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An environmentally friendly Friedel-Crafts reaction was demonstrated between indoles and functionalized nitroallylic acetates in the presence of silica gel, providing the corresponding C-3-selective regioisomers in good to high overall chemical yields (70-93%). [ABSTRACT FROM AUTHOR]

BACKGROUND: Oral anti-diabetes drugs plus basal insulin (OAD + insulin) therapy in patients with newly diagnosed type 2 diabetes might improve [beta]-cell function and result in extended glycaemic remission. This randomised trial compared the effect on [beta]-cell function and diabetes remission rate between oral drug alone or with addition of basal insulin. METHODS: One hundred and twenty-nine patients, aged 35-50 years, were enrolled between June 2005 and June 2009. For initial correction of hyperglycaemia, patients with fasting plasma glucose >=9.0 mmol/L and HbA(1c) >= 9.0%, were randomly assigned to therapy with oral drugs + insulin or oral drugs alone. Treatment was stopped after normoglycaemia was maintained for 3 months. Patients were then followed-up with diet and physical exercise. Blood glucose, HbA(1c) and insulin were measured prior to treatment and at 1-year follow-up. RESULTS: More patients achieved target glycaemic control in the oral drugs + insulin group [98.3% (58 of 59)] in less time [(10.4 ± 2.5) days] than those in the oral drug group [95.7% (67 of 70) and (12.4 ± 3.4) days]. At 1-year follow-up, more patients maintained target glycaemia without any drugs in the oral drug + insulin group than in the oral drug group [37.9% (22 of 58) vs 20.9% (14 of 67)]. Both treatments improved homeostasis model assessment-[beta] (HOMA-[beta]) and homeostasis model assessment-insulin resistance (HOMA-IR) significantly. They had similar effects on insulin resistance [lg(HOMA-IR): (0.50 ± 0.09) vs (0.48 ± 0.09), p = 0.23]. However, oral drugs + insulin could recover [beta]-cell function much more than OAD alone could [lg(HOMA-[beta]): (2.17 ± 0.14) vs (2.11 ± 0.13), p = 0.03]. CONCLUSION: In newly diagnosed type 2 diabetes, therapy with oral drugs + insulin has had favourable outcomes on recovery and maintenance of [beta]-cell function and protracted glycaemic remission compared with treatment with oral drugs alone. [ABSTRACT FROM AUTHOR]

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukaemia (ALL), a high-risk subtype characterised by genomic alterations that activate cytokine receptor and kinase signalling, is associated with inferior outcomes in most childhood ALL clinical trials. Half of the patients with Ph-like ALL have kinase rearrangements or fusions. We examined the frequency and spectrum of these fusions using a retrospective cohort of 212 newly diagnosed patients with childhood B-cell ALL. Samples without known chromosomal alterations were subject to multiplex reverse transcription polymerase chain reaction to identify known Ph-like kinase fusions. Immunoglobulin heavy chain locus (IGH) capture and kinase capture were applied to samples without known kinase fusions. We detected known kinase fusions in five of 212 patients, comprising EBF1-PDGFRB, ETV6-ABL1, ZC3HAV1-ABL2, EPOR-IGH, and CNTRL-ABL1. Two patients with P2RY8-CRLF2 were identified. Patients with non-Ph kinase fusions had inferior 5-year event-free survival and overall survival compared with patients with other common genetic alterations. The prevalence of non-Ph kinase fusions in our Taiwanese cohort was lower than that reported in Caucasian populations. Future clinical trials with tyrosine kinase inhibitors may be indicated in Taiwan because of the inferior outcomes for B-cell ALL with kinase fusions. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • CTGF was up-regulated in the intestinal mucosa tissues of UC patients. • The imbalanced intestinal flora and increased inflammation were showed in UC mice. • Suppression of CTGF improved DSS-induced inflammation and intestinal flora. • Inhibiting CTGF reversed DSS-induced intestinal injury in UC mice via ERK pathway. Abstract Objective To examine the effect of connective tissue growth factor (CTGF)-mediated ERK signaling pathway on the inflammatory response and intestinal flora in ulcerative colitis (UC). Methods CTGF expression was determined through immunohistochemistry in UC and colon polyp patients. Dextran sulfate sodium (DSS) was used to construct UC models. Wild-type (WT) and CTGF-deficient (CTGF−/−) mice were randomly divided into WT/CTGF−/− + saline, WT/CTGF−/− + DSS, and WT/CTGF−/− + DSS + U0126 (ERK pathway inhibitor) groups. HE staining was conducted to observe the pathological changes in intestinal mucosa. The quantity of intestinal flora was tested in the feces. ELISA, qRT-PCR, and Western blotting were used to detect related-molecules expressions. Results CTGF was up-regulated in the intestinal mucosa of UC patients in relation to the severity and grade. Moreover, UC patients showed enhanced the expressions of p-ERK/ERK and pro-inflammatory factors (IL-1β, IL-6, TNF-α, MPO), increased the quantity of Bacteriodes fragilis (B. fragilis) and Escherichia coli (E. coli) , and decreased Bifidobacterium and Lactobacillus. CTGF and pERK/ERK expressions were increased in DSS-induced WT mice, but the pERK expression was lower in CTGF−/− + DSS group than that in the WT + DSS group. U0126 decreased the expressions of pro-inflammatory factors and improved the intestinal flora in WT mice induced with DSS. No significant differences were found in the above indexes between CTGF−/− + DSS group and WT + DSS + U0126 group. Conclusion Inhibiting CTGF could improve inflammatory response and intestinal flora to partially reverse DSS-induced UC via blocking ERK signaling pathway. [ABSTRACT FROM AUTHOR]

Purpose: To analyze factors influencing corneal graft re-epithelialization after penetrating keratoplasty (PK) and evaluate the effect of topical autologous serum in promoting graft re-epithelialization. Design: Prospective interventional study. Methods: We analyzed 165 eyes of 165 patients who underwent PK between January 1, 2005 and December 31, 2007. Patients were divided into 2 groups according to routine use or non-use of postoperative 20% topical autologous serum. Postoperative slit-lamp examination after fluorescein staining was performed, and graft re-epithelialization time was recorded. Recipient/donor characteristics, surgical variables, and topical use of autologous serum were analyzed for their effects on post-PK graft re-epithelialization. Statistical analysis was performed by univariate and multivariate regression analysis using the ordinal logistic fit model to assess the potential risk factors influencing graft re-epithelialization after PK. Results: In univariate analysis, diabetes mellitus (DM), longer death-to-storage time and death-to-surgery time of the donor, and larger recipient size significantly delayed graft re-epithelialization (P < .05). Use of autologous serum significantly expedited graft re-epithelialization (P = .004). In multiple regression analysis, only DM in the recipient (odds ratio [OR] = 5.10, P < .001), postoperative use of autologous serum (OR = 0.54, P = .046), and larger graft size (OR = 4.44, P < .001) influenced graft re-epithelialization. The beneficial and healing effect of autologous serum is particularly significant in diabetic recipients and larger grafts. Conclusions: Several factors may influence graft re-epithelialization after PK. Graft re-epithelialization time was longer in diabetic recipients and larger grafts. Use of autologous serum may be a beneficial strategy in these patients with potentially delayed epithelial healing. [ABSTRACT FROM AUTHOR]

