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Objective: To present our experience using the supraclavicular artery island flap (SCAIF) for head and neck reconstruction., Methods: We performed a retrospective chart review to identify patients who underwent head and neck reconstruction with SCAIF at our institution. The following data were collected: age, sex, surgical indications, flap harvest time, flap dimensions, length of hospital stay, complications, and clinical outcomes., Results: Thirty-three patients underwent SCAIF reconstruction, of whom four underwent pectoralis major myocutaneous flap reconstruction simultaneously. Twenty flaps were used to repair pharyngeal or esophageal defects following resection for tonsillar, hypopharyngeal, laryngeal, and cervical esophageal cancers. Five flaps were used for tracheal reconstruction following resection for tracheal or thyroid gland cancer. Seven flaps were used for reconstruction of cervical skin defects or fistulas related to a previous treatment. One flap for tracheal stenosis following tracheotomy. The mean age of the patients was 60.69 ± 11.47 years. The mean flap harvest time was 32.00 ± 4.44 min. The mean flap size was 10.16 ± 3.91 × 5.78 ± 0.68 cm. The mean length of hospital stay is 24.84 ± 13.78 days. Three patients had partial necrosis of the distal portion of the flap, which resolved with anti-infection therapy and local wound care. One patient developed a fistula that was resolved with wound care and further surgical intervention. Complete flap loss or major complications were not observed. No donor site complication or compromised shoulder function was observed., Conclusion: The SCAIF can be successfully used to reconstruct head and neck defects with good outcomes and limited morbidity., Level of Evidence: 4., Competing Interests: No conflict of interest exists regarding this manuscript., (© 2024 The Author(s). Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.)

Objective: This study aims to evaluate the accuracy of ChatGPT in answering allergic rhinitis (AR) and chronic rhinosinusitis (CRS) related questions., Study Design: This is a cross-sectional study., Setting: Each question was inputted as a separate, independent prompt., Methods: Responses to AR (n = 189) and CRS (n = 242) related questions, generated by GPT-3.5 and GPT-4, were independently graded for accuracy by 2 senior rhinology professors, with disagreements adjudicated by a third reviewer., Results: Overall, ChatGPT demonstrated a satisfactory performance, accurately answering over 80% of questions across all categories. Specifically, GPT-4.0's accuracy in responding to AR-related questions significantly exceeded that of GPT-3.5, but distinction not evident in CRS-related questions. Patient-originated questions had a significantly higher accuracy compared to doctor-originated questions when utilizing GPT-4.0 to respond to AR-related questions. This discrepancy was not observed with GPT-3.5 or in the context of CRS-related questions. Across different types of content, ChatGPT excelled in covering basic knowledge, prevention, and emotion for AR and CRS. However, it experienced challenges when addressing questions about recent advancements, a trend consistent across both GPT-3.5 and GPT-4.0 iterations. Importantly, the accuracy of responses remained unaffected when questions were posed in Chinese., Conclusion: Our findings suggest ChatGPT's capability to convey accurate information for AR and CRS patients, and offer insights into its performance across various domains, guiding its utilization and improvement., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Nucleic acid amplification testing (NAAT) remains one of the most reliable methods for pathogen identification. However, conventional bulk NAATs may not be sufficiently fast or sensitive enough for the detection of clinically-relevant pathogens in point-of-care testing. Here, we have developed a digital droplet RT-LAMP (ddRT-LAMP) assay that rapidly and quantitatively detects the SARS-CoV-2 viral E gene in microfluidic drops. Droplet partitioning using ddRT-LAMP significantly accelerates detection times across a wide range of template concentrations compared to bulk RT-LAMP assays. We discover that a reduction in droplet diameter decreases assay times up to a certain size, upon which surface adsorption of the RT-LAMP polymerase reduces reaction efficiency. Optimization of drop size and polymerase concentration enables rapid, sensitive, and quantitative detection of the SARS-CoV-2 E gene in only 8 min. These results highlight the potential of ddRT-LAMP assays as an excellent platform for quantitative point-of-care testing., Competing Interests: David A. Weitz is an editor‐in‐chief, and Fangfu Ye an associate editor of Smart Medicine. They were not involved in the editorial review or the decision to publish this article. All authors declare that there are no competing interests., (© 2024 The Author(s). Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

Background: The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib-refractory, anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study., Methods: In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two-sided 95% confidence intervals (CIs). Next-generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management., Results: At the data cut-off date (August 31, 2022), with a median follow-up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3-53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks., Conclusion: Ensartinib led to a favorable OS in patients with advanced, crizotinib-resistant, and ALK-positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification., (© 2024 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat‐sen University Cancer Center.)

Background and Purpose: Paramagnetic rims and the central vein sign (CVS) are proposed imaging markers of multiple sclerosis (MS) lesions. Using 7 tesla magnetic resonance imaging, we aimed to: (1) characterize the appearance of paramagnetic rim lesions (PRLs); (2) assess whether PRLs and the CVS are associated with higher levels of MS pathology; and (3) compare the characteristics between subjects with and without PRLs in early MS., Methods: Prospective study of 32 treatment-naïve subjects around the time of diagnosis who were assessed for the presence of PRLs and the CVS. Comparisons of lesion volume and macromolecular pool size ratio (PSR) index, a proxy of myelin integrity, between PRLs and non-PRLs, and CVS-positive and CVS-negative lesions were carried out. Differences in clinical/demographic characteristics between patients with PRLs and those without were tested., Results: Fifteen subjects had ≥1 PRL for a total of 36 PRLs, of which two-thirds had a full rim. PRLs predicted a larger lesion size and decreased PSR signal. Lesion volume and presence of cervical spine lesions were significantly different between subjects with PRLs and those without, although neither remained significant after adjusting for multiple comparisons. One hundred and eighty-one lesions with CVS were identified with no differences between CVS-positive and CVS-negative lesions in volume (p = .27) and PSR values (p = .62)., Conclusions: PRLs, but not CVS-positive lesions, are larger and have lower myelin integrity. Our findings indicate that PRLs are associated with higher levels of lesion-specific pathology prior to the start of disease-modifying therapy., (© 2023 American Society of Neuroimaging.)

