveram hipercapnia, o aumento da freqüência respiratória e a redução do espaço morto instrumental são tão eficientes quanto a lavagem panexpiratória para reduzir PaCO2 e, quando usadas em combinação, ambas as técnicas têm efeitos aditivos e resultam em níveis de PaCO2 próximos aos normais.

Quercetin and crocin are the main active constituents of Eucommia and Gardenia species, respectively. This study was conducted to explore the effects of quercetin and crocin on fat reduction and renal fibrosis and the relationship of these compounds with autophagy. First, a model of high-fat diet- and streptozotocin-induced type 2 diabetes was established and then subjected model animals to 8 weeks of metformin, quercetin and crocin gavage. Then, a high glucose-induced rat mesangial cells (RMCs) model was established, and these cells were cocultured with quercetin and crocin. The results showed that quercetin and crocin can decrease fasting blood glucose levels, reduce fat accumulation in the liver, alleviate renal fibrosis, and reduce blood lipid levels. Quercetin and crocin increased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels in the liver and decreased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels in the kidneys. Moreover, quercetin and crocin inhibited the excessive proliferation of RMCs induced by high-glucose (HG) conditions, decreased autophagy-related protein (LC3, Atg5, Beclin-1 and p-AMPK) levels, and decreased TGF-β1 expression. Importantly, cotreatment with quercetin and crocin had a more significant effect than treatment with either compound alone. These results suggest that combined administration of quercetin and crocin can more significantly reduce blood glucose/lipid levels and improve renal fibrosis than administration of either compound alone and that AMPK-dependent autophagy might be involved in this process. Eucommia ulmoides Oliv. and Gardenia could be developed as drugs for Type 2 diabetes treatment.

Oral cancer is among most common neoplasm of oral cavity; in many cases, it develops at the site of premalignant lesion. Areca nut has been identified as a carcinogen, which was proved to promote the inflammation level and contributes to oral malignancy. Chewing areca nut is the main cause of the premalignant disease oral submucous fibrosis (OSF). Bacterial alterations were suggested to be assonated with oral cancer progression. Therefore, the present study was carried out to determine the changes of microbiota in the mucosa along stage of development of oral cancer with areca nut chewing. 162 participants, reporting to department of oral medical center, were enrolled into the study which includes 45 patients each of OSF, 42 of oral cancer, 29 healthy controls (HC) with areca nut chewing, and 46 healthy controls (HC) never chewing areca nut. Oral swabbing of tongue dorsum, buccal mucosa, and gingiva was evaluated by MiSeq platform of the V3-V4 region of the 16S rRNA gene. These data revealed microbial changes that may mirror oral cancer progression and reflect clinical preconditions such as areca nut chewing. Consequently, revealing microbial changes in patients with oral squamous cell carcinomas and the premalignant disease oral submucous fibrosis (OSF) with areca nut chewing might improve our understanding of the pathobiology of the disease and help in the design of novel diagnostic and treatment strategies.

Objectives The association between outcome and kidney injury detected at discharge from the ICU using different biomarkers remains unknown. The objective was to evaluate the association between 1-year survival and kidney injury at ICU discharge. Design Ancillary investigation of a prospective observational study. Setting Twenty-one ICUs with 1-year follow-up. Patients Critically ill patients receiving mechanical ventilation and/or hemodynamic support for at least 24 hours were included. Interventions Serum creatinine, plasma Cystatin C, plasma neutrophil gelatinase-associated lipocalin, urinary neutrophil gelatinase-associated lipocalin, plasma Proenkephalin A 119-159, and estimated glomerular filtration rate (on serum creatinine and plasma Cystatin C) were measured at ICU discharge among ICU survivors. Measurements and main results The association between kidney biomarkers at discharge and mortality was estimated using logistic model with and without adjustment for prognostic factors previously identified in this cohort. Subgroup analyses were performed in patients with discharge serum creatinine less than 1.5-fold baseline at ICU discharge. Among 1,207 ICU survivors included, 231 died during the year following ICU discharge (19.2%). Estimated glomerular filtration rate was significantly lower and kidney injury biomarkers higher at discharge in nonsurvivors. The association between biomarker levels or estimated glomerular filtration rate and mortality remained after adjustment to potential cofounding factors influencing outcome. In patients with low serum creatinine at ICU discharge, 25-47% of patients were classified as subclinical kidney injury depending on the biomarker. The association between kidney biomarkers and mortality remained and mortality was higher than patients without subclinical kidney injury. The majority of patients who developed acute kidney injury during ICU stay had elevated biomarkers of kidney injury at discharge even with apparent recovery based on serum creatinine (i.e., subclinical acute kidney disease). Conclusions Elevated kidney biomarkers measured at ICU discharge are associated with poor 1-year outcome, including in patients with low serum creatinine at ICU discharge.

Background Hyperglycemia is associated with greater hematoma expansion (HE) and worse clinical prognosis after intracerebral hemorrhage (ICH). However, the clinical benefits of intensive glucose normalization remain controversial, and there are no approved therapies for reducing HE. The aryl hydrocarbon receptor (AHR) has been shown to participate in hyperglycemia‐induced blood–brain barrier (BBB) dysfunction and brain injury after stroke. Herein, we investigated the role of AHR in hyperglycemia‐induced HE in a male mouse model of ICH. Methods and Results CD1 mice (n=387) were used in this study. Mice were subjected to ICH by collagenase injection. Fifty percent dextrose was injected intraperitoneally 3 hours after ICH. AHR knockout clustered regularly interspaced short palindromic repeat was administered intracerebroventricularly to evaluate the role of AHR after ICH. A selective AHR inhibitor, 6,2′,4′‐trimethoxyflavone, was administered intraperitoneally 2 hours or 6 hours after ICH for outcome study. To evaluate the effect of AHR on HE, 3‐methylcholanthrene, an AHR agonist, was injected intraperitoneally 2 hours after ICH. The results showed hyperglycemic ICH upregulated AHR accompanied by greater HE. AHR inhibition provided neurological benefits by restricting HE and preserving BBB function after hyperglycemic ICH. In vivo knockdown of AHR further limited HE and enhanced the BBB integrity. Hyperglycemia directly activated AHR as a physiological stimulus in vivo. The thrombospondin‐1/transforming growth factor‐β/vascular endothelial growth factor axis partly participated in AHR signaling after ICH, which inhibited the expressions of BBB‐related proteins, ZO‐1 and Claudin‐5. Conclusions AHR may serve as a potential therapeutic target to attenuate hyperglycemia‐induced hematoma expansion and to preserve the BBB in patients with ICH.

