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Secondary lymphedema is a debilitating morbidity. This study investigated the outcomes of vascularized lymph node transfer (VLNT) in elderly patients with secondary upper extremity lymphedema.Between 2008 and 2018, elderly (≥65 years) patients with secondary upper extremity lymphedema who underwent VLNT were retrospectively reviewed. Cheng's Lymphedema Grading, Taiwan Lymphoscintigraphy Staging, and indocyanine green lymphography were used to select the procedures. Outcome measurements included complications, circumferential difference, episodes of cellulitis, and the Lymphedema-Specific Quality of Life questionnaire (LYMQoL).Eleven patients with a mean age of 70.2 ± 5.3 years (range 65-80 years) who underwent VLNT survived and no major complications were encountered. At a mean follow-up of 6.5 ± 3.6 years (range 2-13 years), the mean limb circumferential difference was significantly improved from 25.6 ± 11.5% to 8.3 ± 4.2% (p = 0.016), and the mean episode of cellulitis was statistically reduced from 2.4 ± 1.3 to 0.4 ± 0.9 times/year (p = 0.007). At a follow-up of 24 months, four domains of Function (from 30.6 ± 2.8 to 14.5 ± 2.5), Appearance (from 18.2 ± 1.9 to 8.5 ± 2.1), Symptoms (from 30.4 ± 5.9 to 10.9 ± 1.0) and Mood (from 29.2 ± 4.4 to 10.7 ± 1.0), as well as overall LYMQoL score (from 3.9 ± 1.1 to 7.4 ± 0.5), showed statistical improvement (all p0.05).VLNT for secondary upper extremity lymphedema in elderly patients significantly decreased the limb circumferential difference and frequency of cellulitis and improved quality of life without using compression garments postoperatively.

Objectives Immune checkpoint inhibitors are associated with adverse cardiovascular events. However, there are no data characterizing cardiovascular events among Asians on immune checkpoint inhibitors. We aim to determine the incidence and risk of cardiac events associated with immune checkpoint inhibitors in an Asian population. Methods We performed a retrospective, propensity score-matched cohort study at two tertiary referral centers in Taiwan. Immune checkpoint inhibitor users were matched with non-immune checkpoint inhibitor users based on predetermined clinical variables. The primary outcome was major adverse cardiovascular events, defined as a composite of myocardial infarction, ischemic stroke, acute peripheral occlusive disease, pulmonary embolism, deep venous thrombosis, heart failure, pericardial disease, myocarditis, cardiac arrhythmias and conduction block. Results Between January 2010 and November 2021, 868 immune checkpoint inhibitor users were matched 1:1 with non-immune checkpoint inhibitor users. Among immune checkpoint inhibitor users, 67 (7.7%) patients developed major adverse cardiovascular events. During a median follow-up period of 188 days, the incidence rate of major adverse cardiovascular events for immune checkpoint inhibitor and non-immune checkpoint inhibitor users was 94.8 and 46.2 per 1000 patient-years, respectively, resulting in an incidence rate ratio of 2.1 [95% confidence interval: 1.5–2.9]. In multivariate Cox proportional hazard models, immune checkpoint inhibitor users had a 60% increased risk for major adverse cardiovascular events [hazard ratio, 1.6 (95% confidence interval: 1.1–2.3)]. Immune checkpoint inhibitors use was independently associated with increased risk of ischemic stroke [hazard ratio, 3.0 (95% confidence interval: 1.0–9.0)] and pulmonary embolism [hazard ratio, 5.5 (95% confidence interval: 1.4–21.3)]. In multivariate logistic regression analysis, age > 65, metastatic disease, hypertension and baseline platelet-to-lymphocyte ratio Conclusions Among Asians, immune checkpoint inhibitors were associated with an increased risk of major adverse cardiovascular events, particularly ischemic stroke and pulmonary embolism.