Background: The precise temporal and spatial regulation of N 5 -methylcytosine (m 5 C) RNA modification plays essential roles in RNA metabolism, and is necessary for the maintenance of epigenome homeostasis. Howbeit, the mechanism underlying the m 5 C modification in carcinogenesis remains to be fully addressed., Methods: Global and mRNA m 5 C levels were determined by mRNA isolation and anti-m 5 C dot blot in both retinoblastoma (RB) cells and clinical samples. Orthotopic intraocular xenografts were established to examine the oncogenic behaviours of RB. Genome-wide multiomics analyses were performed to identify the functional target of NSUN2, including proteomic analysis, transcriptome screening and m 5 C-methylated RNA immunoprecipitation sequencing (m 5 C-meRIP-seq). Organoid-based single-cell analysis and gene-correlation analysis were performed to verify the NSUN2/ALYREF/m 5 C-PFAS oncogenic cascade., Results: Herein, we report that NSUN2-mediated m 5 C RNA methylation fuels purine biosynthesis during the oncogenic progression of RB. First, we discovered that global and mRNA m 5 C levels were significantly enriched in RBs compared to normal retinas. In addition, tumour-specific NSUN2 expression was noted in RB samples and cell lines. Therapeutically, targeted correction of NSUN2 exhibited efficient therapeutic efficacy in RB both in vitro and in vivo. Through multiomics analyses, we subsequently identified phosphoribosylformylglycinamidine synthase (PFAS), a vital enzyme in purine biosynthesis, as a downstream candidate target of NSUN2. The reintroduction of PFAS largely reversed the inhibitory phenotypes in NSUN2-deficient RB cells, indicating that PFAS was a functional downstream target of NSUN2. Mechanistically, we found that the m 5 C reader protein ALYREF was responsible for the recognition of the m 5 C modification of PFAS, increasing its expression by enhancing its RNA stability., Conclusions: Conclusively, we initially demonstrated that NSUN2 is necessary for oncogenic gene activation in RB, expanding the current understanding of dynamic m 5 C function during tumour progression. As the NSUN2/ALYREF/m 5 C-PFAS oncogenic cascade is an important RB trigger, our study suggests that a targeted m 5 C reprogramming therapeutic strategy may be a novel and efficient anti-tumour therapy approach., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Nerve injury caused by trauma or iatrogenic trauma can lead to loss of sensory and motor function, resulting in paralysis of patients. Inspired by endogenous bioelectricity and extracellular matrix, various external physical and chemical stimuli have been introduced to treat nerve injury. Benefiting from the self-power feature and great biocompatibility, piezoelectric biomaterials have attracted widespread attention in biomedical applications, especially in neural tissue engineering. Here, we provide an overview of the development of piezoelectric biomaterials for neural tissue engineering. First, several types of piezoelectric biomaterials are introduced, including inorganic piezoelectric nanomaterials, organic piezoelectric polymers, and their derivates. Then, we focus on the in vitro and in vivo external energy-driven piezoelectric effects involving ultrasound, mechanical movement, and other external field-driven piezoelectric effects. Neuroengineering applications of the piezoelectric biomaterials as in vivo grafts for the treatment of central nerve injury and peripheral nerve injury are also discussed and highlighted. Finally, the current challenges and future development of piezoelectric biomaterials for promoting nerve regeneration and treating neurological diseases are presented., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

The lung is the respiratory organ of the human body, and the alveoli are the most basic functional units of the lung. Herein, a photo-responsive stretchable Janus membrane was proposed for the reconstruction of the alveolar-capillary barrier in vitro. This Janus membrane was fabricated by photocrosslinking methylacrylamide gelatin (Gelma) hydrogel and N-isoacrylamide (NIPAM) hydrogel mixed with graphene oxide (GO). The Gelma hydrogel containing large amounts of collagen provides a natural extracellular matrix environment for cell growth, while the temperature-sensitive NIPAM hydrogel combined with GO gives the membrane a light-controlled stretching property. Based on this Janus membrane, an open polydimethylsiloxane chip was established to coculture alveolar epithelial cells and vascular endothelial cells at the air-liquid interface. It was demonstrated that the alveolar epithelial cells cultured on the upper side of the Janus membrane could express epithelial cell marker protein E-cadherin and secrete alveolar surfactant. In addition, VE-cadherin, an endothelium-specific protein located at the junction between endothelial cells, was also detected in vascular endothelial cells cultured on the underside of Janus membrane. The constructed lung tissue model with the dynamically stretchable Janus membrane is well-suited for COVID-19 infection studies and drug testing., Competing Interests: The authors declare no conflict of interest. Fangfu Ye is a member of the Smart Medicine editorial board., (© 2023 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

Osteoarthritis (OA) is a common disease that endangers millions of middle-aged and elderly people worldwide. Researchers from different fields have made great efforts and achieved remarkable progress in the pathogenesis and treatment of OA. However, there is still no cure for OA. In this review, we discuss the pathogenesis of OA and summarize the current clinical therapies. Moreover, we introduce various natural and synthetic biomaterials for drug release, cartilage transplantation, and joint lubricant during the OA treatment. We also present our perspectives and insights on OA treatment in the future. We hope that this review will foster communication and collaboration among biological, clinical, and biomaterial researchers, paving the way for OA therapeutic breakthroughs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Fangfu Ye is a member of the Smart Medicine editorial board., (© 2022 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

The monitoring of mechanical indexes involved in body movement has attracted immense interest in the diagnosis of neurodegenerative diseases. Here, we present a hybrid flexible conductive structural color (SC) film with the capability of dual-signal mechanics screening. The film is constructed by oxidatively polymerizing pyrrole on the surface of an inverse opal polyurethane (IPU) membrane, which can be utilized to measure the mechanical indexes through resistance change. Owing to the inverse opal structure, the film shows visual structural color change when stretched and released according to the body movement. Additionally, the highly uniform ordered porous structure endows the conductive film with a lower coefficient of variance on relative resistance change. Benefiting from these features, we have demonstrated that such a flexible conductive SC film could monitor Parkinson's disease (PD) by detecting mechanical indexes simultaneously via dual signals. These features indicate the great value of the stretchable conductive SC films in mechanics sensing applications., Competing Interests: The authors declare no conflict of interest. Fangfu Ye is a member of the Smart Medicine editorial board., (© 2022 The Authors. Smart Medicine published by Wiley‐VCH GmbH on behalf of Wenzhou Institute, University of Chinese Academy of Sciences.)