• miR-205 exerts hepatoprotective effect against alcohol-associated liver disease (ALD). • miR-205 targets and inhibits importinα5 expression. • Baicalin upregulates miR-205 expression. • Baicalin inhibits importinα5 to repress the activation of NF-κB signaling pathway. • This study provides better understanding of the hepatoprotective effect of baicalin in ALD. Recently, baicalin refers to flavonoid compound extracted from Scutellaria baicalensis Georgi has been indicated to hold promising therapeutic effects in alcohol-associated liver disease (ALD). However, knowledge of the molecular mechanisms for its hepatoprotective effect is still very limited. Evidence exists suggesting potential association between miR-205 and baicalin's function. Bioinformatic analysis and dual luciferase reporter assay were conducted to determine the binding affinity between miR-205 and importinα5. Our findings revealed that baicalin could alleviate ALD by raising the expression of miR-205. Additionally, miR-205 repressed NF-κB signaling pathway activation by binding to importinα5 to relieve ALD. Baicalin inhibited importinα5-mediated NF-κB signaling pathway to protect the liver against alcohol-induced injury, inflammation, oxidative stress and hepatocyte apoptosis. Taken conjointly, baicalin confers hepatoprotective effect against ALD through miR-205-mediated importinα5 inhibition via the NF-κB signaling pathway, highlighting a promising therapeutic target for ALD treatment with the help of traditional Chinese medicine. [ABSTRACT FROM AUTHOR]

Introduction: Basal insulin is widely recommended for the treatment of type 2 diabetes mellitus (T2DM) patients who are unable to achieve glycemic control with oral antidiabetic drug(s) (OADs). However, some patients are still unable to control their blood glucose levels even when on basal insulin-supported OAD(s) therapy (BOT). The aim of this study was to investigate the factor(s) predicting patient response to BOT.Methods: A total of 212 patients with T2DM, ranging in age from 18 to 65 years, admitted to the university hospital of Sun Yat-sen University, Guangzhou, China, were enrolled in the study between January 2013 and July 2016. All patients had fasting blood glucose levels of ≥ 10.0 mmol/L despite receiving OAD(s) treatment. According to study design, these patients first received intensive insulin therapy for 2 weeks to attain and maintain their glycemic goals and then were switched to BOT. Responders were defined as subjects who maintained their glycemic targets with BOT for at least 3 months; all others were considered to be non-responders. The characteristics between responders and non-responders were compared.Results: Compared with non-responders, responders had a shorter duration of diabetes (5.1 ± 5.0 vs. and 10.1 ± 3.2 years; P  < 0.001) and a higher 2-h postprandial C-peptide-to-fasting C-peptide ratio (2 h-PCP/FCP: 1.95 ± 0.51 vs. 1.67 ± 0.32; P  < 0.01). Responders showed a lower proportion of previous treatment with insulin (69/100 vs 40/3; P  < 0.001) and sulfonlureas or glinides (116/50 vs 40/0; P <0.001) than non-responders. Multivariate logistic regression analysis showed that previous insulin treatment (odds ratio [OR] 17.677, 95% confidence interval [CI] 5.205-60.027; P  < 0.001) and the 2 h-PCP/FCP ratio (OR 0.241, 95% CI 0.058-0.679; P  = 0.007) had predictive value.Conclusions: A higher 2 h-PCP/FCP ratio and a lack of previous insulin treatment increase the likelihood of BOT success. [ABSTRACT FROM AUTHOR]

In this paper, we proposed and experimentally demonstrated simultaneous transmission of wired and wireless signals based on double sideband optical carrier suppression. By properly adjusting the bias point of the dual-output mach-zehnder modulator (MZM), a central carrier in one output port and a pair of first-order sidebands in another output port are generated. The pair of first-order sidebands are fed into a second MZM to generate second-order order sidebands. A wired signal is embedded on the central carrier while a wireless signal is embedded on the second-order sidebands. Unlike other schemes, we did not use optical filter to separate the carrier from the optical sidebands. The measured bit error rate (BER) and eye-diagrams after a 25 km single-mode-fiber (SMF) transmission proved that the proposed scheme is successful for both wired and wireless signals transmission. Moreover, the power penalty at the BER of 10 −9 is 0.3 and 0.7 dB for wired and wireless signals, respectively. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficacy of the combination of topical 20% autologous serum eye drops (ASEs) and silicone-hydrogel soft contact lenses (SCLs) for the treatment of corneal persistent epithelial defects (PEDs), and to compare the recurrence of epithelial breakdown with or without continuous use of ASEs after silicone-hydrogel SCLs removal.Methods: We conducted a prospective interventional study of 21 eyes of 21 patients with PEDs treated with combined ASEs and silicone-hydrogel SCLs from September 2014 to August 2015. SCLs were removed after total re-epithelialization and patients were subsequently randomized divided into two groups: (1) with and (2) without continuous use of ASEs for an additional 2 weeks. PEDs healing rate and epithelial defect recurrence were evaluated.Results: PEDs healed in all eyes within 3 weeks. Recurrence was noted in five eyes (50%) in patients without continued use of ASEs for 2weeks after total re-epithelialization and SCLs removal during a 3-month follow-up (odds ratio: 23.0; P<0.05). Recurrent epithelial defects were successfully treated with secondary SCLs application combined with autologous serum use. No adverse events were noted during the entire treatment period.Conclusions: The combined use of ASEs and silicone-hydrogel SCLs can successfully treat recalcitrant PEDs. Prolonged use of ASEs after total re-epithelialization can decrease recurrence rates. [ABSTRACT FROM AUTHOR]

Abstract: This study reports a microfluidic cell culture chip encompassing 36 microbioreactors for high throughput perfusion 3-dimensional (3D) cell culture-based chemosensitivity assays. Its advantages include the capability for multiplexed medium delivery, and the function for both efficient and high throughput micro-scale 3D culture construct preparation and loading. The results showed that the proposed medium pumping mechanism was able to provide a uniform pumping rates ranging from 1.2 to 3.9μlh−1. In addition, the simple cell/hydrogel loading scheme has been proven to be able to carry out 3D cell culture construct preparation and loading precisely and efficiently. Furthermore, a chemosensitivity assay was successfully demonstrated using the proposed cell culture chip. The results obtained were also compared with the same evaluation based on a conventional 2D monolayer cell culture. It can be concluded that the choice of cell culture format can result in different chemosensitivity evaluation results. Overall, because of the nature of miniaturized perfusion 3D cell culture, the cell culture chip not only can provide stable, well-defined and more biologically relevant culture environments, but it also features low consumption of research resources. All these traits are found particularly useful for high-precision and high-throughput 3D cell culture-based assays. [Copyright &y& Elsevier]

• An UHPLC-QTOF MS method was developed for global identification of Callicarpa nudiflora. • 96 compounds were characterized in the C. nudiflora. • 26 compounds were quantified in 34 batches of C. nudiflora. • Compound-target-disease network of C. nudiflora was constructed based on reverse docking. • 16 compounds were found as potential anti-inflammation ingredients of C. nudiflora. Callicarpa nudiflora, belonging to the family Verbenaceae, is widely used to treat inflammation caused by bacterial infection.However, the underlying active substances of C. nudiflora against inflammation remains obscure. In this work, an ultra high-performance liquid chromatography (UHPLC) coupled with quadrupole time-of-flight mass spectrometry method was developed to characterize the ingredients in C. nudiflora , and a validated UHPLC coupled with triple quadrupole tandem mass spectrometry method was applied to quantify major components. As a result, a total of 96 chemical compounds were identified in C. nudiflora , and 26 compounds of them were further quantified in 34 batches of C. nudiflora. Based on the identified components from C. nudiflora , a compound-target network for the anti-inflammation effect was constructed by reverse docking target prediction, disease associated genes screening in DisGeNET and the protein-protein interaction from STRING. The compound-target network showed that C. nudiflora might exert anti-inflammation effect on the target of complement 3 and 5 in the pathway of cells and molecules involved in local acute inflammatory response, and 16 effective candidate compounds were found such as catalpol, acteoside, rutin, etc. This study provided an opportunity to deepen the understanding of the chemical composition and the potential anti-inflammatory mechanism of C. nudiflora. [ABSTRACT FROM AUTHOR]