Obstructive sleep apnea (OSA) is characterized by partial or complete airway blockage during sleep. Nocturnal nasal obstruction usually leads to mouth breathing while sleeping, which worsens sleep apnea by aggravating tongue base and lateral pharyngeal wall collapse. The pathogenesis of OSA is multifactorial, and the precipitating factors vary significantly among individuals. Although continuous positive airway pressure (CPAP) is considered the first-line therapy for OSA, its adherence rate remains a challenge. Oral appliances are more suitable for simple snorers or patients with mild OSA. Maxillomandibular advancement (MMA) is highly effective for treating those with mandibular retrognathia and moderate-to-severe OSA. Intrapharyngeal surgeries yield favorable outcomes in patients with large tonsils and low tongue resting position (Friedman Stage I); however, their efficacy declines with time. Each therapy has its own strength and weakness; thus, the principle of multimodality treatment should be adopted. Nasal surgery plays an indispensable role in the holistic care for OSA. In addition to alleviating nasal congestion, nasal surgery significantly reduces snoring intensity and daytime sleepiness, which improves the quality of life of patients with OSA. Although it significantly reduces the respiratory disturbance index, its effect on the apnea-hypopnea index remains controversial. A combination of nasal surgery and multilevel pharyngeal surgery may result in better prognosis. Nasal surgery can significantly reduce the therapeutic pressure and improve the CPAP compliance of patients undergoing CPAP therapy. In conclusion, multimodality treatment and holistic care for OSA should involve nasal surgery for optimizing treatment outcomes.

B cells are a major component of the tumour microenvironment, where they are predominantly associated with tertiary lymphoid structures (TLS). In germinal centres within mature TLS, B cell clones are selectively activated and amplified, and undergo antibody class switching and somatic hypermutation. Subsequently, these B cell clones differentiate into plasma cells that can produce IgG or IgA antibodies targeting tumour-associated antigens. In tumours without mature TLS, B cells are either scarce or differentiate into regulatory cells that produce immunosuppressive cytokines. Indeed, different tumours vary considerably in their TLS and B cell content. Notably, tumours with mature TLS, a high density of B cells and plasma cells, as well as the presence of antibodies to tumour-associated antigens are typically associated with favourable clinical outcomes and responses to immunotherapy compared with those lacking these characteristics. However, polyclonal B cell activation can also result in the formation of immune complexes that trigger the production of pro-inflammatory cytokines by macrophages and neutrophils. In complement-rich tumours, IgG antibodies can also activate the complement cascade, resulting in the production of anaphylatoxins that sustain tumour-promoting inflammation and angiogenesis. Herein, we review the phenotypic heterogeneity of intratumoural B cells and the importance of TLS in their generation as well as the potential of B cells and TLS as prognostic and predictive biomarkers. We also discuss novel therapeutic approaches that are being explored with the aim of increasing mature TLS formation, B cell differentiation and anti-tumour antibody production within tumours.

The potential of micronutrients, including vitamins and minerals, to prevent Alzheimer's disease (AD) has attracted much attention. However, the causal associations between micronutrient levels or supplements and AD risk remain unclear. We performed a two-sample Mendelian randomization (2SMR) analysis to evaluate the causal associations between micronutrient levels and supplements and AD risk. A total of 60 genome-wide association studies (GWAS) related to five types of vitamins (vitamins A, B, C, D, and E) and seven types of minerals (magnesium, calcium, iron, copper, zinc, selenium, and phosphorus) were included. For vitamins, using the data source provided by two GWAS, the analysis of 2SMR indicated that the vitamin D level was causally associated with a decreased risk of AD (IVW, OR: 0.474, 95%CI: 0.269-0.834

Bromodomain-containing protein 4 (BRD4) is an attractive epigenetic target in human cancers. Inhibiting the phosphorylation of BRD4 by casein kinase 2 (CK2) is a potential strategy to overcome drug resistance in cancer therapy. The present study describes the synthesis of multiple BRD4–CK2 dual inhibitors based on rational drug design, structure–activity relationship, and in vitro and in vivo evaluations, and 44e was identified to possess potent and balanced activities against BRD4 (IC(50) = 180 nM) and CK2 (IC(50) = 230 nM). In vitro experiments show that 44e could inhibit the proliferation and induce apoptosis and autophagy-associated cell death of MDA-MB-231 and MDA-MB-468 cells. In two in vivo xenograft mouse models, 44e displays potent anticancer activity without obvious toxicities. Taken together, we successfully synthesized the first highly effective BRD4–CK2 dual inhibitor, which is expected to be an attractive therapeutic strategy for triple-negative breast cancer (TNBC).