Background Destruction of blood–brain barrier (BBB) ​​is one of the main mechanisms of secondary brain injury following intracerebral hemorrhage (ICH). Frizzled-7 is a key protein expressed on the surface of endothelial cells that controls vascular permeability through the Wnt-canonical pathway involving WNT1-inducible signaling pathway protein 1 (WISPI). This study aimed to investigate the role of Frizzled-7 signaling in BBB preservation after ICH in mice. Methods Adult CD1 mice were subjected to sham surgery or collagenase-induced ICH. Frizzled-7 activation or knockdown was performed by administration of Clustered Regularly Interspaced Palindromic Repeats (CRISPR) by intracerebroventricular injection at 48 h before ICH induction. WISP1 activation or WISP1 knockdown was performed to evaluate the underlying signaling pathway. Post-ICH assessments included neurobehavior, brain edema, BBB permeability, hemoglobin level, western blot and immunofluorescence. Results The brain expressions of Frizzled-7 and WISP1 significantly increased post-ICH. Frizzled-7 was expressed in endothelial cells, astrocytes, and neurons after ICH. Activation of Frizzled-7 significantly improved neurological function, reduced brain water content and attenuated BBB permeability to large molecular weight substances after ICH. Whereas, knockdown of Frizzled-7 worsened neurological function and brain edema after ICH. Activation of Frizzled-7 significantly increased the expressions of Dvl, β-Catenin, WISP1, VE-Cadherin, Claudin-5, ZO-1 and reduced the expression of phospho-β-Catenin. WISP1 knockdown abolished the effects of Frizzled-7 activation on the expressions of VE-Cadherin, Claudin-5 and ZO-1 at 24 h after ICH. Conclusions Frizzled-7 activation potentially attenuated BBB permeability and improved neurological deficits after ICH through Dvl​​/β-Catenin/WISP1 pathway. Frizzled-7 may be a potential target for the development of ICH therapeutic drugs.

Background Germinal matrix hemorrhage (GMH) is defined by the rupture of immature blood vessels in the germinal matrix, where subsequent hemorrhage enters the subependymal zone and the cerebral lateral ventricles. The consequent blood clot has been identified as the causative factor of secondary brain injury, which triggers a series of complex parallel and sequential harmful mechanisms, including neuroinflammation. The orphan G-protein-coupled receptor 40 (GPR40), a free fatty acid (FFA) receptor 1, has been shown to exert anti-inflammatory effects when activated and improved outcomes in animal models of stroke. We aimed to investigate the anti-inflammatory effects of GPR40 and its underlying mechanisms after GMH. Methods GMH model was induced in 7-day-old rat pups by an intraparenchymal injection of bacterial collagenase. GPR40 agonist, GW9508, was administered intranasally 1 h, 25 h, and 49 h after GMH induction. CRISPR targeting GPR40, PAK4, and KDM6B were administered through intracerebroventricular injection 48 h before GMH induction. Neurologic scores, microglia polarization, and brain morphology were evaluated by negative geotaxis, right reflex, rotarod test, foot fault test, Morris water maze, immunofluorescence staining, Western blots, and nissl staining respectfully. Results The results demonstrated that GW9508 improved neurological and morphological outcomes after GMH in the short (24 h, 48 h, 72h) and long-term (days 21–27). However, the neuroprotective effects of treatment were abolished by GW1100, a selective GPR40 antagonist. GW9508 treatment increased populations of M2 microglia and decreased M1 microglia in periventricular areas 24 h after GMH induction. GW9508 upregulated the phosphorylation of PAK4, CREB, and protein level of KDM6B, CD206, IL-10, which was also met with the downregulation of inflammatory markers IL-1β and TNF-α. The mechanism study demonstrated that the knockdown of GPR40, PAK4, and KDM6B reversed the neuroprotective effects brought on by GW9508. This evidence suggests that GPR40/PAK4/CREB/KDM6B signaling pathway in microglia plays a role in the attenuation of neuroinflammation after GMH. Conclusions In conclusion, the present study demonstrates that the activation of GPR40 attenuated GMH-induced neuroinflammation through the activation of the PAK4/CREB/KDM6B signaling pathway, and M2 microglia may be a major mediator of this effect. Thus, GPR40 may serve as a potential target in the reduction of the inflammatory response following GMH, thereby improving neurological outcomes in the short- and long-term.

Highlights Small-sized trastuzumab-targeted micelles (T-MP) were engineered using a surfactant-stripping approach that yielded concentrated phthalocyanines with strong near infrared absorption.T-MP accumulated more in the lymph node (LN) metastases of orthotopic colorectal cancer compared to the micelles conjugated with control IgG.Following surgical resection of the primary tumor, minimally invasive photothermal treatment of the metastatic LN with T-MP, but not the control micelles, extended mouse survival. Tumor lymph node (LN) metastasis seriously affects the treatment prognosis. Studies have shown that nanoparticles with size of sub-50 nm can directly penetrate into LN metastases after intravenous administration. Here, we speculate through introducing targeting capacity, the nanoparticle accumulation in LN metastases would be further enhanced for improved local treatment such as photothermal therapy. Trastuzumab-targeted micelles (

BackgroundAcute promyelocytic leukemia (APL) is characterized by the presence of coagulopathy at onset and translocation t (15; 17) (q22; 21), meanwhile, other translocation variants of APL have also been reported. The FIP1L1–RARA fusion gene has recently been reported as a novel RARA-associated fusion gene.ObjectivesWe report a case of de novo myeloid sarcoma (MS) type of APL with FIP1L1–RARA found by next-generation sequencing (NGS) that was not detected by conventional analyze analysis for RARA translocations.MethodsWe performed typical morphological, magnetic resonance imaging (MRI), conventional tests for PML–RARA dual-fusion translocation probe, high-through sequencing and NGS. Meanwhile, bioinformatics analyses were done by using public repositories, including ONCOMINE, COSMIC, and GeneMANIA analysis.ResultsA 28-month-old girl with a complex karyotype that includes 46,XX,t(4;17)(q12;q22)[9]/46,idem,del(16)(q22)[3]/45,idem,-x,-4,-9,-15,del(16)(q22),+marl,+mar2,+mar3[7]/46,xx[3], c.38G>A (p.Gly13Asp) in the KRAS gene, and a cryptic insertion of RARA gene into the FIP1L1 gene was diagnosed with APL complicated by the de novo MS.ConclusionWe report a FIP1L1–RARA fusion in a child with APL who presented with an extramedullary tumor in the skull without the classic karyotype using NGS, whom we treated with good results. NGS analysis should be considered for APL variant cases. Further experimental studies to the association between the mutation in KRAS gene and FIP1L1–RARA fusion on the clinical phenotype and progression of APL are needed to identify more effective therapeutic targets for APL.

Background: Performance evaluation is an important means to promote the hospital's medical ability and management ability. Therefore, the aim of this study was to explore the effect of DRG payment mode on the performance of inpatient services in large tertiary hospitals. Methods: Based on the relevant report data of DRG pilot hospital and control hospital from 2015 to 2020, CN-DRG was used as grouping method, and case mix index (CMI), DRG group number, cost consumption index, time consumption index, low-risk group mortality and other indicators were used to analyze the impact of DRG on hospital inpatient service performance from the aspects of medical service ability, medical service efficiency, medical safety. Results: The average annual growth rate of DRG group was 4.07%, the average annual growth rate of CMI was 0.95%, the time consumption index and cost consumption index were lower than 1, and the mortality rate of low-risk group decreased by 27.56%. Conclusions: DRG medical insurance payment can improve the performance of inpatient service in the process of hospital management.