Background: Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC., Methods: ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m 2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety., Results: Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001)，for sintilimab treatment., Conclusions: Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC., (© 2022 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Objective: Evidence proves that integrins affect almost every step of hepatocellular carcinoma (HCC) progression. The current study aimed at constructing an integrin-based signature for prognostic prediction of HCC., Methods: TCGA-LIHC and ICGC-LIRI-JP cohorts were retrospectively analyzed. Integrin genes were analyzed via univariate Cox regression, followed by generation of a prognostic signature with LASSO approach. Independent factors were input into the nomogram. WGCNA was adopted to select this signature-specific genes. Gene Ontology (GO) enrichment together with Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were conducted to explore the function of the dysregulated genes. The abundance of tumor microenvironment components was estimated with diverse popular computational methods. The relative importance of genes from this signature was estimated through random-forest method., Results: Eight integrin genes (ADAM15, CDC42, DAB2, ITGB1BP1, ITGB5, KIF14, LIMS2, and SELP) were adopted to define an integrin-based signature. Each patient was assigned the riskScore. High-riskScore subpopulation exhibited worse overall survival, with satisfying prediction efficacy. Also, the integrin-based signature was independent of routine clinicopathological parameters. The nomogram (comprising integrin-based signature, and stage) accurately inferred prognostic outcome, with the excellent net benefit. Genes with the strongest positive interaction to low-riskScore were primarily linked to biosynthetic, metabolic, and catabolic processes and immune pathways; those with the strongest association with high-riskScore were principally associated with diverse tumorigenic signaling. The integrin-based signature was strongly linked with tumor microenvironment components. Among the genes from this signature, LIMS2 possessed the highest importance, and its expression was proven through immunohistochemical staining., Conclusion: Altogether, our study defined a quantitative integrin-based signature that reliably assessed HCC prognosis and tumor microenvironment features, which possessed the potential as a tool for prognostic prediction., Competing Interests: The authors declared no conflicts of interest., (Copyright © 2022 Fengning Ye et al.)

Objective: Acute coronary syndrome (ACS) is the most dangerous and deadly form of coronary heart disease. Herein, we aimed to explore ACS-specific circulating lncRNAs and their regulatory mechanisms., Methods: This study collected serum samples from ACS patients and healthy controls for microarray analysis. Dysregulated circulating lncRNAs and mRNAs were determined with |log2fold - change| > 1 and p < 0.05. lncRNA-mRNA coexpression analysis was carried out. ENST00000538705.1 and ALOX15 expression was further verified in serum specimens. In human coronary artery endothelial cells (HCAECs), ENST00000538705.1 and ALOX15 were knocked out through transfecting specific siRNAs. Thereafter, proliferation and migration were investigated with CCK-8 and wound-healing assays. Myocardial infarction rat models were established and administrated with siRNAs against ENST00000538705.1 or ALOX15. Myocardial damage was investigated with H&E staining, and serum TC, LDL, and HDL levels were measured., Results: Microarray analysis identified 353 dysregulated circulating lncRNAs and 441 dysregulated circulating mRNAs in ACS. Coexpression analysis indicated the interaction between ENST00000538705.1 and ALOX15. RT-qPCR confirmed the remarkable upregulation of circulating ENST00000538705.1 and ALOX15 in ACS patients. In HCAECs, ENST00000538705.1 knockdown lowered the expression of ALOX15 but ALOX15 did not alter the expression of ENST00000538705.1. Silencing ENST00000538705.1 or ALOX15 weakened the proliferation and migration of HCAECs. Additionally, knockdown of ENST00000538705.1 or ALOX15 relieved myocardial damage, decreased serum TC and LDL levels, and elevated HDL levels in myocardial infarction rats., Conclusion: Collectively, our findings demonstrate that circulating ENST00000538705.1 facilitates ACS progression through modulating ALOX15, which provide potential targets for ACS treatment., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Hao Chen et al.)