Burns are common traumatic injuries affecting many people worldwide. Development of specialized burn units, advances in acute care modalities, and burn prevention programs have successfully reduced the mortality rate of severe burns. Autologous skin grafting has been considered as the gold standard for wound coverage after the removal of burned skin. For full-thickness burns of a larger scale, however, the autograft donor site may be quickly exhausted, so that alternative skin coverage is necessary. Although rapid progress has been made in the development of skin substitutes for burn wounds during the last decade, no skin substitute has fulfilled the criteria as a perfect replacement for the damaged skin. Extracellular matrix (ECM) derived components have emerged as a source for the engineering of biomaterials capable of inducing desirable cell-specific responses and one of the most promising biomaterials for burn wound healing. Among these, acellular dermal matrix, small intestinal submucosa, and amniotic membrane have been applied to treat burn wounds with acceptable outcomes. This review has explored the use of biomaterials derived from naturally occurring ECM and their derivatives for approaches aiming to promote burn wound healing, and summarized the ECM-based wound dressings products applicable in burn wound and postburn scar contracture to date., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: As the global use of extracorporeal membrane oxygenation (ECMO) treatment increases, survival rates have not correspondingly improved, emphasizing the need for refined patient selection to optimize resource allocation. Currently, prognostic markers at the molecular level are limited., Methods: Thirty-four cardiogenic shock (CS) patients were prospectively enrolled, and peripheral blood mononuclear cells (PBMCs) were collected at the initiation of ECMO (t0), two-hour post-installation (t2), and upon removal of ECMO (tr). The PBMCs were analyzed by comprehensive epigenomic assays. Using the Wilcoxon signed-rank test and least absolute shrinkage and selection operator (LASSO) regression, 485,577 DNA methylation features were analyzed and selected from the t0 and tr datasets. A random forest classifier was developed using the t0 dataset and evaluated on the t2 dataset. Two models based on DNA methylation features were constructed and assessed using receiver operating characteristic (ROC) curves and Kaplan-Meier survival analyses., Results: The ten-feature and four-feature models for predicting in-hospital mortality attained area under the curve (AUC) values of 0.78 and 0.72, respectively, with LASSO alpha values of 0.2 and 0.25. In contrast, clinical evaluation systems, including ICU scoring systems and the survival after venoarterial ECMO (SAVE) score, did not achieve statistical significance. Moreover, our models showed significant associations with in-hospital survival (p < 0.05, log-rank test)., Conclusions: This study identifies DNA methylation features in PBMCs as potent prognostic markers for ECMO-treated CS patients. Demonstrating significant predictive accuracy for in-hospital mortality, these markers offer a substantial advancement in patient stratification and might improve treatment outcomes., (© 2024. The Author(s).)

Pain is a common public health problem and remains as an unmet medical need. Currently available analgesics usually have limited efficacy or are accompanied by many adverse side effects. To achieve satisfactory pain relief by multimodal analgesia, new combinations of nefopam and gabapentinoids (pregabalin/gabapentin) were designed and assessed in inflammatory, osteoarthritis and neuropathic pain. Isobolographic analysis was performed to analyze the interactions between nefopam and gabapentinoids in carrageenan-induced inflammatory pain, mono-iodoacetate-induced osteoarthritis pain and paclitaxel-induced peripheral neuropathic pain in mice. The anti-inflammatory effect and motor performance of monotherapy or their combinations were evaluated in the carrageenan-induced inflammatory responses and rotarod test, respectively. Nefopam (1, 3, 5, 10, 30 mg/kg, p.o.), pregabalin (3, 6, 12, 24 mg/kg, p.o.) or gabapentin (25, 50, 75, 100 mg/kg, p.o.) dose-dependently reversed mechanical allodynia in three pain models. Isobolographic analysis indicated that the combinations of nefopam and gabapentinoids exerted synergistic anti-nociceptive effects in inflammatory, osteoarthritis, and neuropathic pain mouse models, as evidenced by the experimental ED 50 (median effective dose) falling below the predicted additive line. Moreover, the combination of nefopam-pregabalin/gabapentin alleviated carrageenan-induced inflammation and edema, and also prevented gabapentinoids-related sedation or ataxia by lowering their effective doses. Collectively, the co-administration of nefopam and gabapentinoids showed synergistic analgesic effects and may result in improved therapeutic benefits for treating pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: ICU readmissions and post-discharge mortality pose significant challenges. Previous studies used EHRs and machine learning models, but mostly focused on structured data. Nursing records contain crucial unstructured information, but their utilization is challenging. Natural language processing (NLP) can extract structured features from clinical text. This study proposes the Crucial Nursing Description Extractor (CNDE) to predict post-ICU discharge mortality rates and identify high-risk patients for unplanned readmission by analyzing electronic nursing records., Objective: Developed a deep neural network (NurnaNet) with the ability to perceive nursing records, combined with a bio-clinical medicine pre-trained language model (BioClinicalBERT) to analyze the electronic health records (EHRs) in the MIMIC III dataset to predict the death of patients within six month and two year risk., Design: A cohort and system development design was used., Setting(s): Based on data extracted from MIMIC-III, a database of critically ill in the US between 2001 and 2012, the results were analyzed., Participants: We calculated patients' age using admission time and date of birth information from the MIMIC dataset. Patients under 18 or over 89 years old, or who died in the hospital, were excluded. We analyzed 16,973 nursing records from patients' ICU stays., Methods: We have developed a technology called the Crucial Nursing Description Extractor (CNDE), which extracts key content from text. We use the logarithmic likelihood ratio to extract keywords and combine BioClinicalBERT. We predict the survival of discharged patients after six months and two years and evaluate the performance of the model using precision, recall, the F 1 -score, the receiver operating characteristic curve (ROC curve), the area under the curve (AUC), and the precision-recall curve (PR curve)., Results: The research findings indicate that NurnaNet achieved good F 1 -scores (0.67030, 0.70874) within six months and two years. Compared to using BioClinicalBERT alone, there was an improvement in performance of 2.05 % and 1.08 % for predictions within six months and two years, respectively., Conclusions: CNDE can effectively reduce long-form records and extract key content. NurnaNet has a good F 1 -score in analyzing the data of nursing records, which helps to identify the risk of death of patients after leaving the hospital and adjust the regular follow-up and treatment plan of relevant medical care as soon as possible., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

RNA-binding proteins (RBPs) regulate diverse cellular processes by dynamically interacting with RNA targets. However, effective methods to capture both stable and transient interactions between RBPs and their RNA targets are still lacking, especially when the interaction is dynamic or samples are limited. Here we present an assay of reverse transcription-based RBP binding site sequencing (ARTR-seq), which relies on in situ reverse transcription of RBP-bound RNAs guided by antibodies to identify RBP binding sites. ARTR-seq avoids ultraviolet crosslinking and immunoprecipitation, allowing for efficient and specific identification of RBP binding sites from as few as 20 cells or a tissue section. Taking advantage of rapid formaldehyde fixation, ARTR-seq enables capturing the dynamic RNA binding by RBPs over a short period of time, as demonstrated by the profiling of dynamic RNA binding of G3BP1 during stress granule assembly on a timescale as short as 10 minutes., (© 2024. The Author(s).)