In article number 2003679, Chao Fang, Hong‐Zhuan Chen, and co‐workers develop a biomimetic liposomal nano‐Pt for targeted cancer chemophototherapy. At the tumor site, oxygen produced by nano‐Pt catalyzation improves the verteporfin‐mediated photodynamic therapy, which in turn triggers the release of nano‐Pt via membrane permeabilization. The ultrasmall 3–5 nm nano‐Pt enables better penetration in tumors for enhanced chemotherapy. [Image: see text]

Deregulation of E3 ubiquitin ligases is intimately implicated in breast cancer pathogenesis and progression, but the underlying mechanisms still remain elusive. Here we report that RING finger protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3 ubiquitin ligases, functions as a tumor suppressor in breast cancer. RNF144A was downregulated in a subset of primary breast tumors and restoration of RNF144A suppressed breast cancer cell proliferation, colony formation, migration, invasion in vitro, tumor growth, and lung metastasis in vivo. In contrast, knockdown of RNF144A promoted malignant phenotypes of breast cancer cells. Quantitative proteomics and biochemical analysis revealed that RNF144A interacted with and targeted heat-shock protein family A member 2 (HSPA2), a putative oncoprotein that is frequently upregulated in human cancer and promotes tumor growth and progression, for ubiquitination and degradation. Notably, the ligase activity-defective mutants of RNF144A impaired its ability to induce ubiquitination and degradation of HSPA2, and to suppress breast cancer cell proliferation, migration, and invasion as compared with its wild-type counterpart. Moreover, RNF144A-mediated suppression of breast cancer cell proliferation, migration, and invasion was rescued by ectopic HSPA2 expression. Clinically, low RNF144A and high HSPA2 expression in breast cancer patients was correlated with aggressive clinicopathological characteristics and decreased overall and disease-free survival. Collectively, these findings reveal a previously unappreciated role for RNF144A in suppression of breast cancer growth and metastasis, and identify RNF144A as the first, to our knowledge, E3 ubiquitin ligase for HSPA2 in human cancer.

The E3 ubiquitin ligase ring finger protein 115 (RNF115) is overexpressed in more than half of human breast tumors and is implicated in the pathogenesis and progression of breast cancer. However, the mechanism behind RNF115 overexpression in breast tumors remains largely unknown. Here we report that ubiquitin-specific protease 9X (USP9X), a substrate-specific deubiquitinating enzyme, stabilizes RNF115 and thereby regulates its biological functions in breast cancer cells. Immunoprecipitation and GST pull-down assays showed that USP9X interacted with RNF115. Depletion of RNF115 by siRNAs or overexpression of RNF115 did not significantly affect USP9X expression. In contrast, knockdown of USP9X in breast cancer cells by siRNAs reduced RNF115 protein abundance, which was partially restored following treatment with proteasome inhibitor MG-132. Moreover, depletion of USP9X reduced the half-life of RNF115 and increased its ubiquitination. Conversely, overexpression of USP9X resulted in an accumulation of RNF115 protein, accompanied by a decrease in its ubiquitination. RNF115 mRNA levels were unaffected by overexpression or knockdown of USP9X. Furthermore, USP9X protein expression levels correlated positively with RNF115 in breast cancer cell lines and breast tumor samples. Importantly, reintroduction of RNF115 in USP9X-depleted cells partially rescued the reduced proliferation, migration, and invasion of breast cancer cells by USP9X knockdown. Collectively, these findings indicate that USP9X is a stabilizer of RNF115 protein and that the USP9X-RNF115 signaling axis is implicated in the breast cancer malignant phenotype.

AIM: To evaluate the efficacy and safety of intravitreal injection of conbercept in patients with neovascular age-related macular degeneration (AMD). METHODS: Retrospective review of 66 eyes of 63 patients with neovascular AMD. All patients received 0.5 mg intravitreal injections of conbercept monthly for 3 consecutive months, and then pro re nata treatment was performed. The changes of best-corrected visual acuity (BCVA) and central macular thickness (CMT) were observed before and after treatments. Minimum follow-up time was 12mo. SPSS 22.0 statistical software was used for statistical analysis. RESULTS: The mean BCVA and CMT of 66 eyes (63 patients) were 1.11±0.60, 533.20±219.95 µm at baseline, and were 0.68±0.38, 310.28±125.60 µm at 3mo. No subjects were lost during the first three months, the improvements were all significantly (P

Azithromycin (AZM), that is a macrolide antibiotic, has been found to treat diffuse panbronchiolitis (DPB) effectively. However, the mechanism of action underlying the therapeutic effects remains unclear. We selected 64 patients with DPB from 305 patients who were diagnosed with DPB at the outpatient clinic in Shanghai Pulmonary Hospital from Jan 2010 to Oct 2014. The primary PBLs, CD4 + T cells, and Jurkat T cells were treated with AZM or erythromycin (EM), and the effects of AZM and EM on IL-17A and CXCL-2 production, proliferation, apoptosis and autophagy were evaluated. AZM and EM significantly inhibited IL-17A and CXCL-2 production in patients’ PBLs (all P

Background: The development of chemoresistance is one of the leading causes of chemotherapy failure in gastric cancer (GC). Emerging evidence highlights the multifunctional role of noncoding RNAs (ncRNAs) in GC chemoresistance. However, the comprehensive expression profile and competing endogenous RNAs (ceRNAs) regulatory network between ncRNAs and mRNAs in GC chemoresistance remain unanswered.Methods: GC cell line MGC-803 was employed to create cisplatin-resistant MGC-803/DDP cells by continuous exposure to increasing doses of cisplatin. The whole-transcriptome sequencing (RNA sequencing) was performed to comprehensively analyze the differentially expressed (DE) lncRNAs, miRNAs and mRNAs in MGC-803/DDP and MGC-803 cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted to investigate the biological functions implicated with the DEncRNAs. Then, the cisplatin-resistant-related ceRNA network and potential regulatory axes were constructed by bioinformatic analysis.Results: We successfully generated cisplatin-resistant GC cell line MGC-803/DDP. Differential expression analysis showed that a total of 1,936 DElncRNAs, 2,194 DEmRNAs and 174 DEmiRNAs were identified. Functional enrichment analysis indicated that those DEncRNAs were mainly involved in neuroactive ligand-receptor interaction, drug metabolism, Hippo signaling pathway, cAMP pathway and P53 pathway. Subsequently, the cisplatin-resistant-related ceRNA network consisting of 71 DElncRNAs, 121 DEmRNAs and 8 DEmiRNAs was constructed with the widely accepted vital chemo-resistant-related genes and signaling pathways. In addition, two constructed regulatory axes (include FAM66C/miR-129-5p/7 mRNAs and SFTA1P/miR-206/FN1 or NRP1) were successfully validated by the Genomic Data Commons (GDC) GC data.Conclusion: Our study has shown that differentially expressed ncRNAs have complex and intricate interactions in the cisplatin resistance of GC. The novel ceRNA network and the potential regulatory axes may provide the most comprehensive view of GC chemoresistance to date. Our findings uncovered potential biomarkers for prognostic prediction and novel therapeutic targets for reversing cisplatin resistance in GC.

To investigate the influence of miR-18a-3p and ADCY5 on OP and osteogenic differentiation of human Mesenchymal stem cell (hBMSCs) and its possible mechanism. Samples were collected from osteoporotic patients with or without vertebral compression fracture, and without OP volunteers. MiR-18a-3p and ADCY5 mRNA expression levels in the tissue samples and hBMSCs during osteogenic differentiation were detected。MiR-18a-3p mimic and OE-ADCY5 were introduced into hBMSCs to research the effects of miR-18a-3p and ADCY5 on osteogenesis differentiation of hBMSCs. Dual luciferase reporter system and RNA pull-down were applied to determine whether ADCY5 was a target gene of miR-18a-3p. Compared with the control group, ADCY5 expression level was down-regulated in patients with OP-no-Frx and OP-Frx, but that of miR-18a-3p was up-regulated. In addition, ADCY5 increased during osteogenesis differentiation of hBMSCs, whereas miR-18a-3p did not. OE-ADCY5 significantly facilitated calcium deposition, ALP activity, osteoblast protein expression (OSX, ALP and EUNX2), miR-18a-3p mimic inhibited osteogenic differentiation, and partially reversed the effect of OE-ADCY5 on osteogenic differentiation. In general, miR-18a-3p targets ADCY5 to promote OP and may be involved in spinal fracturs.