Background: To detect the expression of histone methyltransferase SETDB1 in hepatocellular carcinoma, and to analyze the relationship between SETDB1 expression and tumor size, microvascular invasion, pTNM stage, gender, age, tumor number, tumor differentiation, and other clinicopathological characteristics., Methods: Immunohistochemical method was used to detect the expression of SETDB1 proteins in liver cancer tissues and adjacent tissues of 100 cases. The qRT-PCR method was used to detect the expression of SETDB1 mRNA in hepatocellular carcinoma and adjacent tissues of 64 cases., Results: The expression of SETDB1 protein and mRNA in hepatocellular carcinoma was higher than that of adjacent normal liver tissue (p < 0.05). High protein expression of SETDB1 was associated with tumor size, MVI presence, and pTNM stage (p < 0.05). Univariate analysis revealed that the tumor size, tumor differentiation, MVI grade, and pTNM stage were correlated with DFS, while tumor size, MVI grade, pTNM stage, and SETDB1 protein expression were correlated with OS. Multivariate analysis showed that the combination of MVI grade and pTNM stage has statistical significance in predicting prognosis, while SETDB1 protein expression was not significant prognosis factor., Conclusions: SETDB1 has a certain role in HCC progression and may act as a prognostic predictor concerning the survival of HCC patients., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Recently, several studies have reported an association between lipid profiles and sudden sensorineural hearing loss (SSNHL), yet there is considerable variability between the individual studies in defining the precise association between serum lipids levels and SSNHL. This study sought to identify a possible relationship between dyslipidemia and the prevalence and prognosis of SSNHL., Methods: A case-control study was carried out at two independent medical centers, including 2,288 SSNHL patients and 2,288 healthy controls. Clinical characteristics and serum lipid parameters were assessed, including total cholesterol (CHOL), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (Trig), apolipoprotein AI (ApoAI), apolipoprotein B (ApoB), and lipoprotein a (Lpa). Multivariate logistic regression analysis was performed to assess the relationship between lipid profiles and SSNHL in the 4,576 subjects., Results: Significant differences were identified in several conventional serum lipid markers including CHOL, Trig, HDL, LDL, ApoAI, ApoB, and Lpa, between SSNHL patients and healthy controls. Serum ApoAI levels were significantly lower in patients with bilateral SSNHL compared to unilateral SSNHL. Binary logistic regression analysis revealed that higher levels of ApoB, LDL, Trig, and lower levels of ApoAI and HDL were all associated with an increased risk of SSNHL. After clinical characterization, multivariate analysis showed that only low levels of ApoB predicted likelihood of a recovery of more than 30 dB among patients with SSNHL., Conclusions: Serum lipids are associated with the incidence and prognosis of SSNHL. Identification of dyslipidemia may improve early evaluation and management of SSNHL risks., (© 2021 The Authors. Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: To date, there is no approved blood-based biomarker for breast cancer detection. Herein, we aimed to assess semaphorin 4C (SEMA4C), a pivotal protein involved in breast cancer progression, as a serum diagnostic biomarker., Methods: We included 6,213 consecutive inpatients from Tongji Hospital, Qilu Hospital, and Hubei Cancer Hospital. Training cohort and two validation cohorts were introduced for diagnostic exploration and validation. A pan-cancer cohort was used to independently explore the diagnostic potential of SEMA4C among solid tumors. Breast cancer patients who underwent mass excision prior to modified radical mastectomy were also analyzed. We hypothesized that increased pre-treatment serum SEMA4C levels, measured using optimized in-house enzyme-linked immunosorbent assay kits, could detect breast cancer. The endpoints were diagnostic performance, including area under the receiver operating characteristic curve (AUC), sensitivity, and specificity. Post-surgery pathological diagnosis was the reference standard and breast cancer staging followed the TNM classification. There was no restriction on disease stage for eligibilities., Results: We included 2667 inpatients with breast lesions, 2378 patients with other solid tumors, and 1168 healthy participants. Specifically, 118 patients with breast cancer were diagnosed with stage 0 (5.71%), 620 with stage I (30.00%), 966 with stage II (46.73%), 217 with stage III (10.50%), and 8 with stage IV (0.39%). Patients with breast cancer had significantly higher serum SEMA4C levels than benign breast tumor patients and normal controls (P < 0.001). Elevated serum SEMA4C levels had AUC of 0.920 (95% confidence interval [CI]: 0.900-0.941) and 0.932 (95%CI: 0.911-0.953) for breast cancer detection in the two validation cohorts. The AUCs for detecting early-stage breast cancer (n = 366) and ductal carcinoma in situ (n = 85) were 0.931 (95%CI: 0.916-0.946) and 0.879 (95%CI: 0.832-0.925), respectively. Serum SEMA4C levels significantly decreased after surgery, and the reduction was more striking after modified radical mastectomy, compared with mass excision (P < 0.001). The positive rate of enhanced serum SEMA4C levels was 84.77% for breast cancer and below 20.75% for the other 14 solid tumors., Conclusions: Serum SEMA4C demonstrated promising potential as a candidate biomarker for breast cancer diagnosis. However, validation in prospective settings and by other study groups is warranted., (© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Background: Previous studies have demonstrated the preclinical pharmacological and toxicological consistency, and clinical pharmacokinetic equivalence of bevacizumab biosimilar LY01008 with reference bevacizumab (Avastin). This randomized controlled trial aimed to compare the efficacy and safety of LY01008 with Avastin in first-line treatment of Chinese patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC)., Methods: Stage IIIB-IV NSCLC patients with evaluable lesions, good physical status, and adequate organ functions from 67 centers across China were randomized in a ratio of 1:1 to receive LY01008 or Avastin 15 mg/kg intravenously in combination with paclitaxel/carboplatin (combined treatment) for 4-6 cycles, followed by maintenance monotherapy with LY01008 until disease progression, intolerable toxicity, or death. The primary endpoint was objective response rate (ORR) in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 confirmed by independent radiological review committees (IRRC). Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. This study was registered in ClinicalTrials.gov (NCT03533127)., Results: Between December 15 th , 2017, and May 15 th , 2019, a total of 649 patients were randomized to the LY01008 (n = 324) or Avastin (n = 325) group. As of September 25 th , 2019 for primary endpoint analysis, 589 patients received ORR evaluation, with a median number of combined treatment cycles of 5 (range 1-6) and median duration of treatment of 3.0 (range 0.0-5.1) months. ORR of response-evaluable patients in the LY01008 and Avastin groups were 48.5% and 53.0%, respectively. The stratified ORR ratio was 0.91 (90% CI 0.80-1.04, within the prespecified equivalence margin of 0.75-1.33). Up to May 15 th , 2020, with a median follow-up of 13.6 (range 0.8-28.4) months, no notable differences in DCR, median DoR, median PFS, median OS, and 1-year OS rate were observed between the LY01008 and Avastin groups. There were no clinically meaningful differences in safety and immunogenicity across treatment groups., Conclusions: LY01008 demonstrated similarity to Avastin in terms of efficacy and safety in Chinese patients with advanced or recurrent non-squamous NSCLC. LY01008 combined with paclitaxel/carboplatin is expected to become a new treatment option for unresectable, metastatic, or recurrent non-squamous NSCLC patients in the first-line setting., (© 2021 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

This study was conducted to verify the relative expression patterns of SHOX2 and its regulation by tumor necrosis factor alpha (TNF-α) during the development of intervertebral disc degeneration (IVDD). A rat disc-degeneration model was subjected to disc puncture (DP) and intradiscal injections with TNF-α to determine the roles of TNF-α and SHOX2 expression in IVDD in vivo. TNF-α and SHOX2 expression patterns in different degenerative rat nucleus pulposus (NP) tissues were measured by immunohistochemistry (IHC). The effects of TNF-α on IVDD were determined by magnetic resonance imaging (MRI) and pain development of wet-dog shakes (WDS) were blinded assessment by pain-behavior testing, respectively. Changes in TNF-α on SHOX2 expression were measured by Western blot analysis and real-time reverse transcription polymerase chain reaction (RT-PCR). The roles of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK) in TNF-α-mediated SHOX2 activation were studied using viral transfection, Western blot analysis, and real-time RT-PCR. In vivo, TNF-α accelerated the process of IVDD and suppressed SHOX2 expression; compared to the DP group, WDS was significantly increased in TNF-α intradiscal injection group at 2 to 6 weeks after puncture (P < .05); In NP cells, TNF-α negatively affected the IVDD-associated SHOX2 suppression. While TNF-α promotes IVDD through activation of both MAPK and NF-κB signaling, it seemed that only NF-κB signaling controlled the TNF-α-mediated SHOX2 suppression that is associated with IVDD. The results of this study indicated that TNF-α inhibits SHOX2 expression and has promoted effects on IVDD in the rat model, and these effects might be associated with through NF-κB signaling pathway and promotes IVDD and related pain in a rat model., (© 2020 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Pituitary adenoma (PA) is a benign intracranial neoplasm originated from pituitary gland. Surgery is the first-line therapy for most of PAs, but lead to unsatisfactory prognosis in some cases. Tetrandrine (Tet) has anticancer effect on some cancers. However, growth inhibition effect on PA is unknown. To elucidate the inhibitory effect of Tet on the growth of PA and its potential mechanisms, we validated the in vitro and in vivo anti-PA effect of Tet and illustrated the cellular and molecular alterations by confocal microscopy observation, flow cytometry, and RNA interference. Tet inhibited PA cell growth in vitro and tumor progression in vivo. Tet induced autophagy and apoptosis in a dose-dependent manner. Low dosage (1.25 μM) of Tet induced PA cell autophagy by down-regulation of MAPK/STAT3 signal. While, higher dosage (5.0 μM) of Tet partially induced PA cell death through caspase-dependent apoptosis. Autophagy inhibitors enhanced Tet-induced caspase activity and apoptotic cell death. These findings demonstrated that Tet has anti-PA effect by inducing autophagy and apoptosis through MAPK/STAT3 signaling pathway attenuation and autophagy inhibition might enhance its anti-PA effect, indicating that Tet (or combined with autophagy inhibitor) is a potential therapeutic regimen for PAs., (© 2021 John Wiley & Sons Ltd.)