Object: The study aims to determine whether multimorbidity status is associated with cerebrospinal fluid (CSF) biomarkers for neurodegenerative disorders., Methods: A total of 827 patients were enrolled from the Parkinson's Progression Markers Initiative (PPMI) database, including 638 patients with early-stage Parkinson's disease (PD) and 189 healthy controls (HCs). Multimorbidity status was evaluated based on the count of long-term conditions (LTCs) and the multimorbidity pattern. Using linear regression models, cross-sectional and longitudinal analyses were conducted to assess the associations of multimorbidity status with CSF biomarkers for neurodegenerative disorders, including α-synuclein (αSyn), amyloid-β 42 (Aβ 42 ), total tau (t-tau), phosphorylated tau (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL)., Results: At baseline, the CSF t-tau (p = 0.010), p-tau (p = 0.034), and NfL (p = 0.049) levels showed significant differences across the three categories of LTC counts. In the longitudinal analysis, the presence of LTCs was associated with lower Aβ 42 (β < -0.001, p = 0.020), and higher t-tau (β = 0.007, p = 0.026), GFAP (β = 0.013, p = 0.022) and NfL (β = 0.020, p = 0.012); Participants with tumor/musculoskeletal/mental disorders showed higher CSF levels of t-tau (β = 0.016, p = 0.011) and p-tau (β = 0.032, p = 0.044) than those without multimorbidity., Conclusion: Multimorbidity, especially severe multimorbidity and the pattern of mental/musculoskeletal/ tumor disorders, was associated with CSF biomarkers for neurodegenerative disorders in early-stage PD patients, suggesting that multimorbidity might play a crucial role in aggravating neuronal damage in neurodegenerative diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Chronic pain is a common public health problem and remains an unmet medical need. Currently available analgesics usually have limited efficacy for the treatment of chronic pain, including neuropathic pain and persistent inflammatory pain, or they are accompanied by many adverse side effects. The voltage-gated calcium channel blocker (pregabalin) and potassium channel openers (flupirtine and retigabine) have been widely used for the management of chronic pain, but their effectiveness in combination is unclear. In this research, we evaluated the antinociceptive effects of pregabalin in combination with flupirtine or retigabine in carrageenan-induced inflammatory pain and paclitaxel-induced peripheral neuropathy in mice using the von Frey test. Isobolographic analysis indicated that pregabalin exerted synergistic antinociceptive effects when combined with flupirtine or retigabine in neuropathic and inflammatory pain models. Furthermore, the antinociceptive effects of pregabalin, flupirtine/retigabine, and their combinations were significantly attenuated by the Kv7 channel blocker XE991. The favored dose ratio between pregabalin and flupirtine/retigabine in combinations was also investigated. Finally, we evaluated the motor coordination of their combinations using the rotarod test, and the outcomes underpinned their safety. Collectively, our results support the potential use of pregabalin in combination with flupirtine or retigabine to alleviate chronic pain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: No published studies to date have evaluated the detailed pathologic and genetic features of lung adenocarcinoma after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and salvage surgery. We aimed to evaluate the pathologic and genetic changes of tumors in patients with advanced lung adenocarcinoma treated with EGFR TKI therapy and salvage surgery., Methods: This study retrospectively collected data from 29 advanced lung adenocarcinoma patients who underwent EGFR TKI therapy, followed by salvage operation, between January 2010 and December 2018. All patients had partial response or stable disease without evidence of progressive disease. Next-generation sequencing was used to determine whether acquired resistant mutations in morphologically treatment-sensitive and morphologically treatment-resistant regions of tumor existed., Results: There were 3, 22, and 4 patients with clinical stage IIIB, IVA, and IVB, respectively. After a mean TKI treatment duration of 134 days, 27 patients had partial response, 2 had stable disease, and 27.6% of patients were downstaged before salvage surgery. All patients had residual viable tumor cells in their tumor bed; 5 patients (17.2%) had a major pathologic response. Acquired T790M mutations (n = 4), histologic transformations (n = 2), and acquired T790M mutation with histologic transformation (n = 1) were identified in the morphologically treatment-resistant regions of tumors. The 3-year overall survival was 75.9%., Conclusions: The presence of morphologically treatment-resistant tumor regions with acquired T790M mutations and histologic transformations demonstrate the existence of resistant subclones in TKI-treated tumors before disease progression. Salvage surgery performed in selected patients before disease progression may improve survival by removing TKI-resistant subclones., (Copyright © 2023 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

PD-L1 immunohistochemistry has been approved as a diagnostic assay for immunotherapy. However, an international comparison across multiple cancers is lacking. This study aimed to assess the performance of PD-L1 diagnostic assays in non-small cell lung cancer (NSCLC), head and neck squamous cell cancer (HNSCC) and urothelial cancer (UC). The excisional specimens of NSCLC, HNSCC and UC were assayed by Ventana SP263 and scored at three sites in each country, including Australia, Brazil, Korea, Mexico, Russia and Taiwan. All slides were rotated to two other sites for interobserver scoring. The same cohort of NSCLC was assessed with Dako 22C3 pharmDx PD-L1 for comparison. The PD-L1 immunopositivity was scored according to the approved PD-L1 scoring algorithms which were the percentage of PD-L1-expressing tumour cell (TC) and tumour proportion score (TPS) by Ventana SP263 and Dako 22C3 staining, respectively. In NSCLC, the comparison demonstrated the comparability of the SP263 and 22C3 assays (cut-off of 1%, κ=0.71; 25%, κ=0.75; 50%, κ=0.81). The interobserver comparisons showed moderate to almost perfect agreement for SP263 in TC staining at 25% cut-off (NSCLC, κ=0.72 to 0.86; HNSCC, κ=0.60 to 0.82; UC, κ=0.68 to 0.91) and at 50% cut-off for NSCLC (κ=0.64 to 0.90). Regarding the immune cell (IC) scoring in UC, there was a lower correlation (concordance correlation coefficient=0.10 to 0.68) and poor to substantial agreements at the 1%, 5%, 10% and 25% cut-offs (κ= -0.04 to 0.76). The interchangeability of SP263 and 22C3 in NSCLC might be acceptable, especially at the 50% cut-off. In HNSCC, the performance of SP263 is comparable across five countries. In UC, there was low concordance of IC staining, which may affect treatment decisions. Overall, the study showed the reliability and reproducibility of SP263 in NSCLC, HNSCC and UC., (Copyright © 2022 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Objectives: We aimed to explore the shared and specific signalling pathways involved in diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN) and diabetic nephropathy (DN)., Methods: Differentially expressed mRNAs and lncRNAs were identified by high-throughput sequencing. Subsequently, functional enrichment analysis, protein-protein interaction (PPI) analysis and lncRNAs-mRNAs networks were conducted to determine the pathogenic mechanisms underlying DR, DPN and DN., Results: Twenty-six biological pathways were shared among DR, DPN and DN groups compared to the type 2 diabetes mellitus (T2DM) group without complications, and most of the shared pathways and core proteins were involved in immune and inflammatory responses of microvascular damage. Cytokine‒cytokine receptor interactions and chemokine signalling pathway were the most significant and specific pathways for DR, and the lncRNA‒mRNA regulatory networks affected DR by targeting these pathways. Sphingolipid metabolism and neuroactive ligand-receptor pathways were found to be specific for the pathogenesis of DPN. Moreover, multiple amino acid metabolic pathways were involved in the occurrence and progression of DN., Conclusions: Diabetic retinopathy, DPN and DN exhibited commonality and heterogeneity simultaneously. The shared pathologic mechanisms underlying these diabetic complications are involved in diabetic microvascular damage via immune and inflammatory pathways. Our findings predict several biomarkers and therapeutic targets for these diabetic complications.