PUMILIO (PUM) proteins belong to the highly conserved PUF family post-transcriptional regulators involved in diverse biological processes. However, their function in carcinogenesis remains under explored. Here, we found that the expression of Pum1 and Pum2 are increased in clinical colorectal cancer (CRC). Intestine-specific knockout of Pum1 and Pum2 significantly inhibited the progression of colitis associated cancer in the AOM/DSS model. Knockout or knockdown of Pum1 and/or Pum2 resulted in a significant decrease in the tumorigenicity. In addition, delayed G1/S transition was observed. We identified p21/Cdkn1a as direct target of PUM1, and abrogation of the PUM1 binding site in p21 resulted in decreased tumor cell growth as well as delayed G1/S transition. Furthermore, intravenous injection of nanoparticle-encapsulated anti-Pum1 and Pum2 siRNAs reduced colorectal tumor growth in murine orthotopic colon cancer models. These findings reveal a tumor growth promoting role of PUM proteins in CRC and its potential as therapeutic targets.

Background Glioma is the most common type of malignant brain tumor with limited treatment strategy and poor prognosis. Proteasome 26S subunit ATPase 2 (PSMC2) is a key member of the 26S proteasome 19S regulatory subunit, whose role in glioma is still not clear. In this context, we aim to explore the role of PSMC2 in glioma in vitro and in vivo. Methods Expression of PSMC2 in in glioma tissues and normal tissues are detected by immunohistochemical (IHC) analysis. The proliferation assays (MTT assay and Celigo cell counting assay), flow cytometry and migration assays (wound-healing assay and Transwell) are used to detect the effects of PSMC2 knockdown on glioma cells. The influence of PSMC2 knockdown on tumor growth in vivo was evaluated by mice xenograft models. In addition, the downstream target of PSMC2 is determined by human GeneChip and Ingenuity Pathway Analysis (IPA). Results PSMC2 is overexpressed in glioma tissues than normal tissues. Moreover, knockdown of PSMC2 can inhibit the proliferation, migration and arrest cell cycle in G2 phase of glioma cells. Additionally, PSMC2 knockdown promotes glioma cell apoptosis by increasing expression of caspase3, caspase8, IGFBP-1, while reducing expression of IGF-I, Survivin, TRAILR-4. In vivo findings reveal that PSMC2 knockdown inhibit the tumorigenicity of glioma cells. Furthermore, downstream of PSMC2 is explored, identifying E2F transcription factor 1 (E2F1) as a potential target. Notably, E2F1 knockdown exhibits similar effects on the development of glioma with PSMC2, which could strengthen the inhibition effects of PSMC2 knockdown on glioma synergistically. Conclusions PSMC2 is closely associated with glioma development by targeting E2F1, and might be considered as a novel therapeutic target in patients with glioma.

Infectious pathogens contribute to about 20% of the total tumor burden. Fusobacterium nucleatum (Fn) has been associated with the initiation, progression, and therapy resistance in colorectal cancer (CRC). The over-abundance of Fn has been observed in patients with right-sided CRC than in those with left-sided CRC. While the KRAS/NRAS/BRAF wild-type status of the CRC conferred better response to cetuximab in patients with left-sided CRC than with right-sided CRC. However, treatment failure remains the leading cause of tumor relapse and poor clinical outcome in patients with CRC. Here, we have studied the association of Fn to cetuximab resistance. Our functional studies indicate that Fn facilitates resistance of CRC to cetuximab in vitro and in vivo. Moreover, Fn was found to target the PI3K/AKT and JAK/STAT3 pathways, which altered the response to cetuximab therapy. Therefore, assessing the levels and targeting Fn and the associated signaling pathways may allow modulating the treatment regimen and improve prognoses of CRC patients.

The current study aimed to investigate whether sarpogrelate and rosuvastatin possess anti-arterial injury, and attempted to elucidate the mechanism of action underlying this activity. Sarpogrelate, a 5-hydroxytryptamine type 2A antagonist, is extensively used to prevent arterial thrombosis; however, its effects on atherosclerosis remain unknown. In the present study, sarpogrelate combined with rosuvastatin or rosuvastatin alone were administered to male ApoE-/- mice fed a high-fat diet (HFD) for 8 weeks. Metabolic parameters in the blood samples were analyzed using an automatic analyzer. Aortic tissues were stained with hematoxylin and eosin for morphological analysis. The expression levels of oxidized-low density lipoprotein (LDL) specific scavenging receptors, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and cluster of differentiation 68 were detected via immunostaining. mRNA expression levels of interleukin (IL)-1β, IL-6 and tumor necrosis factor-α were determined via reverse transcription-quantitative PCR analysis, while protein expression levels of LOX-1 and phosphor(p)-ERK were determined via western blot analysis. The results demonstrated that sarpogrelate combined with rosuvastatin treatment significantly decreased total cholesterol and LDL cholesterol levels in the serum, and alleviated intimal hyperplasia and lipid deposition, accompanied by decreased inflammatory cell infiltration and lower expression levels of inflammatory cytokines, compared with rosuvastatin monotherapy or HFD treatment. Furthermore, sarpogrelate combined with rosuvastatin treatment significantly decreased the expression levels of LOX-1 and p-ERK. Taken together, these results suggest that the positive effects of sarpogrelate combined with rosuvastatin treatment on aortic injury may be associated with the regulation of the LOX-1/p-ERK signaling pathway. Sarpogrelate and rosuvastatin synergistically decreased aortic damage in ApoE-/- HFD mice, and thus provide a basis for the treatment of aortic injury caused by hyperlipidemia with sarpogrelate.

Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano‐Pt) as a catalase‐like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano‐Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano‐Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed “nano‐Pt/VP@MLipo,” is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano‐Pt catalyzation improves the VP‐mediated PDT, which in turn triggers the release of nano‐Pt via membrane permeabilization. The ultrasmall 3–5 nm nano‐Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano‐Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity., The biomimetic liposomal nano‐Pt (nano‐Pt/VP@MLipo) targets the tumor sites, where oxygen produced by nano‐Pt catalyzation enhances the verteporfin (VP)‐mediated photodynamic therapy (PDT). PDT in turn permeabilizes the liposome membrane for efficient nano‐Pt release. These ultrasmall particles (3–5 nm) achieve penetration in deeper tumor tissue, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy.

Brain edema is a vital contributor to early brain injury after subarachnoid hemorrhage (SAH), which is responsible for prolonged hospitalization and poor outcomes. Pharmacological therapeutic targets on edema formation have been the focus of research for decades. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to participate in neural development and brain injury. Here, we used PACAP knockout CRISPR to demonstrate that endogenous PACAP plays an endogenous neuroprotective role against brain edema formation after SAH in rats. The exogenous PACAP treatment provided both short- and long-term neurological benefits by preserving the function of the blood–brain barrier and glymphatic system after SAH. Pretreatment of inhibitors of PACAP receptors showed that the PACAP-involved anti-edema effect and neuroprotection after SAH was facilitated by the selective PACAP receptor (PAC1). Further administration of adenylyl cyclase (AC) inhibitor and sulfonylurea receptor 1 (SUR1) CRISPR activator suggested that the AC–cyclic adenosine monophosphate (cAMP)–protein kinase A (PKA) axis participated in PACAP signaling after SAH, which inhibited the expression of edema-related proteins, SUR1 and aquaporin-4 (AQP4), through SUR1 phosphorylation. Thus, PACAP may serve as a potential clinical treatment to alleviate brain edema in patients with SAH. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-020-00925-3) contains supplementary material, which is available to authorized users.