Background: Robust and reliable prognosis prediction models have not been developed and validated for Asian patients with breast cancer, a rapidly growing yet understudied population in the United States., Methods: We used longitudinal data from the Shanghai Breast Cancer Survival Study, a population-based prospective cohort study (n = 5042), to develop prediction models for 5- and 10-year disease-free survival (DFS) and overall survival (OS). The initial models considered age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, and estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status. We then evaluated whether the addition of modifiable lifestyle factors (physical activity, soy isoflavones intake, and postdiagnostic weight change) improved the models. All final models have been validated internally and externally in the National Cancer Database when applicable., Results: Our final models included age at diagnosis, tumor grade, tumor size, number of positive nodes, TNM stage, chemotherapy, tamoxifen therapy, ER status, PR status, 6-month postdiagnostic weight change, interaction between ER status and tamoxifen therapy, and interaction between age and TNM stage. The internal validation yielded C-statistics of 0.76, 0.74, 0.78, and 0.75 for 5-year DFS, 10-year DFS, 5-year OS, and 10-year OS, respectively. The external validation yielded C-statistics of 5- and 10-year OS both at 0.78 for Chinese ethnicity, 0.79 for East Asian ethnicity, and 0.75 and 0.76 for all ethnic groups combined., Conclusion: We developed prediction models for breast cancer prognosis from a large prospective study. Our prognostic models performed very well in women from the United States-particularly in Asian American women-and demonstrated high prediction accuracy and generalizability., (© 2021 American Cancer Society.)

Objective: This study is aimed at investigating the therapeutic effects of tetrandrine (Tet) on myocardial ischemia reperfusion (I/R) injury and probe into underlying molecular mechanism., Methods: H9C2 cells were divided into hypoxia/oxygenation (H/R) group, H/R+Tet group, H/R+Tet+negative control (NC) group, and H/R+Tet+miR-202-5p inhibitor group. RT-qPCR was utilized to monitor miR-202-5p and TRPV2 expression, and TRPV2 protein expression was detected via western blot and immunohistochemistry in H9C2 cells. Cardiomyocyte apoptosis was evaluated through detection of apoptosis-related markers and flow cytometry. Furthermore, myocardial enzyme levels were detected by ELISA. Rats were randomly separated into sham operation group, I/R group, I/R+Tet group (50 mg/kg), I/R+Tet+NC group, and I/R+Tet+miR-202-5p inhibitor group. miR-202-5p and TRPV2 mRNA expression was assessed by RT-qPCR. TRPV2 protein expression was detected through western blot and immunohistochemistry in myocardial tissues. Apoptotic levels were assessed via apoptosis-related proteins and TUNEL. Pathological changes were observed by H&E staining. Myocardial infarction size was examined by Evans blue-TCC staining., Results: Abnormally expressed miR-202-5p as well as TRPV2 was found in H/R H9C2 cells and myocardial tissues of I/R rats, which was ameliorated following Tet treatment. Tet treatment significantly suppressed H/R- or I/R-induced cardiomyocyte apoptosis. ELISA results showed that CK-MB and LDH levels were lowered by Tet treatment in H/R H9C2 cells and serum of I/R rats. H&E staining indicated that Tet reduced myocardial injury in I/R rats. Also, myocardial infarction size was lowered by Tet treatment. The treatment effects of Tet were altered following cotreatment with miR-202-5p inhibitor., Conclusion: Our findings revealed that Tet may ameliorate myocardial I/R damage via targeting the miR-202-5p/TRPV2 axis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wei Zhao et al.)

Nitrogen mustard (NM) causes severe skin injury with an obvious inflammatory response, which is lack of effective and targeted therapies. Vitamin D3 (VD3) has excellent anti-inflammatory properties and is considered as a potential candidate for the treatment of NM-induced dermal toxicity; however, the underlying mechanisms are currently unclear. Cyclooxygenase-2 (COX2; a widely used marker of skin inflammation) plays a key role in NM-induced cutaneous inflammation. Herein, we initially confirmed that NM markedly promoted COX2 expression in vitro and in vivo. NM also increased NOD-like receptor family pyrin domain containing 3 (NLRP3) expression, caspase-1 activity, and interleukin-1β (IL-1β) release. Notably, treatment with a caspase-1 inhibitor (zYVAD-fmk), NLRP3 inhibitor (MCC950), and NLRP3 or caspase-1 siRNA attenuated NM-induced NLRP3 inflammasome activation, with subsequent suppression of COX2 expression and IL-1β release in keratinocytes. Meanwhile, NM increased mitochondrial reactive oxygen species (mtROS) and decreased manganese superoxide dismutase 2 (SOD2) and sirtuin 3 (SIRT3) activities. Mito-TEMPO (a mtROS scavenger) ameliorated NM-caused NLRP3 inflammasome activation in keratinocytes. Moreover, VD3 improved SIRT3 and SOD2 activities, decreased mtROS contents, inactivated the NLRP3 inflammasome, and attenuated cutaneous inflammation induced by NM in vitro and in vivo. The beneficial activity of VD3 against NM-triggered cutaneous inflammation was enhanced by the inhibitors of IL-1, mtROS, NLRP3, caspase-1, and NLRP3 or caspase-1 siRNAs, which was abolished in SIRT3 inhibitor or SIRT3 siRNA-treated keratinocytes and skins from SIRT3 -/- mice. In conclusion, VD3 ameliorated NM-induced cutaneous inflammation by inactivating the NLRP3 inflammasome, which was partially mediated through the SIRT3-SOD2-mtROS signaling pathway., (© 2021 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