Liquid biopsy test has a better uptake for colorectal cancer (CRC) screening. However, suboptimal detection of early-staged colorectal neoplasia (CRN) limits its application. Here, we established an early-staged CRN blood test using error-corrected sequencing by comparing clonal hematopoiesis (CH) of 63 CRN patients and that of 32 controls. We identified 1,446 variants and classified the uniqueness in CRN patients. There was no significance difference in the amount of variant between CRNs and controls, but the uniqueness of variants with defective DNA mismatch repair-related mutational signature was addressed from peripheral blood in early-staged CRN patients. By machine learning approach, the early-staged CRNs was discriminated from controls with an AUC of 0.959 and an accuracy of 0.937 (95% CI, 0.863 to 0.968). The CRN predictive model was further validated by additional 20 CRNs and 10 controls and showed the accuracy, sensitivity, specificity, positive prediction value (PPV) and negative prediction value (NPV) of 0.933 (95% CI: 0.779 to 0.992), 0.95, 0.90, 0.95 and 0.90, respectively. In summary, we develop a CH-based liquid biopsy test with machine learning approach, which not only increase screening uptake but also improve the detection rate of early-staged CRN., Competing Interests: None., (AJCR Copyright © 2022.)

Objective: We aim to evaluate the clinical effect of combined topical 20% autologous serum eye drops (ASEs) along with silicone-hydrogel soft contact lenses (SCLs) in the treatment of chemical burn-induced bilateral corneal persistent epithelial defects (PEDs) and to review the literature of related studies., Methods: From January 1, 2017, to December 31, 2019, we conducted a retrospective chart review of 8 patients with chemical burn-induced bilateral corneal PEDs who were unsuccessfully treated with conventional medical therapy and were then treated with combined topical 20% (v/v) ASEs and silicone-hydrogel CLs. The clinical effects and effectiveness of the combined treatment were evaluated., Results: The bilateral corneal PEDs healed in all sixteen eyes of the eight patients within 2 weeks. The patients did not report any discomfort associated with the combined treatment. Improved ocular comfort/visual acuity and decreased conjunctival injection correlated with healing. No recurrent corneal epithelial breakdown was noted during the 3-month posttreatment follow-up., Conclusions: The combined treatment of silicone-hydrogel CLs and ASEs can help to stabilize the ocular surface and successfully treat chemical burn-induced bilateral corneal PEDs. It may be considered as an alternative treatment method for patients with bilateral chemical burn-induced corneal PEDs with potential corneal melting., Competing Interests: None of the authors has conflict of interest with this submission., (Copyright © 2022 Yan-Ming Chen et al.)

Objective: Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy, and its pathogenesis is still unclear. Studies have shown that circular RNAs (circRNAs) can regulate blood glucose levels by targeting mRNAs, but the role of circRNAs in GDM is still unknown. Therefore, a joint microarray analysis of circRNAs and their target mRNAs in GDM patients and healthy pregnant women was carried out., Methods: In this study, microarray analyses of mRNA and circRNA in 6 GDM patients and 6 healthy controls were conducted to identify the differentially expressed mRNA and circRNA in GDM patients, and some of the discovered mRNAs and circRNAs were further validated in additional 56 samples by quantitative realtime PCR (qRT-PCR) and droplet digital PCR (ddPCR)., Results: Gene ontology and pathway analyses showed that the differentially expressed genes were significantly enriched in T cell immune-related pathways. Cross matching of the differentially expressed mRNAs and circRNAs in the top 10 KEGG pathways identified 4 genes ( CBLB , ITPR3 , NFKBIA , and ICAM1 ) and 4 corresponding circRNAs (circ-CBLB, circ-ITPR3, circ-NFKBIA, and circ-ICAM1), and these candidates were subsequently verified in larger samples. These differentially expressed circRNAs and their linear transcript mRNAs were all related to the T cell receptor signaling pathway, and PCR results confirmed the initial microarray results. Moreover, circRNA/miRNA/mRNA interactions and circRNA-binding proteins were predicted, and circ-CBLB, circ-ITPR3, and circ-ICAM1 may serve as GDM-related miRNA sponges and regulate the expression of CBLB, ITPR3, NFKBIA, and ICAM1 in cellular immune pathways., Conclusion: Upregulation of T cell receptor signaling pathway components may represent the major pathological mechanism underlying GDM, thus providing a potential approach for the prevention and treatment of GDM., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Zhu, Cai, Zhao, Yao, Zhou, Ji and Xu.)

One of the central goals in molecular evolutionary biology is to determine the sources of variation in the rate of sequence evolution among proteins. Gene expression level is widely accepted as the primary determinant of protein evolutionary rate, because it scales with the extent of selective constraints imposed on a protein, leading to the well-known negative correlation between expression level and protein evolutionary rate (the E-R anticorrelation). Selective constraints have been hypothesized to entail the maintenance of protein function, the avoidance of cytotoxicity caused by protein misfolding or nonspecific protein-protein interactions, or both. However, empirical tests evaluating the relative importance of these hypotheses remain scarce, likely due to the nontrivial difficulties in distinguishing the effect of a deleterious mutation on a protein's function versus its cytotoxicity. We realized that examining the sequence evolution of viral proteins could overcome this hurdle. It is because purifying selection against mutations in a viral protein that result in cytotoxicity per se is likely relaxed, whereas purifying selection against mutations that impair viral protein function persists. Multiple analyses of SARS-CoV-2 and nine other virus species revealed a complete absence of any E-R anticorrelation. As a control, the E-R anticorrelation does exist in human endogenous retroviruses where purifying selection against cytotoxicity is present. Taken together, these observations do not support the maintenance of protein function as the main constraint on protein sequence evolution in cellular organisms., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Background: The folding of proteins is challenging in the highly crowded and sticky environment of a cell. Regulation of translation elongation may play a crucial role in ensuring the correct folding of proteins. Much of our knowledge regarding translation elongation comes from the sequencing of mRNA fragments protected by single ribosomes by ribo-seq. However, larger protected mRNA fragments have been observed, suggesting the existence of an alternative and previously hidden layer of regulation., Results: In this study, we performed disome-seq to sequence mRNA fragments protected by two stacked ribosomes, a product of translational pauses during which the 5'-elongating ribosome collides with the 3'-paused one. We detected widespread ribosome collisions that are related to slow ribosome release when stop codons are at the A-site, slow peptide bond formation from proline, glycine, asparagine, and cysteine when they are at the P-site, and slow leaving of polylysine from the exit tunnel of ribosomes. The structure of disomes obtained by cryo-electron microscopy suggests a different conformation from the substrate of the ribosome-associated protein quality control pathway. Collisions occurred more frequently in the gap regions between α-helices, where a translational pause can prevent the folding interference from the downstream peptides. Paused or collided ribosomes are associated with specific chaperones, which can aid in the cotranslational folding of the nascent peptides., Conclusions: Therefore, cells use regulated ribosome collisions to ensure protein homeostasis.