Background Cardiogenic stroke has increasing morbidity in China and brought economic burden to patient families. In cardiogenic stroke diagnosis, echocardiograph examination is one of the most important examinations. Sonographers will investigate patients’ heart via echocardiograph, and describe them in the echocardiograph reports. In this study, we developed a machine learning model to automatically identify diagnosis evidences of cardiogenic stroke providing to neurologist for clinical decision making. Methods We collected 4188 Chinese echocardiograph reports of 4018 patients, with average length 177 Chinese characters in free-text style. Collaborating with neurologists and sonographers, we summarized 149 phrases on diagnosis evidence of cardiogenic stroke such as “二尖瓣重度狭窄” (severe mitral stenosis), “主动脉瓣退行性变” (aortic valve degeneration) and so on. Furthermore, we developed an annotated corpus via mapping 149 phrases to the 4188 reports. We selected 11 most frequent diagnosis evidence types such as “二尖瓣狭窄” (mitral stenosis) for further identifying. The generated corpus is divided into training set and testing set in the ratio of 8:2, which is used to train and validate a machine learning model to identify the evidence of cardiogenic stroke using BiLSTM-CRF algorithm. Results Our machine learning method achieved the average performance on the diagnosis evidence identification is 98.03, 90.17 and 93.94% respectively. In addition, our method is capable to identify the novel diagnosis evidence of cardiogenic stroke description such as “二尖瓣中-重度狭窄” (mitral stenosis), “主动脉瓣退行性病变” (aortic valve calcification) et al. Conclusions In this study, we analyze the structure of the echocardiograph reports and summarized 149 phrases on diagnosis evidence of cardiogenic stroke. We use the phrases to generate an annotated corpus automatically, which greatly reduces the cost of manual annotation. The model trained based on the corpus also has a good performance on the testing set. The method of automatically identifying diagnosis evidence of cardiogenic stroke proposed in this study will be further refined in the practice.

As one of the common cancers that threaten human life, the recurrence and metastasis of colorectal cancer seriously affect the prognosis of patients. Although new drugs and comprehensive treatments have been adopted, the current treatment effect on this tumor, especially in advanced colorectal cancer, is still not satisfactory. More and more evidence shows that tumors are likely to be a stem cell disease. In recent years, the rise of cancer stem cell theory has provided a new way for cancer treatment. Studies have found that a small number of special cells in colorectal cancer tissues that induce tumorigenesis, proliferation, and promote tumor migration and metastasis, namely, colorectal cancer stem cells. Colorectal cancer stem cells are defined with a group of cell-surface markers, such as CD44, CD133, CD24, epithelial cell adhesion factor molecule, LGR5, and acetaldehyde dehydrogenase. They are highly tumorigenic, aggressive, and chemoresistant and thus are critical in the metastasis and recurrence of colorectal cancer. Therefore, targeting colorectal cancer stem cells may become an important research direction for the future cure of colorectal cancer.

International audience; Rationale: Subclinical acute kidney injury (sub-AKI) refers to patients with low serum creatinine but elevated alternative biomarkers of AKI. Its incidence and outcome in critically ill patients remain, however, largely unknown. Plasma proenkephalin A 119–159 (penKid) has been proposed as a sensitive biomarker of glomerular function.Objectives: In this ancillary study of two cohorts, we explored the incidence and outcome of sub-AKI based on penKid.Methods: A prospective observational study in ICUs was conducted. FROG-ICU (French and European Outcome Registry in ICUs) enrolled 2,087 critically ill patients, and AdrenOSS-1 (Adrenomedullin and Outcome in Severe Sepsis and Septic Shock-1) enrolled 583 septic patients. The primary endpoint was 28-day mortality after ICU admission. Sub-AKI was defined by an admission penKid concentration above the normal range (i.e., >80 pmol/L) in patients not meeting the definition of AKI. A sensitivity analysis was performed among patients with estimated glomerular filtration rate above 60 ml/min/1.73 m2 at ICU admission.Measurements and Main Results: In total, 6.1% (122/2,004) and 6.7% (39/583) of patients from the FROG-ICU and AdrenOSS-1 cohorts met the definition of sub-AKI (11.6% and 17.5% of patients without AKI). In patients without AKI or with high estimated glomerular filtration rate, penKid was associated with higher mortality (adjusted standardized hazard ratio [HR], 1.4 [95% confidence interval, 1.1–1.8]; P = 0.010; and HR, 1.6 [95% confidence interval, 1.3–1.8]; P

Background: Alveolar flooding and airway obstruction are present in the acute respiratory distress syndrome. The impact of positive end- expiratory pressure on regional airway aeration has not been described. Aim: To assess bronchial and lung recruitment and distension during an incremental positive endexpiratory pressure trial in patients with acute respiratory distress syndrome. Methods: Six patients underwent lung and airway imaging at four positive end-expiratory pressure levels in a cohort trial. Images were post-processed by means of Functional Respiratory Imaging. This technique offers 3-dimensional visualisation and quantification of patients' airway and lung geometry on a regional level. Results: With increasing positive end-expiratory pressure from 0 to 20 cmH2O, the median bronchial recruitment was 151% and the median bronchial distension 43%. Non-aerated lower lobes bronchi had more bronchial volume increase at high positive end-expiratory pressure than partially aerated upper lobes bronchi. Lung recruitment tended to be higher in patients with non-focal acute respiratory distress syndrome. In two patients, bronchial volume increase at high positive end-expiratory pressure largely exceeded bronchial volume increase observed in matched healthy control subjects at total lung capacity, suggesting severe bronchial over-distension. Conclusions: In early acute respiratory distress syndrome, Functional Respiratory Imaging gives an innovative insight into the relationship between positive end-expiratory pressure-induced bronchial distension and recruitment, positive end-expiratory pressure-induced lung recruitment and hyperinflation and lung morphology. C 2020 Socie ' te ' francaise d'anesthe ' sie et de re ' animation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

Oxidative stress, inflammation, and hypertension constitute a self-perpetuating vicious circle to exacerbate hypertension and subsequent hypertensive cardiac hypertrophy. NADPH oxidase (Nox) 1/4 inhibitor GKT137831 alleviates hypertensive cardiac hypertrophy in models of secondary hypertension; however, it remains unclear about its effect on hypertensive cardiac hypertrophy in models of essential hypertension. This study is aimed at determining the beneficial role of GKT137831 in hypertensive cardiac hypertrophy in spontaneously hypertensive rats (SHRs) and its mechanisms of action. Treating with GKT137831 prevented cardiac hypertrophy in SHRs. Likewise, decreasing production of reactive oxygen species (ROS) with GKT137831 reduced epidermal growth factor receptor (EGFR) activity in the left ventricle of SHRs. Additionally, EGFR inhibition also reduced ROS production in the left ventricle and blunted hypertensive cardiac hypertrophy in SHRs. Moreover, inhibition of the ROS-EGFR pathway with Nox1/4 inhibitor GKT137831 or selective EGFR inhibitor AG1478 reduced protein and mRNA levels of proinflammatory cytokines tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β), as well as the activities of Akt and extracellular signal-regulated kinase (ERK) 1/2 in the left ventricle of SHRs. In summary, GKT137831 prevents hypertensive cardiac hypertrophy in SHRs, Nox-deprived ROS regulated EGFR activation through positive feedback in the hypertrophic myocardium, and inhibition of the ROS-EGFR pathway mediates the protective role of GKT137831 in hypertensive cardiac hypertrophy via repressing cardiac inflammation and activation of Akt and ERK1/2. This research will provide additional details for GKT137831 to prevent hypertensive cardiac hypertrophy.