To inform seroepidemiological studies, we characterized the IgG- responses in COVID-19 patients against the two major SARS-CoV-2 viral proteins, spike (S) and nucleocapsid (N). We tested 70 COVID-19 sera collected up to 85 days post-symptom onset and 230 non-COVID-19 sera, including 27 SARS sera from 2003. Although the average SARS-CoV-2 S and N-IgG titers were comparable, N-responses were more variable among individuals. S- and N-assay specificity tested with non-COVID-19 sera were comparable at 97.5% and 97.0%, respectively. Therefore, S will make a better target due to its lower cross-reactive potential and its' more consistent frequency of detection compared to N., (© 2020 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Pulmonary hypertension (PH) related to old anterior myocardial infarction (OAMI) always accompanies a bad prognosis, and thus, we aimed to screen serum biomarkers related to PH in OAMI patients. According to right ventricular systolic pressure, we divided mice into sham, OAMI, and PH-OAMI groups and evaluated body, heart and lung weight, heart function, pulmonary blood flow velocity, cardiac fibrotic area, and pulmonary arteriole condition. Lung and serum were under the proteomic analysis. Levels of three identified proteins were measured. Compared with sham and OAMI mice, PH-OAMI mice showed heart dysfunction, low pulmonary blood flow, high right ventricular systolic pressure, heavy heart and lung weight, large cardiac fibrotic area, and pathological pulmonary arteriole remodeling ( P <0.05 or P <0.01). Haptoglobin, annexin A5, and Ig mu chain C region of lung and serum were changed significantly in PH-OAMI mice ( P <0.01). Then, we collected serum and clinical data, measured three serum protein levels, and performed multivariate regression and receiver operating characteristic curve in patients (normal, OAMI, and PH-OAMI groups). Compared with normal and OAMI patients, serum levels of three proteins in PH-OAMI patients were also altered notably ( P <0.01). These three proteins can predict PH in OAMI patients ( P <0.01). Receiver operating characteristic curve analysis revealed haptoglobin (cut-off value: 78.295, sensitivity: 62.8%, specificity: 94.4%), annexin A5 (cut-off value: 151.925, sensitivity: 41.9%, specificity: 82.4%), and Ig mu chain C region (cut-off value: 168.885, sensitivity: 86.0%, specificity: 79.6%) ( P <0.01). Three circulating serum proteins can be useful for the categorization of OAMI patients with and without PH., (© The Author(s) 2020.)

Background: Severe COVID-19 patients typically test positive for SARS-CoV-2 RNA for extended periods of time, even after recovery from severe disease. Due to the timeframe involved, these patients may have developed humoral immunity to SARS-CoV-2 while still testing positive for viral RNA in swabs. Data are lacking on exposure risks in these situations. Here, we studied SARS-CoV-2 environmental contamination in an ICU and an isolation ward caring for such COVID-19 patients., Methods: We collected air and surface samples in a hospital caring for critical and severe COVID-19 cases from common areas and areas proximal to patients., Results: Of the 218 ICU samples, an air sample contained SARS-CoV-2 RNA. Of the 182 isolation ward samples, nine contained SARS-CoV-2 RNA. These were collected from a facemask, the floor, mobile phones, and the air in the patient room and bathroom. Serum antibodies against SARS-CoV-2 were detected in these patients at the beginning of the study., Conclusions: While there is a perception of increased risk in the ICU, our study demonstrates that isolation wards may pose greater risks to healthcare workers and exposure risks remain with clinically improved patients, weeks after their initial diagnoses. As these patients had serum antibodies, further studies may be warranted to study the utility of serum antibodies as a surrogate of viral clearance in allowing people to return to work. We recommend continued vigilance even with patients who appear to have recovered from COVID-19., (© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Iron overload has been implicated in the pathogenesis of varicose veins (VVs). However, the association of serum iron status with other vascular diseases (VDs) is not well understood, which might be a potential target for VD prevention. This study was aimed at investigating the causal associations between iron status and VDs using the Mendelian randomization (MR) method., Methods: A two-sample MR was designed to investigate whether iron status was associated with VDs, based on iron data from a published genome-wide association study meta-analysis of 48,972 subjects of European descent and VD data obtained from the UK Biobank, including 361,194 British subjects (167,020 males and 194,174 females). We further explored whether there was sex difference in the associations between genetically predicted iron status and VDs., Results: The results demonstrated that iron status had a significant causal effect on VVs of lower extremities ( P < 0.001) and a potential effect on coronary atherosclerosis ( P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively), but not on other VDs. Furthermore, higher iron status exerted a detrimental effect on VVs of lower extremities in both genders ( P < 0.05) and a protective effect on male patients with coronary atherosclerosis ( P < 0.05 for serum iron, ferritin, and transferrin saturation, respectively)., Conclusions: This MR study provides robust evidence that higher iron status increases the risk of VVs of lower extremities, whereas it reduces the incidence of coronary atherosclerosis in the male population, which indicates that iron has divergent effects on vascular pathology., Competing Interests: The authors have declared that no conflicts of interests exist., (Copyright © 2020 Fangkun Yang et al.)

This study is aimed at identifying potential molecular mechanisms and candidate biomarkers in the left atrial regions for the diagnosis and treatment of valvular atrial fibrillation (VAF). Multibioinformatics methods, including linear models for microarray analysis (LIMMA), an SVA algorithm, CIBERSORT immune infiltration, and DNA methylation analysis, were employed. In addition, the protein-protein interaction (PPI) network, Gene Ontology (GO), and molecular pathways of differentially expressed genes (DEGs) or differential methylation regions were constructed. In all, compared with the normal rhythm group, 243 different mRNAs (29 downregulated and 214 upregulated) and 26 different lncRNAs (3 downregulated and 23 upregulated) were detected in the left atrium (LA) of atrial fibrillation (AF) patients, and the neutrophil and CD8 + T cell were infiltrated. Additionally, 199 different methylation sites (107 downregulated and 92 upregulated) were also identified based on DNA methylation analysis. After integration, ELOVL2, CCR2, and WEE1 were detected for differentially methylated and differentially transcribed genes. Among them, WEE1 was also a core gene identified by the competing endogenous RNA (ceRNA) network that included WEE1-KRBOX1-AS1-hsa-miR-17-5p, in VAF left atrial tissue. We combined the DNA methylation and transcriptional expression differential analysis and found that WEE1 (cg13365543) may well be a candidate gene regulated by DNA methylation modification. Moreover, KRBOX1-AS1 and WEE1 can compete endogenously and may mediate myocardial tissue infiltration into CD8 + T cells and participate in the AF process., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2020 Jiafeng Wu et al.)