Objectives/hypothesis To examine the pathogenic bacterial spectra and prognosis of deep neck infection (DNI) in end-stage renal disease (ESRD) patients. Study design Retrospective study. Methods Patients diagnosed with DNI between 2004 and 2015 in Chang Gung Memorial Hospital were enrolled and divided into three groups, namely ESRD-DNI, chronic kidney disease (CKD)-DNI, and non-CKD-DNI. Differences in pathogenic bacteria, treatment, and prognosis were compared across the three groups. Results The bacterial spectra differed among the three groups. The main three facultative anaerobic or aerobic bacteria causing ESRD-DNIs were methicillin-resistant Staphylococcus aureus (MRSA; 25.4%), methicillin-susceptible S. aureus (MSSA; 14.1%), and Klebsiella pneumoniae (KP; 12.7%). For CKD-DNIs, they were KP (23.5%), Viridans streptococci (VS; 23.5%), and MSSA (14.7%). For non-CKD-DNIs, they were VS (31.7%), KP (17.2%), and coagulase-negative staphylococci (8.0%). Compared with the other groups, the ESRD-DNI group had higher white blood cell and C-reactive protein levels, longer hospital stays, more frequent admissions to the intensive care unit, more mediastinal complications, and a significantly higher mortality rate. Conclusions The ESRD-DNI group exhibited more severe disease activity and higher mortality compared with those of the CKD-DNI and non-CKD-DNI groups. MRSA was the leading pathogen for patients with ESRD-DNI. Physicians must implement strategies for the early detection of MRSA to accurately prescribe antibiotics and prevent nosocomial transmission. Level of evidence 4 Laryngoscope, 2021.

Bromodomain-containing protein 4 (BRD4), as the most studied member of the bromodomain and extra-terminal (BET) family, is a chromatin reader protein interpreting epigenetic codes through binding to acetylated histones and non-histone proteins, thereby regulating diverse cellular processes including cell cycle, cell differentiation, and cell proliferation. As a promising drug target, BRD4 function is closely related to cancer, inflammation, cardiovascular disease, and liver fibrosis. Currently, clinical resistance to BET inhibitors has limited their applications but synergistic antitumor effects have been observed when used in combination with other tumor inhibitors targeting additional cellular components such as PLK1, HDAC, CDK, and PARP1. Therefore, designing dual-target inhibitors of BET bromodomains is a rational strategy in cancer treatment to increase potency and reduce drug resistance. This review summarizes the protein structures and biological functions of BRD4 and discusses recent advances of dual BET inhibitors from a medicinal chemistry perspective. We also discuss the current design and discovery strategies for dual BET inhibitors, providing insight into potential discovery of additional dual-target BET inhibitors.