Microphthalamia-associated transcription factor (MITF) is a critical mediator in melanocyte differentiation and exerts oncogenic functions in melanoma progression. However, the role of MITF in non-small cell lung cancer (NSCLC) is still unknown. We found that MITF is dominantly expressed in the low-invasive CL1-0 lung adenocarcinoma cells and paired adjacent normal lung tissues. MITF expression is significantly associated with better overall survival and disease-free survival in NSCLC and serves as an independent prognostic marker. Silencing MITF promotes tumor cell migration, invasion and colony formation in lung adenocarcinoma cells. In xenograft mouse model, MITF knockdown enhances metastasis and tumorigenesis, but decreases angiogenesis in the Matrigel plug assay. Whole transcriptome profiling of the landscape of MITF regulation in lung adenocarcinoma indicates that MITF is involved in cell development, cell cycle, inflammation and WNT signaling pathways. Chromatin immunoprecipitation assays revealed that MITF targets the promoters of FZD7 , PTGR1 and ANXA1 . Moreover, silencing FZD7 reduces the invasiveness that is promoted by silencing MITF. Strikingly, MITF has significantly inverse correlations with the expression of its downstream genes in lung adenocarcinoma. In summary, we demonstrate the suppressive role of MITF in lung cancer progression, which is opposite to the canonical oncogenic function of MITF in melanoma.

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Background: Asthma is one of the most common chronic diseases in the world, with approximately 300 million asthma patients worldwide. The mortality rate of asthma is 1.6 to 36.7 / 100,000 people, and China has become one of the countries with the highest asthma death rate in the world. Asthma is a chronic allergic airway inflammatory disease. Patients with this disease may have symptoms such as cough, wheezing, and difficulty breathing. For many years, Western medicine has mainly used anti-inflammatory, anti-bronchial spasm, asthma, cough and oxygen to treat this disease, but the effect is not good. Clinical studies in recent years have found that the use of acupuncture in the treatment of bronchial asthma has a good clinical application prospect. This study was conducted to study the effect of using acupuncture to treat asthma., Methods and Analysis: We will search for PubMed, Cochrane Library, AMED, EMbase, WorldSciNet; Nature, Science online and China Journal Full-text Database (CNKI), China Biomedical Literature CD-ROM Database (CBM), and related randomized controlled trials included in the China Resources Database. The time is limited from the construction of the library to November 2019. We will use the criteria provided by Cochrane 5.1.0 for quality assessment and risk assessment of the included studies, and use the Revman 5.3 and Stata13.0 software for meta-analysis of the effectiveness, recurrence rate, and symptom scores of asthma., Ethics and Dissemination: This systematic review will evaluate the efficacy and safety of acupuncture for asthma. Because all of the data used in this systematic review and meta-analysis has been published, this review does not require ethical approval. Furthermore, all data will be analyzed anonymously during the review process Trial.

Objective: To investigate the expression of β-catenin in the skin lesions of patients with systemic scleroderma (SSc) and its effect on epithelial-mesenchymal transition (EMT) of human epidermal keratinocytes., Methods: The expression of β-catenin, Snail1 and E-cadherin in the skin lesions sample of 45 SSc patients and normal skin sample from 20 healthy adults was detected with SP immunohistochemistry. HaCaT, the human epidermal keratinocytes, were treated with different concentrations of Wnt10b (0 ng/mL (control), 2 ng/mL and 4 ng/mL) for 48 h. then detected the localization of β-catenin in HaCaT cells by immunofluorescence assay, determined the mRNA levels of Snail1 and Snail2 in HaCaT cells by real-time fluorescent quantitative PCR, detected the proteins expression of β-catenin, Vimentin, N-cadherin and E-cadherin in HaCaT cells by Western blot., Results: The positive rates of β-catenin, Snail1 and E-cadherin in skin lesions of SSc patients were 100%, 88.89% and 2.22% respectively, while in healthy adult skin, the corresponding positive rates were 0%, 10.00%, and 95.00%. The difference between the two groups was significant. Compared with control group, treatment with different concentrations of Wnt10b (2 ng/mL and 4 ng/mL) induced up-regulation of β-catenin expression and promoted translocation of β-catenin from cytoplasm to nucleus, increased the mRNA levels of Snail1 and Snail2 ( P < 0.05), and up-regulated the proteins expression of Vimentin, N-cadherin, down-regulated the E-cadherin protein expression in HaCaT cells ( P < 0.05)., Conclusions: Abnormally activated Wnt/β-catenin signaling pathway and abnormally expressed EMT-related proteins are observed in SSc lesions. Activation of Wnt/β-catenin signaling pathway may promote EMT in HaCaT cells., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Science Edition).)

Objectives: In vivo confocal microscopy was used to observe the morphological presentations and anatomical correlations between corneal neovascularization (NV) and intracorneal lipid deposition in a rabbit model of contact lens (CL)-induced lipid keratopathy secondary to corneal NV., Methods: Rabbits were divided into 3 groups: (1) 8-week normal diet, (2) 8-week high-cholesterol diet, and (3) 4-week normal diet followed by 4-week high-cholesterol diet. Corneal NV was induced by closed-eye CL. The formation and maturation of corneal NV were shown by immunohistochemical staining against CD31 and high-molecular-weight melanoma-associated antigen. In vivo confocal microscopy identified corneal NV and lipid deposition. Acquired images for each eye were arranged and mapped into subconfluent montages., Results: In group 1, corneal NV sprouting formed from the peripheral to the central cornea by the end of week 4. Pericytes around vessels were shown after 2 weeks of CL wear. In group 2, lipid deposition started from the peripheral cornea and progressively covered the whole cornea. In group 3, lipid deposition was found first in the central cornea after 2 weeks of high-cholesterol diet and progressed to cover the peripheral cornea. In vivo confocal microscopy demonstrated four different patterns of intracorneal lipid deposition: spindle shapes arranged randomly or in parallel, amorphous shapes, multiangular shapes, and mixed types. Intracorneal lipid deposition was distributed from basal corneal epithelium to deep stroma., Conclusions: Intracorneal lipids tend to accumulate around newly formed corneal NV but can extend to the area covered with mature NV. In vivo confocal microscopy can demonstrate various shapes and depths of intracorneal lipid deposition.

Aim: To investigate the effect of activating transcription factor-3 (ATF3)-deletion on apoptosis of cultured retinal ganglion cells (RGCs)., Methods: Three ATF3 siRNA (ATF3-rat-651, ATF3-rat-319, ATF3-rat-520) were constructed, and were transiently transfected into RGC-5 cells. Quantitative real-time polymerase chain reaction (PCR) was used to examine ATF3 expression and the most effective ATF3 siRNA was selected for further studies. Flow cytometry was applied to investigate the effects of ATF3 deletion on RGC-5 apoptosis under elevated hydrostatic pressure. Quantitative real-time PCR and Western blot were performed to validate differentially expressed genes and proteins in ATF3-knockdown RGC-5 cells., Results: ATF3 specific siRNA effectively down-regulated ATF3 expression and significantly inhibited cell apoptosis in RGC-5 cells. Quantitative real-time PCR and Western blot confirmed that ATF3 knockdown remarkably decreased Jun-B and increased c-Jun at both mRNA and protein levels in RGC-5 cells., Conclusion: ATF/cAMP-response element-binding family of transcription factors may be involved in the development of glaucoma and could be novel treatment targets for glaucoma.