Background: Greater than one-half of patients with melanoma who are treated with antibodies blocking programmed cell death protein 1 receptor (anti-PD-1) experience disease progression. The objective of the current study was to identify prognostic factors and outcomes in patients with metastatic melanoma that progressed while they were receiving anti-PD-1 therapy., Methods: The authors evaluated 383 consecutively treated patients who received anti-PD-1 for advanced melanoma between 2009 and 2019. Patient and disease characteristics at baseline and at the time of progression, subsequent therapies, objective response rate (ORR), overall survival, and progression-free survival were assessed., Results: Of 383 patients, 247 experienced disease progression. The median survival after progression was 6.8 months. There was no difference in survival noted after disease progression based on primary tumor subtype, receipt of prior therapy, or therapy type. However, significantly improved survival after disease progression correlated with clinical features at the time of progression, including normal lactate dehydrogenase, more favorable metastatic stage (American Joint Committee on Cancer eighth edition stage IV M1a vs M1b, M1c, or M1d), mutation status (NRAS or treatment-naive BRAF V600 vs BRAF/NRAS wild-type or treatment-experienced BRAF-mutant), decreasing tumor bulk, and progression at solely existing lesions. After progression, approximately 54.3% of patients received additional systemic therapy. A total of 41 patients received BRAF/MEK inhibition (ORR of 58.6%, including 70.4% for BRAF/MEK-naive patients), 30 patients received ipilimumab (ORR of 0%), and 11 patients received ipilimumab plus nivolumab (ORR of 27.3%)., Conclusions: The current study identified prognostic factors in advanced melanoma for patients who experienced disease progression while receiving anti-PD-1, including lactate dehydrogenase, stage of disease, site of disease progression, tumor size, and mutation status., (© 2020 American Cancer Society.)

Cisplatin is widely used in the treatment of tongue squamous cell carcinoma (TSCC), but its clinical efficacy is limited by drug resistance and toxic side effects. Hence, a novel compound capable of enhancing the anticancer effect of cisplatin while reducing the side effects is urgently needed. We have previously shown that plumbagin (PLB), an anticancer phytochemical, is able to inhibit the growth of TSCC in vitro and in vivo . The objective of this study was to investigate the effect of PLB in reversing the resistance of TSCC to cisplatin as well as its molecular mechanisms. Here, we found that PLB enhances cisplatin-induced cytotoxicity, apoptosis, and autophagy in CAL27 and cisplatin-resistant CAL27/CDDP cells. PLB could inhibit the viability and growth of TSCC cells by increasing the production of intracellular reactive oxygen species (ROS). In addition, the combination treatment of PLB and cisplatin resulted in a synergistic inhibition of TSCC viability, apoptosis, and autophagy by increasing intracellular ROS, which may be achieved by activating JNK and inhibiting AKT/mTOR signaling pathways. Finally, the synergistic treatment was also demonstrated in vivo . Therefore, PLB combined with cisplatin is a potential therapeutic strategy against therapy TSCC cisplatin resistance., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 Danfeng Xue et al.)

Background: Reports showed no change of 7-day mortality after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) between 2001 and 2011 in China. National rolling one-year interventional standardized training programme began in September 2009. However, the improvement in clinical outcome following STEMI PCI after 2011 remains unclear., Methods and Results: This multicentre MOODY registry study aimed to analyse the clinical improvement after STEMI PCI. Of a total of 9265 acute MI patients registered from 24 centres, 3142 STEMIs having a first medical contact time ≤12 hours and undergoing primary PCI were assigned to the Pre Group (n = 1014, between March 1999 and October 2010) or the Post Group (n = 2128, between 2010 November and 2016 October). The primary endpoint was in-hospital cardiac death. Study endpoints were also compared between trained and untrained operators and between experienced (≥50 primary PCIs/year) and inexperienced personnel. In-hospital death after PCI was 3.0% in the Pre Group, significantly higher than 1.6% in the Post Group (P = .035). The improvements in clinical outcome after PCI between the 2016 and Pre Groups were stably sustained through one-year follow-up. The significant reduction for in-hospital death was noted when primary PCI was performed by trained (1.4% vs 5.4%, P < .001) or experienced (2.7% vs 4.8%, P = .001) operators, compared to untrained or inexperienced operators, respectively. Inclusion of the untrained operator into the conventional risk model strongly enhanced the prediction for endpoints. Age, Killip Class 3, diabetes, trans-radial approach and system delay were five predictors of in-hospital death after primary PCI., Conclusion: PCI for STEMI by a trained and experienced operator was associated with significant reduction of in-hospital death. Our results strongly warrant the need for promoting the current system response and patient education., (© 2020 Stichting European Society for Clinical Investigation Journal Foundation.)

Background: In situ vaccination-induced local inflammatory response resulted in the establishment of a pool of tissue-resident memory T (T RM ) cells and new vessels after the resolution of inflammation. T RM cells have received increasing attention; however, the role of new vessels in protective response is still unknown., Materials and Methods: We performed the laparotomy to access the stomach and injected alum-based vaccine into the gastric subserous layer (GSL). At 28 days post vaccination, a parabiosis mouse model along with depletion of anti-CD90.2 antibody was employed to explore the function of perivascular lymphocyte clusters in recall responses. The composition of the gastric lymphocyte clusters was analyzed by immunofluorescence staining. Antibody responses were detected using ELISA. Gastric lymphocytes were analyzed using flow cytometry., Results: GSL vaccination induced the formation of new vessels in the inflamed region. These new vessels were different from native vessels in that they were generally accompanied by perivascular lymphocyte clusters that mainly consisted of CD90-expressing cells. Additionally, histological analysis revealed the presence of CD4 + and CD8 + T cells in the perivascular lymphocyte clusters. Administration of a dose of an anti-CD90.2 antibody to GSL-vaccinated mice resolved these clusters. The efficacy of protection was compared in the parabiosis mice. Upon challenge, the presence of perivascular lymphocyte clusters was responsible for the fast recall response, as depletion of these clusters by CD90.2 antibody administration resulted in decreased expressions of VCAM-1, Madcam-1, and TNF- α , as well as lower recruitment of proinflammatory immune cells, decreased antibody levels, and poor protection., Conclusions: Our research demonstrates that in situ vaccination-induced regional inflammatory response contributes to optimal recall response not only by establishing a CD4 + T RM pool but also by creating an "expressway," i.e., perivascular lymphocyte cluster., Competing Interests: The authors declare that they have no conflict of interest in this paper., (Copyright © 2020 Chupeng Hu et al.)