In order to conduct high-throughput genome-wide translocation sequencing based on CRISPR/Cas9, Nalm6-cas9 monoclonal cell line expressing Cas9 protein was constructed by lentivirus transduction.Lentiviral vectors LentiCas9-Blast, pSPAX2, and pMD2.G were used to co-transfect HEK293T cells to obtain recombinant lentivirus. After Nalm6 cells were infected with the recombinant lentivirus, the cells were screened by Blasticidin, and multiple monoclonal cell lines expressing Cas9 protein were obtained by limited dilution. Western blot was used to detect the expression level of Cas9 protein in monoclonal cell lines, and cell count analysis was used to detect the proliferation activity of monoclonal cell lines. LentiCRISPRV2GFP-Δcas9, LentiCRISPRV2GFP-Δcas9-AF4, LentiCRISPRV2GFP-Δ cas9-MLL plasmids were constructed, and transfected with pSPAX2 and pMD2.G, respectively. T vector cloning was used to detect the function of Cas9 protein in Nalm6-Cas9 monoclonal cell line infected with virus.Western blot showed that Nalm6-Cas9_1-6 monoclonal cell line had high expression of Cas9 protein. Cell count analysis showed that high expression of Cas9 protein in Nalm6-Cas9_1-6 monoclonal cell line did not affect cell proliferation activity. The Nalm6-Cas9_1-6 monoclonal cell line had high cleavage activity, and the editing efficiency of AF4 and MLL genes was more than 90% which was determined by T vector cloning.Nalm6-Cas9_1-6 monoclonal cell line stably expressing highly active Cas9 protein was obtained, which provided a basis for exploring the translocation of MLL in therapy-related leukemias based on CRISPR/Cas9 genome-wide high-throughput genome-wide translocation sequencing.用于全基因组易位测序的Nalm6-Cas9细胞系的构建.为进行基于CRISPR-Cas9的全基因组高通量易位测序，利用慢病毒转导构建表达Cas9蛋白的Nalm6-Cas9单克隆细胞系.使用慢病毒载体lentiCas9-Blast、psPAX2和pMD2.G共转染HEK293T细胞包装病毒，病毒感染Nalm6细胞后使用杀稻瘟菌素（Blasticidin）筛选，通过有限稀释法获得多个表达Cas9蛋白的单克隆细胞株。Western blot检测单克隆细胞株中Cas9蛋白的表达水平，细胞计数检测单克隆细胞株的细胞增殖活性。构建lentiCRISPRv2GFP-Δcas9、lentiCRISPRv2GFP-Δcas9-AF4、lentiCRISPRv2GFP-Δcas9-MLL质粒，并分别与pSPAX2、pMD2.G质粒共转染包装病毒，收集病毒感染Nalm6-Cas9单克隆细胞株，使用T载体克隆检测单克隆细胞株的Cas9蛋白的功能.Western blot结果显示，Nalm6-Cas9_1-6单克隆细胞株高水平表达Cas9蛋白；细胞计数分析结果显示，Nalm6-Cas9_1-6单克隆细胞株细胞增殖活性与对照细胞比较无显著差异；T载体克隆检测显示，Nalm6-Cas9_1-6单克隆细胞株Cas9蛋白具有高水平切割活性，对AF4和MLL基因的编辑效率在90%以上.本研究得到了稳定表达高活性Cas9蛋白的Nalm6-Cas9_1-6单克隆细胞株，为基于CRISPR/Cas9全基因组高通量易位测序技术探究治疗相关性白血病中MLL易位连接机制提供依据.

Background At present, the hereditary hearing loss homepage, (https://hereditaryhearingloss.org/), includes 258 deafness genes and more than 500 genes that have been reported to cause deafness. With few exceptions, the region-specific distributions are unclear for many of the identified variants and genes. Methods Here, we used a custom capture panel to perform targeted sequencing of 518 genes in a cohort of 879 deaf Chinese probands who lived in Yunnan. Mutation sites of the parents were performed by high-throughput sequencing and validated by Sanger sequencing. Results The ratio of male to female patients was close to 1:1 (441:438) and the age of onset was mainly under six. Most patients (93.5%) were diagnosed with moderate to severe deafness. Four hundred and twenty-eight patients had variants in a deafness gene, with a detection rate of 48.7%. Pathogenic variants were detected in 98 genes and a number of these were recurrent within the cohort. However, many of the variants were rarely observed in the cohort. In accordance with the American College of Medical Genetics and Genomics, pathogenic, likely pathogenic and variants of uncertain significance accounted for 34.3%, 19.3% and 46.4% of all detected variants, respectively. The most common genes included GJB2, SLC26A4, MYO15A, MYO7A, TMC1, CDH23, USH2A and WFS1, which contained variants in more than ten cases. The two genes with the highest mutation frequency were GJB2 and SLC26A4, which accounted for 28.5% (122/428) of positive patients. We showed that more than 60.3% of coding variants were rare and novel. Of the variants that we detected, 80.0% were in coding regions, 17.9% were in introns and 2.1% were copy number variants. Conclusion The common mutation genes and loci detected in this study were different from those detected in other regions or ethnic groups, which suggested that genetic screening or testing programs for deafness should be formulated in accordance with the genetic characteristics of the region.