Aging of population brings related social problems, such as muscle attenuation and regeneration barriers with increased aging. Muscle repair and regeneration depend on muscle stem cells (MuSCs). Obstructive sleep apnea (OSA) rises in the aging population. OSA leads to hypoxia and upper airway muscle injury. However, little is known about the effect of increasing age and hypoxia to the upper airway muscle. The genioglossus (GG) is the major dilator muscle to keep the upper airway open. Here, we reported that muscle fiber and MuSC function declined with aging in GG. Increasing age also decreased the migration and proliferation of GG MuSCs. p53 and p21 were high expressions both in muscle tissue and in GG MuSCs. We further found that hypoxia inhibited GG MuSC proliferation and decreased myogenic differentiation. Then, hypoxia enhanced the inhibition effect of aging to proliferation and differentiation. Finally, we investigated that hypoxia and aging interact to form a vicious circle with upregulation of p53 and p21. This vicious hypoxia plus aging damage accelerated upper airway muscle injury. Aging and hypoxia are the major damage elements in OSA patients, and we propose that the damage mechanism of hypoxia and aging in GG MuSCs will help to improve upper airway muscle regeneration.

Objective The aim of the present study was to compare the outcomes of patients with chronic subdural hematoma after undergoing burr hole craniotomy with subperiosteal or subgaleal drainage (SPGD) with those of patients who have undergone burr hole craniotomy with subdural drainage. Methods We searched 4 databases (PubMed, Web of Science, Embase, and Cochrane Library) for relevant reports from January 1995 to September 2019. Two reviewers recorded the major outcomes data as follows: recurrence, mortality, postoperative seizures, postoperative bleeding events, surgical infection, pneumocephalus, modified Rankin scale scores, and Glasgow outcome scale scores. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results A total of 3149 patients from 10 studies were included in our analysis. Compared with the SSD group, the SPGD group had a lower recurrence rate (OR, 0.72; 95% CI, 0.57–0.91) and a smaller risk of postoperative bleeding (OR, 0.41; 95% CI, 0.22–0.78). Also, no significant differences were found in the incidence of mortality (OR, 0.79; 95% CI, 0.54–1.18), postoperative seizures (OR, 0.74; 95% CI, 0.39–1.40), surgical infection (OR, 0.98; 95% CI, 0.55–1.76), pneumocephalus (OR, 0.58; 95% CI, 0.28–1.20), modified Rankin scale score 0–3 (OR, 1.04 at discharge; OR, 1.33 at 6 months), and Glasgow outcome scale score 4–5 (OR, 1.48; 95% CI, 0.82–2.67). Conclusions Burr hole craniotomy with SPGD can be recommended as an effective and safe surgical therapy for patients with chronic subdural hematoma owing to its lower recurrence rate and reduced incidence of postoperative brain injuries, in addition to no increase in the rate of some postoperative complications. However, more studies are necessary for further confirmation.

International audience; Purpose: Acute kidney injury (AKI) is associated with the activation of the renin–angiotensin system. Whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB) improve outcome in patients recovering from AKI remains unexplored. The purpose was to investigate the association between prescription of ACEi/ARB at intensive care unit (ICU) discharge and 1-year outcome in patients recovering from AKI.Methods: Association between ACEi/ARB and 1-year mortality rate was explored in 1551 patients discharged from 21 European ICUs in an observational cohort. One-year all-cause mortality after ICU discharge was the primary endpoint. AKI was defined using the kidney disease improvement global outcome definition. Propensity score matching was used to consider the probability to receive ACEi/ARB at ICU discharge and included chronic heart failure, ACEi/ARB on ICU admission, Charlson Comorbidity Index, age, diabetes mellitus, chronic kidney disease, estimated glomerular filtration rate and arterial blood pressure at ICU discharge vasopressors and renal replacement therapy.Results: Overall, 1-year mortality was 28 and 15% in patients with AKI (n = 611, 39%) and without AKI (n = 940), respectively. In patients with AKI, unadjusted, adjusted and propensity-score matched 1-year mortality rates were lower in patients treated with ACEi/ARB at ICU discharge [HR of 0.55 (0.35–0.89), HR of 0.45 (0.27–0.75), and HR of 0.48 (0.27–0.85, p

Tracheostomy has proven benefits for patients requiring prolonged mechanical ventilation. However, whether early tracheostomy (ET;10 days after injury) can also improve outcomes in patients with severe traumatic brain injury (TBI) (Glasgow Coma Scale score ≤8) remains controversial. The aim of this study was to clarify this question.We searched 4 databases (PubMed, Web of Science, Elsevier ScienceDirect, and Cochrane Library) for articles comparing the outcomes of ET with late tracheotomy or prolonged intubation in patients with severe TBI. Two reviewers were asked to record the major outcome data as follows: length of intensive care unit (ICU) stay, duration of mechanical ventilation, mortality, and incidence of pneumonia. Both random-effects and fixed-effects models were used.Eight studies met our inclusion criteria, with a total of 797 patients in the ET group and 871 patients in the late tracheostomy or prolonged intubation (not-ET) group. A meta-analysis of these 8 studies suggested that ET could reduce the length of ICU stay (mean difference [MD], -3.08; 95% confidence interval [CI], -3.75 to -2.41), duration of mechanical ventilation (MD, -4.92; 95% CI, -6.82 to -3.02), length of hospital stay (MD, -4.79; 95% CI, -8.63 to -0.94), and incidence of pneumonia (odds ratio [OR], 0.64; 95% CI, 0.53-0.78), but seemed to be independent of mortality (OR, 1.25; 95% CI, 0.90-1.75).The available evidence suggests that ET may reduce the length of ICU and hospital stays, duration of mechanical ventilation, and incidence of pneumonia in patients with severe TBI. Well-designed randomized controlled trials are needed to confirm these findings.

BACKGROUND This study aimed to clarify the diagnosis and expand the understanding of dopa-responsive dystonia (DRD). MATERIAL AND METHODS Relevant data from clinical diagnoses and genetic mutational analyses in 3 Han Chinese patients with sporadic DRD were collected and analyzed. Protein structure/function was predicted. RESULTS One novel mutation of c.679A>G (p.T227A) in GCH1 and 3 known mutations of c.457C>T (p.R153X), c.739G>A (p.G247S), and c.698G>A (p.R227H) in tyrosine hydroxylase (TH) have been found and predicted to be damaging or deleterious. All of the mutations were localized in conserved sequences. The iterative threading assembly refinement (I-TASSER) server generated three-dimensional (3D) atomic models based on protein sequences from the novel nonsense mutation of c.679A>G (p.T227A) in GCH1, which showed that residue 227 was located in the GCH1 active site. CONCLUSIONS Patients carrying different non-synonymous variants had remarkable variation in clinical phenotype. This study expands the spectrum of genotypes and phenotypes of DRD in the Han Chinese ethnicity, provides new insights into the molecular mechanism of DRD, and helps the diagnosis and treatment of DRD.