Background: Oestrogen has anti-inflammatory property in obesity. However, the mechanism is still not defined., Objective: To investigate the effect of oestrogen on LPS-induced monocyte chemoattractant protein-1 (MCP-1) production in adipocytes., Methods: Lipopolysaccharides (LPS) was used to imitate inflammatory responses and monocyte chemotactic protein-1 (MCP-1) was selected as an inflammatory marker to observe. 17β-Estradiol (E 2 ), SB203580 (SB), pyrrolidine dithiocarbamate (PDTC), pertussis toxin (PTX), wortmannin (WM), p65 siRNA and p38 MAPK siRNA were pre-treated respectively or together in LPS-induced MCP-1. Then p38 MAPK and NF-κB cascade were silenced successively to observe the change of each other. Lastly, oestrogen receptor (ER) α agonist, ERβ agonist and ER antagonist were utilised., Results: LPS-induced MCP-1 largely impaired by pre-treatment with E 2 , SB, PDTC or silencing NF-κB subunit. E 2 inhibited LPS-induced MCP-1 in a time- and dose-dependent manner, which was related to the suppression of p65 translocation to nucleus. Furthermore, LPS rapidly activated p38 MAPK, while E 2 markedly inhibited this activation. It markedly attenuated LPS-stimulated p65 translocation to nucleus and MCP-1 production by transfecting with p38 MAPK siRNA or using p38 MAPK inhibitor. The oestrogen's inhibitory effect was mimicked by the ERα agonist, but not by the ERβ agonist. The inhibition of E 2 on p38 MAPK phosphorylation was prevented by ER antagonist., Conclusions: E 2 inhibits LPS-stimulated MCP-1 in adipocytes. This effect is related to the inhibition of p38 MAPK/NF-κB cascade, and ERα appears to be the dominant ER subtype in these events., (Copyright © 2016 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

Aim: To study the clinical efficacy of traditional Chinese medicine (TCM) intervention "tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment" ("TTK") for treating liver failure due to chronic hepatitis B., Methods: We designed the study as a randomized controlled clinical trial. Registration number of Chinese Clinical Trial Registry is ChiCTR-TRC-12002961. A total of 144 patients with liver failure due to infection with chronic hepatitis B virus were enrolled in this randomized controlled clinical study. Participants were randomly assigned to the following three groups: (1) a modern medicine control group (MMC group, 36 patients); (2) a "tonifying qi and detoxification" ("TQD") group (72 patients); and (3) a "tonifying the kidney to promote liver regeneration and repair by affecting stem cells and their microenvironment" ("TTK") group (36 patients). Patients in the MMC group received general internal medicine treatment; patients in the "TQD" group were given a TCM formula "tonifying qi and detoxification" and general internal medicine treatment; patients in the "TTK" group were given a TCM formula of "TTK" and general internal medicine treatment. All participants were treated for 8 wk and then followed at 48 wk following their final treatment. The primary efficacy end point was the patient fatality rate in each group. Measurements of various virological and biochemical indicators served as secondary endpoints. The one-way analysis of variance and the t-test were used to compare patient outcomes in the different treatment groups., Results: At the 48-wk post-treatment time point, the patient fatality rates in the MMC, "TQD", and "TTK" groups were 51.61%, 35.38%, and 16.67%, respectively, and the differences between groups were statistically significant (P < 0.05). However, there were no significant differences in the levels of hepatitis B virus DNA or prothrombin activity among the three groups (P > 0.05). Patients in the "TTK" group had significantly higher levels of serum total bilirubin compared to MMC subjects (339.40 μmol/L ± 270.09 μmol/L vs 176.13 μmol/L ± 185.70 μmol/L, P = 0.014). Serum albumin levels were significantly increased in both the "TQD" group and "TTK" group as compared with the MMC group (31.30 g/L ± 4.77 g/L, 30.72 g/L ± 2.89 g/L vs 28.57 g/L ± 4.56 g/L, P < 0.05). There were no significant differences in levels of alanine transaminase among the three groups (P > 0.05). Safety data showed that there was one case of stomachache in the "TQD" group and one case of gastrointestinal side effect in the "TTK" group., Conclusion: Treatment with "TTK" improved the survival rates of patients with liver failure due to chronic hepatitis B. Additionally, liver tissue was regenerated and liver function was restored.

Purpose: We used a rabbit model to evaluate the interface embedded between the recipient corneas and transplanted donor corneal discs after non-Descemet's stripping automated endothelial keratoplasty (nDSAEK)., Methods: Unilateral DSAEK and nDSAEK surgeries were performed on New Zealand white rabbits. In vivo confocal microscopy was performed to show: the changes in corneal endothelial cells embedded between the recipient corneas and the transplanted donor corneal discs (CEEB); and the interface opacity by z profile. Immunohistochemistry were performed to evaluate the functional change of CEEB at post-nDSAEK 3 months. Transmission electron microscopy was performed to evaluate the morphology of CEEB after nDSAEK at post-nDSAEK 1, 3, and 6 months., Results: In vivo confocal microscopy showed a time-dependent decrease in the density of CEEB at postoperative 1, 2, or 3 months (P < 0.01). Interface opacity was higher in the nDSAEK group than the DSAEK group at all examination points, but the difference was statistically insignificant. At 3 months after surgery, the CEEB were negative for Na(+)/K(+)-ATPase staining. Staining with TUNEL showed apoptotic changes in some areas. During a 6-month observation, the CEEB showed a time-dependent thickening and loss of uniform thickness of cellular morphology. At 3 and 6 months post nDSAEK, extensions of the cellular processes into the donor graft stroma combined with intracellular vacuoles containing collagen-like materials were also found., Conclusions: After non-Descemet's stripping automated endothelial keratoplasty, the CEEB showed decreased density, loss of pump function, apoptosis and changed morphology. However, the interface opacity was not significantly greater compared with DSAEK eyes., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

The technology of non-water-soluble mediator anaerobic biological catalysis has attracted more and more attention in the field of environment technology. In this study, five kinds of quinonly compounds were grafted on the chloromethylation polystyrene macromolecular carrier by Friedel-Crafts reaction. Reaction factors of temperature and molar ratio for the 1,4-naphthoquinone grafting carrier were optimized, and the optimal temperature was 78 degreesC while the optimal molar ratio of 1, 4-naphthoquinone and chloromethylation polystyrene was 2: 1. Fourier infrared spectrum analysis confirmed that the quinone groups were successfully grafted on the macromolecular backbone chloromethylation polystyrene. Catalysis using the five kinds of quinonly materials as non-water-soluble redox mediators enhanced the biological denitrification rate and the decoloration of azo dyes, meanwhile these materials showed good reusability in the biodegradation of azo dye. This study developed a new method for the preparation of quinonly materials and revealed a new field in the technology of mediator catalysis.