Instruction: Several factors affect the in-stent intimal healing process after drug-eluting stents (DESs) implantation. We hope to investigate the influence of plaque characteristics on subsequent heterogeneous neointimal hyperplasia (NIH) using optical coherence tomography (OCT)., Methods: The study population consisted 217 patients with single-vessel de novo lesions who underwent both pre-procedural OCT scan and 12-month follow-up OCT examination. NIH is defined as at least five consecutive cross-sectional images with no less than 100µm neointimal thickness. According to OCT follow-up, patients were divided into three groups: neointima-covered group, homogeneous, and heterogeneous NIH group., Results: 102 patients were categorized in neointima-covered group, 91 and 24 patients in homogeneous and heterogeneous group, respectively. Time interval between OCT scans was similar (P = 0.55). No significant differences in the patients' age, gender, comorbidities, laboratory findings, procedural, and lesion-related findings were found among these three groups. Heterogeneous group tended to have more subjects presented as acute coronary syndrome (ACS) (P = 0.04) and mean macrophage grade was higher in this group (P = 0.01). While no statistically significant difference concerning mean intimal thickness (P = 0.21) or neointimal burden (P = 0.73) was found between homogeneous and heterogeneous group. Multivariate logistic regression analysis showed that mean macrophage grade (OR: 2.26, 95%CI: 1.12 to 4.53, P = 0.02) and initial clinical presentation of ACS (OR: 2.81, 95%CI: 1.03 to 7.72, P = 0.04) were significant independent risk factors for heterogeneous NIH., Conclusion: Mean macrophage grade measured by OCT as a semi-quantitative morphological risk factor, as well as clinical presentation of ACS, was associated with in-stent neointimal heterogeneity after DES implantation., (© 2018 Wiley Periodicals, Inc.)

Parenteral prostacyclin therapy is the most efficacious pharmacologic treatment for pulmonary arterial hypertension (PAH), but clinical response is variable. We sought to identify clinical, hemodynamic, and genetic associations with response to prostacyclin therapy. We performed a retrospective analysis of patients within a de-identified electronic health record and associated DNA biobank. Patients with PAH and a right heart catheterization (RHC) in the six months before initiation of a parenteral prostacyclin were included. Responders were defined a priori by attainment of World Health Organization (WHO) functional class (FC) 2 or better at the time of repeat RHC within two years. We performed exploratory analyses to identify genomic associations with prostacyclin response. Of 129 patients identified, 54 met our criteria for "responders." These patients were younger, more likely to be male, and were less likely to have connective tissue disease-related PAH. At follow-up, responders had improved hemodynamics, 6-min walk distance, and long-term survival. Baseline PA oxygen saturation (hazard ratio [HR] 0.568 [0.34-0.95]) and follow-up FC (HR = 2.57 [1.22-5.43]) were associated with survival. Prostacyclin responders were enriched in alleles related to cell development and circulatory system development and pathways related to aldosterone metabolism, cAMP signaling, and vascular smooth muscle contraction ( P < 0.001). Age at treatment initiation, WHO FC at short-term follow-up, and PA O 2 % are associated with survival in patients with PAH exposed to parenteral prostacyclins. Exploratory genetic analysis yielded associations in biologically relevant pathways in the pathogenesis of PAH.

Background and Purpose: Neuromelanin of the brainstem, which is considered a marker of neurodegeneration in Parkinson's disease (PD), can be detected by T1-weighted neuromelanin-sensitive magnetic resonance imaging (NM-MRI). Our aim was to investigate the NM-MRI features of de novo PD and to determine whether these features are associated with motor and non-motor symptoms in de novo PD patients., Methods: Fifty-one patients with de novo PD (Hoehn and Yahr stage 1-2) and 28 healthy controls were recruited. All subjects underwent clinical and MRI examinations including an NM-MRI sequence. The width and contrast-to-noise ratio (CNR) of the substantia nigra pars compacta (SNc) and the CNR of the locus coeruleus (LC) were measured on NM-MRI images., Results: Both the width and CNR values of the high intensity signals in the SNc were significantly decreased in the lateral, central and medial SNc parts in de novo PD patients compared to control subjects. The changes in the SNc on NM-MRI were not significantly different between the motor subgroups. The CNR values of the left LC were significantly lower in the PD group than in the control group. Specifically, the subtype of PD patients with depressive symptoms exhibited a significantly lower CNR in the left LC than the control group and PD patients without depressive symptoms., Conclusions: Substantia nigra pars compacta neuromelanin changes occur across both motor and non-motor (with and without depressive symptoms) subtypes, whilst LC changes are more notable in PD patients with depressive symptoms. Our results may provide new evidence to understand the pathophysiology of non-motor symptoms in PD., (© 2018 EAN.)

The objective of this study was to evaluate the effects of the incorporation of oat β-glucan (OβG) on the sensory and nutritional quality of steamed bread. Wheat flour was substituted with OβG at levels varying from 0 g/100 g to 5 g/100 g. The results showed that the products containing 1 g/100 g and 3 g/100 g OβG produced a comparable overall consumer acceptance while a significantly lower score was given to the product with 5 g/100 g. Nutritionally, the presence of OβG impeded in vitro starch hydrolysis by amylolytic enzymes. More importantly, the addition of OβG up to 5 g/100 g did bring about a lower in vitro predicted glycaemic index to steamed bread, but it generated insignificant effects on the in vivo glycaemic response. The current work first demonstrated the feasibility of fabricating OβG-enriched steamed bread and its nutritional superiority compared to the corresponding normal product., Practical Applications: Modern methods of food elaboration and processing frequently reduce the content of dietary fiber (DF). Despite the well-known health benefits of DF consumption, average intake levels still fall far below recommended ones. Oat β-glucan (OβG) is a kind of indigestible polysaccharide with diverse bioactivity. This article evaluated the effects of OβG incorporation on quality, structure, consumer acceptance, and glycaemic response of steamed bread. The addition of less than 3 g/100 g of OβG had negligible effects on the consumer acceptance of steamed bread. The enrichment at 5 g/100 g indeed deteriorated the consumer acceptance. Moreover, OβG highly lowered the glycaemic response of steamed bread. The current work first demonstrated the feasibility of fabricating OβG-enriched steamed bread and its nutritional superiority compared to the corresponding normal product. OβG enriched steamed bread may offer an alternative to improve DF intake of residents., (© 2017 Wiley Periodicals, Inc.)