Long noncoding RNAs (lncRNAs) serve important functions in many crucial biological processes; however, the effects of lncRNAs in early gastric cancer (EGC) are not entirely clear. The present study aimed to demonstrate the potential of lncRNAs to be used as biomarkers in EGC. Reverse transcription‑quantitative polymerase chain reaction was used to measure the expression levels of lncRNAs, including X inactive‑specific transcript (XIST), Yiya, brain cytoplasmic RNA 1 (BCYRN1), ribosomal RNA processing 1B (RRP1B), KCNQ1 opposite transcript 1 (KCNQ1OT1) and testes development related 1 (TDRG1), in EGC tissues compared with normal adjacent tissues (NATs). XIST, BCYRN1, RRP1B and TDRG1 were identified as differentially expressed in EGC tissues compared with NATs. The specificity and sensitivity of XIST, BCYRN1, RRP1B and TDRG1 were determined by receiver operating characteristic curve analysis. In addition, RRP1B expression was revealed to be significantly correlated with distal metastasis (P=0.020) and tumor‑node‑metastasis staging (P=0.018), and TDRG1 expression was significantly correlated with lymph node metastasis (P=0.001). Furthermore, BCYRN1, RRP1B and TDRG1 expression levels were compared between EGC tissues and plasma, and the results indicated that there were significant positive correlations of XIST, BCYRN1, RRP1B and TDRG1 expression levels between the EGC tissues and plasma. Therefore, the present study suggested that XIST, BCYRN1, RRP1B and TDRG1 may be served as potential diagnostic biomarkers for EGC.

Background Reactive astrogliosis is one of the significantly pathological features in ischemic stroke accompanied with changes in gene expression, morphology, and proliferation. KCa3.1 was involved in TGF-β-induced astrogliosis in vitro and also contributed to astrogliosis-mediated neuroinflammation in neurodegeneration disease. Methods Wild type mice and KCa3.1−/− mice were subjected to permanent middle cerebral artery occlusion (pMCAO) to evaluate the infarct areas by 2,3,5-triphenyltetrazolium hydrochloride staining and neurological deficit. KCa3.1 channels expression and cell localization in the brain of pMCAO mice model were measured by immunoblotting and immunostaining. Glia activation and neuron loss was measured by immunostaining. DiBAC4 (3) and Fluo-4AM were used to measure membrane potential and cytosolic Ca2+ level in oxygen-glucose deprivation induced reactive astrocytes in vitro. Results Immunohistochemistry on pMCAO mice infarcts showed strong upregulation of KCa3.1 immunoreactivity in reactive astrogliosis. KCa3.1−/− mice exhibited significantly smaller infarct areas on pMCAO and improved neurological deficit. Both activated gliosis and neuronal loss were attenuated in KCa3.1−/− pMCAO mice. In the primary cultured astrocytes, the expressions of KCa3.1 and TRPV4 were increased associated with upregulation of astrogliosis marker GFAP induced by oxygen-glucose deprivation. The activation of KCa3.1 hyperpolarized membrane potential and, by promoting the driving force for calcium, induced calcium entry through TRPV4, a cation channel of the transient receptor potential family. Double-labeled staining showed that KCa3.1 and TRPV4 channels co-localized in astrocytes. Blockade of KCa3.1 or TRPV4 inhibited the phenotype switch of reactive astrogliosis. Conclusions Our data suggested that KCa3.1 inhibition might represent a promising therapeutic strategy for ischemia stroke. Electronic supplementary material The online version of this article (10.1186/s12974-017-0973-8) contains supplementary material, which is available to authorized users.

IntroductionPre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia.Methods and analysisAcademic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee.Ethics and disseminationThe protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals.Trial registration numbersEudraCT 2016-001054-17 and NCT03149640.

Early prediction and intervention are known to be critical for acute graft-versus-host disease (aGVHD) prevention and treatment. Significant progress has been made in the development of human plasma biomarkers for the risk stratification of aGVHD severity. Whether donor-derived immune cells may predict the occurrence of severe aGVHD early after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains poorly understood. The objective of this retrospective study was to evaluate the results of allo-HSCT in pediatric patients with different counts and frequencies of dendritic cell (DC) subsets at engraftment in pediatric patients at the Children's Hospital of Soochow University. A total of 45 patients as a discovery cohort were enrolled from March 2018 to December 2018 at the hospital. The validation cohort (30 patients) was enrolled from December 2019 to May 2020. Plasma samples collected from 2016 to 2018 were used for testing ST2 and Reg3α in pediatric patients undergoing allo-HSCT. Patients with grade II-IV aGVHD (n = 18; termed severe aGVHD) showed 3- and 6-fold fewer frequency and numbers, respectively, of plasmacytoid dendritic cells (pDCs) in the peripheral blood (PB) at the engraftment time than patients with grade 0-I aGVHD (n = 27; termed no/mild aGVHD). Using a receiver operating characteristic curve analysis, we identified the threshold of pDC level at 0.3 cell/μL as a cutoff to evaluate the difference in patients with high (0.3 cell/μL) versus low (0.3 cell/μL) pDC counts. Of these 45 patients, 21 (46.7%) had a high number of pDCs and 24 (53.3%) had low pDCs. The patients with low pDCs at the time of engraftment had a significantly higher probability of developing severe aGVHD (P.05). The sensitivity of distinguishing severe aGVHD from no/mild aGVHD was 75%, and the specificity was 94%. In addition, the low pDC patients had higher transplantation-related mortality compared with the high pDC patients (12.5% versus 0%). Using an additional cohort of 30 allo-HSCT patients, we validated this observation. Our findings demonstrate that donor pDC count in PB at the time of engraftment is a valuable biomarker for predicting severe aGVHD in pediatric patients undergoing allo-HSCT.

Acute pancreatitis (AP) is a common non‑bacterial disease compromising pancreatic tissues. Adipocyte‑derived leptin is closely associated with the severity and clinical outcome of pancreatitis. The potential protective effects of exogenous leptin administration on a rat model of severe AP (SAP) remain to be elucidated, and were examined in the present study. Male Wistar rats were divided into a sham operation group (SO), SAP model group (SAP) and leptin group (LEP). Each group was divided into three sub‑groups by observation time (24, 48 and 72 h). The SAP models were prepared by retrograde injection of 6% sodium taurocholate into the pancreatic‑bile duct. Following model establishment, exogenous leptin was intraperitoneally injected into mice at 50 mg/kg in the LEP group. Subsequently, serum amylase, lipase and glucose levels at particular time‑points were analyzed using a fully‑automatic biochemical analyzer, and serum levels of tumor necrosis factor (TNF)‑α and interleukin (IL)‑10 were detected using an enzyme‑linked immunosorbent assay. The pathological changes in pancreatic tissues were observed using hematoxylin and eosin staining, and the pancreatic expression of the long form of the leptin receptor (OB‑Rb) was detected and evaluated using Nest‑polymerase chain reaction analysis. The mortality rates of the model rats were compared between the groups. Following the administration of exogenous leptin, the serum level of amylase in the LEP group was significantly decreased at 48 h, compared with that in the SAP group, with serum lipase levels decreased at 48 and 72 h, and blood glucose levels decreased at 72 h. Regarding the serum inflammatory factors, the level of TNF‑α in the LEP group was significantly lower, compared with that in the SAP group at 24 h; whereas no significant difference was observed in the serum level of IL‑10 between the two groups. Regarding the pathological changes in the pancreas, the tissues in the LEP group showed significantly alleviated pancreatic inflammation. In addition, the pancreatic expression of OB‑Rb in the LEP group was significantly higher, compared with that in the SAP group at 24 and 48 h. No significant difference in 3‑day mortality rates were observed between the SAP group and the LEP group. Taken together, exogenous leptin administration regulated inflammatory factors and the expression of OB‑Rb at the early stage of AP, which exerted protective effects by through the immunological and endocrinal pathways.