Due to progress in the research of glioma stem cells and the glioma niche, development of an animal model that facilitates the elucidation of the roles of the host tissue and cells is necessary. The aim of the present study was to develop a subcutaneous xenograft green fluorescent protein nude mouse model and use this model to analyze the roles of host cells in tumor necrosis repair. Tumors derived from the human glioma stem/progenitor cell line SU3 were subcutaneously implanted in green fluorescent protein nude mice. The implanted tumors were then passed from animal to animal for 10 generations. Finally, subcutaneous xenografts were assayed with traditional pathology, immunopathological techniques and fluorescence photography. For each generation, the tumorigenicity rate was 100%. Subcutaneous xenografts were rich in blood vessels, and necrotic and hemorrhagic foci, which highly expressed hypoxia-inducible factor-1α, tumor necrosis factor, Ki-67, CD68 and CD11b. In the interstitial tissue, particularly in old hemorrhagic foci, there were numerous cells expressing green fluorescent protein, CD68 and CD11b. Green fluorescent protein nude mouse subcutaneous xenografts not only consistently maintained the high invasiveness and tumorigenicity of glioma stem/progenitor cells, but also consisted of a high concentration of tumor blood vessels and necrotic and hemorrhagic foci. Subcutaneous xenografts also expressed high levels of tumor microenvironment-related proteins and host-derived tumor interstitial molecules. The model has significant potential for further research on tumor tissue remodeling and the tumor microenvironment.

Objective: To evaluate the clinical characteristics of patients with adrenocorticotropin-independent macronodular adrenal hyperplasia (AIMAH)., Methods: A total of 10 AIMAH cases were enrolled in this retrospective study. The clinical and laboratory findings of all patients were collected and analyzed., Results: All patients manifested some clinical features and biochemical evidence of Cushing's syndrome. The plasma adrenocorticotropic hormone (ACTH) level was undetectable in all the patients and their serum cortisol secretion rhythm was abnormal. Low and high-dose dexamethasone suppression tests failed to suppress the cortisol secretion. The bilateral macronodular adrenal enlargement was shown by CT/magnetic resonance imaging. The supine-upright posture test was positive in four patients. Three patients were performed bilateral adrenalectomy, five were unilateral adrenalectomy and the remaining two patients were taken propranolol. All the patients had followed up for 10 to 89 months. Contralateral adrenalectomy was performed in two patients with recurrent symptoms after unilateral adrenalectomy and two patients given propranolol were underwent bilateral adrenalectomy when their symptoms had not been improved or recurred., Conclusion: AIMAH is a relatively rare subtype of Cushing's syndrome with unique clinical and laboratory findings. Propranolol is a good choice if the supine-upright posture test is positive. Unilateral adrenalectomy appears to be an effective and safe alternative treatment for AIMAH. Bilateral adrenalectomy could be performed if the symptoms have not been improved or recurred after unilateral adrenalectomy.

In this paper, a recording and analysis system is designed and developed for outdoor activity patterns characterization. Some mental problems of aging, especially the occurrence of dementia, are not easily noticed in early stage. In this study, the proposed system is employed for outdoor activity patterns analysis. From the pattern analysis, the abnormal activity which is different from the usual patterns may be differentiated and warned. The proposed system integrates the tablet PC and GPS to track and to detect the occurrence of abnormal condition off-line. In the beginning, the sequence of GPS data is segmented in time frame, and represented in vector form for data reduction. Some filtering technique is also applied for noise reduction.

Objective: During the process of tissue remodeling in human tumor transplantation models, the roles of the inoculated tumor cells and host tissue in tumor progression is still largely unknown. The aim of this study was to investigate the relationships and interactions between these two sides using GFP-RFP double fluorescence tracing technique., Methods: Red fluorescence protein (RFP) gene was stably transfected into glioma stem cell line SU3, then SU3-RFP cells were transplanted into the brain of athymic nude mice with green fluorescence protein (GFP) expression. After the intracerebral tumors were formed, the relationship and interaction between GFP cells and RFP cells were analyzed. Highly proliferative GFP cells were screened out, and monocloned with micro-pipetting. DNA content assay, chromosome banding and carcinogenicity test of the GFP cells were performed to observe the GFP cells' cancerous phenotype in nude mice., Results: In the transplantable tumor tissue, besides a great quantity of RFP cells, there were still a proportion of GFP cells and GFP/RFP fusion cells. The proportion of RFP cells, GFP cells and GFP/RFP cells were (88.99 ± 1.46)%, (5.59 ± 1.00)%, and (4.11 ± 1.020)%, respectively. Two monoclonal host GFP cells (H1 and H9) were cloned, which demonstrated the properties of immortality, loss of contact inhibition, and ultra-tetraploid when cultured in vitro. Both H1 and H9 cells expressed CNP, a specific marker of oligodendrocytes. The GFP cells also demonstrated 100% tumorigenic rate and high invasive properties in vivo., Conclusions: In this glioma transplantation model, the transplanted tumor tissues contained not only transplanted glioma stem cells but also cancerous host GFP cells. Our findings offer important clues to further research on the relationships among different members in the tumor microenvironment.

Objective: To analyze the expression of angiotensin II (ANG II) receptor and apoptosis in myocardium in rats of endotoxemia., Methods: Model of endotoxemia was induced by intraperitoneal injection with lipopolysaccharide (LPS) 10 mg/kg in male Wistar rats and saline was injected into control group. The rats were killed at 2 h or 6 h after saline (control) or LPS . Expression of the correlation factors related to apoptosis of Bcl-2, Bax, AT1 and AT2 receptor in myocardial tissue were detected with immunohistochemistry (IHC), and changes of myocardial cells apoptosis was detected by the method of TUNEL. The gene expression of AT1 and AT2 receptor was examined by RT-PCR. The pathological changes of myocardial tissue were observed by electron microscope., Results: Compared with control group , the expression of AT1 and AT2 receptor were significantly decreased, especially in 6 h group; and the expression of Bcl-2 and Bax were decreased, the ratio of Bcl-2/Bax had the downtrend as well as the apoptosis of myocardial cells., Conclusion: Interfered by LPS, the down regulation of AT1 and AT2 receptor expression has the negative relation with apoptosis of myocardial cells, this result indicated that down regulation of AT1 and AT2 receptor expression maybe related to cardiac functional impairment, which maybe help us to find a new protective path to prevent myocardial damage induced by systemic inflammatory.

Mammalian cells are sensitive to extracellular microenvironments. In order to precisely explore the physiological responses of cells to tensile loading, a stable and well-defined culture condition is required. In this study, a high-throughput perfusion-based microbioreactor platform capable of providing dynamic equibiaxial tensile loading to the cultured cells under a steady culture condition was proposed. The mechanism of generating tensile stimulation to cells is based on the pneumatically-driven deformation of an elastic polydimethylsiloxan (PDMS) membrane which exerts tensile loading to the attached cells. By modulating the magnitude and frequency of the applied pneumatic pressure, various tensile loading can be generated in a controllable manner. In this study, the microbioreactor platform was designed with the aid of the experimentally-validated finite element (FE) analysis to ensure the loading of tensile strain to cells is uniform and definable. Based on this design, the quantitative relationship between the applied pneumatic pressure and the generated tensile strain on the PDMS membrane was established via FE analysis. Results demonstrated that the proposed device was able to generate the tensile strain range (0~0.12), which covers the physiological condition that articular chondrocytes experience tensile strain under human walking condition. In this study, moreover, the effect of tensile loading on the metabolic, biosynthetic and proliferation activities of articular chondrocytes was investigated. Results disclosed that the dynamic tensile loading of 0.12 strain at 1 Hz might significantly up-regulate the synthesis of glycosaminoglycans while such stimulation was found no significant influence on the metabolic activity, the synthesis of collagen, and the proliferation of chondrocytes. Overall, this study has presented a high throughput perfusion micro cell culture device that is suitable for precisely exploring the effect of tensile loading on cell physiology.