A series of N(4)-substituted thiosemicarbazones (TSCs) bearing pyrrole unit (1a-1e) were synthesized and fully characterized by elemental analyses, infrared spectra, 1H nuclear magnetic resonance and single crystal X-ray diffraction. The compounds were assessed as potential chemotherapeutic agents. All newly synthesized compounds were screened for their anticancer activity against lung cancer PC-9, esophageal cancer Eca-109 and gastric cancer SGC-7901 cell lines. The results of MTT, Terminal deoxynucleotidyl transferase dUTP nick end labeling and fluorescence-activated cell sorting assays indicated that all the prepared compounds exhibited cytotoxicity against PC-9, Eca-109 and SGC-7901 cells in vitro. All the compounds significantly induced cancer cell apoptosis accompanied by increasing the Bax/Bcl-2 ratio and activation of caspase-3. The structure-activity association was discussed and the potential pre-clinical trials may be conducted. The present findings have a great potential in biomedical applications of novel N(4)-substituted TSCs.

Alzheimer’s disease (AD) is the most common type of dementia and is characterized by a progression from decline of episodic memory to a global impairment of cognitive function. Astrogliosis is a hallmark feature of AD, and reactive gliosis has been considered as an important target for intervention in various neurological disorders. We previously found in astrocyte cultures that the expression of the intermediate conductance calcium-activated potassium channel KCa3.1 was increased in reactive astrocytes induced by TGF-β, while pharmacological blockade or genetic deletion of KCa3.1 attenuated astrogliosis. In this study, we sought to suppress reactive gliosis in the context of AD by inhibiting KCa3.1 and evaluate its effects on the cognitive impairment using murine animal models such as the senescence-accelerated mouse prone 8 (SAMP8) model that exhibits some AD-like symptoms. We found KCa3.1 expression was increased in reactive astrocytes as well as neurons in the brains of both SAMP8 mice and Alzheimer’s disease patients. Blockade of KCa3.1 with the selective inhibitor TRAM-34 in SAMP8 mice resulted in a decrease in astrogliosis as well as microglia activation, and moreover an attenuation of memory deficits. Using KCa3.1 knockout mice, we further confirmed that deletion of KCa3.1 reduced the activation of astrocytes and microglia, and rescued the memory loss induced by intrahippocampal Aβ1–42 peptide injection. We also found in astrocyte cultures that blockade of KCa3.1 or deletion of KCa3.1 suppressed Aβ oligomer-induced astrogliosis. Our data suggest that KCa3.1 inhibition might represent a promising therapeutic strategy for AD treatment.

BACKGROUND: The value of ultrasound in assessing lung aeration of patients with ARDS who require venovenous extracorporeal membrane oxygenation (ECMO) has, to our knowledge, never been studied. The objective of the study was to evaluate by using ultrasound lung aeration at ECMO initiation and withdrawal in subjects with severe ARDS supported by venovenous ECMO. METHODS: Fifty subjects were included in this pilot retrospective study. The lung ultrasound aeration score (LUS) and respiratory variables were collected at ECMO initiation (T0) and ECMO withdrawal (T1). The LUS at T0 between the subjects who survived to ICU discharge and those who died in ICU was compared. The relationship between changes in LUS and changes in PaO2/FIO2 from T0 to T1 was assessed. RESULTS: The ICU mortality was 34%. The LUS at T0 did not differ between survivors and non-survivors (median 22 [interquartile range] {IQR} 19–26 vs median 24 [IQR, 19–28]; P = .60). From T0 to T1, the LUS decreased significantly in survivors (median 22 [IQR, 19–26] vs median 16 [IQR, 13–19]; P CONCLUSION: At the time of ECMO placement, the subjects who survived ARDS had aeration loss close to that observed in the subjects who did not survive. At the time of ECMO withdrawal, there was a significant improvement in lung aeration in the survivors, whereas a severe loss of lung aeration persisted in the non-survivors, although some were weaned off ECMO. Lung ultrasound provided a valuable tool for bedside assessment of lung aeration in subjects supported by ECMO.

The fully human anti-lipopolysaccharide (LPS) immunoglobulin M (IgM) monoclonal antibody panobacumab was developed as an adjunctive immunotherapy for the treatment of O11 serotype Pseudomonas aeruginosa infections. We evaluated the potential clinical efficacy of panobacumab in the treatment of nosocomial pneumonia. We performed a post-hoc analysis of a multicenter phase IIa trial (NCT00851435) designed to prospectively evaluate the safety and pharmacokinetics of panobacumab. Patients treated with panobacumab (n = 17), including 13 patients receiving the full treatment (three doses of 1.2 mg/kg), were compared to 14 patients who did not receive the antibody. Overall, the 17 patients receiving panobacumab were more ill. They were an average of 72 years old [interquartile range (IQR): 64-79] versus an average of 50 years old (IQR: 30-73) (p = 0.024) and had Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of 17 (IQR: 16-22) versus 15 (IQR: 10-19) (p = 0.043). Adjunctive immunotherapy resulted in an improved clinical outcome in the group receiving the full three-course panobacumab treatment, with a resolution rate of 85 % (11/13) versus 64 % (9/14) (p = 0.048). The Kaplan-Meier survival curve showed a statistically significantly shorter time to clinical resolution in this group of patients (8.0 [IQR: 7.0-11.5] versus 18.5 [IQR: 8-30] days in those who did not receive the antibody; p = 0.004). Panobacumab adjunctive immunotherapy may improve clinical outcome in a shorter time if patients receive the full treatment (three doses). These preliminary results suggest that passive immunotherapy targeting LPS may be a complementary strategy for the treatment of nosocomial O11 P. aeruginosa pneumonia.

Value of differential diagnosis of contrast-enhanced ultrasound in benign and malignant thyroid nodules with microcalcification was explored. A total of 184 patients with thyroid nodules with microcalcification, treated in People's Hospital of Shanxi Province from April 2015 to March 2017, were selected as research subjects. Contrast-enhanced ultrasound was used for imaging examination of the thyroid nodules. Three regions of interest were drawn at the positions with the strongest ultrasound imaging, for which the time-intensity curve (TIC), time to peak (Tp), peak intensity (Peak), area under curve (AUC) and mean transit time (MTT) were obtained separately. The features of contrast-enhanced ultrasound for malignant thyroid nodules were manifested as irregular focus edge, unclear boundary, low fiber reinforcement of the whole focus, uneven distribution of images and blood perfusion defect inside the focus, especially severe blood perfusion defect in the nodule center. The TIC showed a slow ascending and slow descending trend in general. The TIC features and the features of contrast-enhanced ultrasound for malignant thyroid nodules were prominently different from those for benign thyroid nodules. Compared with those in the surrounding normal tissues of thyroid gland, the Peak was remarkably shorter, and the AUC was notably smaller in the center and edge of malignant thyroid nodules (P