Background To date, treating nasal polyps (NPs) is still a medical challenge. However, we have developed an innovative therapy using licorice extract (LE: Glycyrrhiza glabra) to treat rhinitis and sinusitis via nasal irrigation and have discovered that it significantly affects treatment of NPs. Hypothesis/purpose This study investigated the mechanism of LE on NPs. Study design NPs were collected from three patients using tissue biopsies before and 2 weeks after nasal irrigation with licorice for histopathological analysis. Additionally, NPs from two patients were collected, and nasal polyp-derived fibroblasts (NPDF) were isolated and cultured. Methods The TGF-β1-stimulated NPDF model was used to examine the effect of LE on fibroblast differentiation (biomarker: α-SMA), the consequent production of extracellular matrix (ECM; biomarkers: fibronectin, FBN), and the functional signaling pathway. Results Immunohistochemistry (IHC) revealed that the number of eosinophils and the expression of α-SMA and interstitial collagen of polyps after licorice treatment significantly decreased. Additionally, RT-PCR, western blotting, and immunofluorescence (IF) showed that α-SMA and FBN expressions were significantly increased in the NPDF, which was stimulated by TGF-β1, and LE dose-dependently could effectively reduce this effect. Furthermore, western blotting showed that LE could attenuate α-SMA and FBN expressions by preventing the signaling pathway of MAPK/ERK-1/2, which IHC and IF further confirmed. In addition, LE effectively suppressed the cell migration of NPDF, which is related to polyp expansion. Conclusion LE is clinically used to treat sinusitis with NPs through nasal irrigation, which significantly reduces the size of NPs. This effect could attenuate fibroblast differentiation, ECM production and cell migration, and one of the functional mechanisms may be through inhibition of the MAPK/ERK-1/2 signaling pathway. Trial registration ISRCTN (No. 51425529) registered on 17/04/2020 (retrospectively registered) - http://www.isrctn.com/ISRCTN51425529

Background Chronic rhinosinusitis (CRS) affects the quality of life of many people worldwide and can cause comorbidities. Our previous research proved that Sjogren’s syndrome (SS) is a predisposing factor for CRS, with a 2.5-fold associated risk. Antibiotics are important in CRS treatment; however, there is a paucity of research on the pathogenic bacteria of SS-CRS in the past. We conducted this study to investigate the pathogenic difference of SS-CRS and non-SS-CRS and aimed to give clinicians references when selecting antibiotics to treat SS-CRS. Materials and methods A total of 14,678 patients hospitalized for CRS operation from 2004 to 2018 were identified from the Chang Gung Research Database. These CRS cases were classified as either SS-CRS or non-SS-CRS. We analyzed their bacterial distribution by studying the results of the pus cultures performed alongside surgery. Results The top three facultative anaerobic or aerobic isolated bacteria in the SS-CRS group were coagulase-negative Staphylococcus (CoNS: 34.3%), Pseudomonas aeruginosa (28.6%), methicillin-sensitive Staphylococcus aureus (MSSA: 20%), and Staphylococcus epidermidis (20%). In the non-SS-CRS group, S. epidermidis (29.3%), CoNS (25.7%), and MSSA (14.2%) were identified. The top three anaerobic bacterial genera were Cutibacterium (54.3%), Peptostreptococcus (11.4%), and Fusobacterium (11.4%) in the SS-CRS group and Cutibacterium (53.8%), Peptostreptococcus (25%), and Prevotella (12.9%) in the non-SS-CRS group. Conclusions P.aeruginosa is a major pathogen in SS-CRS patients. In addition, physicians should be aware of potential Fusobacterium and antibiotic-resistant bacterial infection in patients with SS-CRS.

OBJECTIVE To investigate whether prognostic nutritional index (PNI) predicts patient survival outcomes in oral cavity squamous cell carcinoma (OSCC). MATERIALS AND METHODS The data of a total of 360 patients subjected to primary surgery for OSCC were retrospectively analysed. Patients were categorised into high-PNI (≥51.75) and low-PNI (

Background The tongue has been identified as a high-risk site for malignant transformation of oral leukoplakia. The purpose of this study was to investigate the clinicopathological characteristics and treatment outcomes of the dorsal and ventrolateral tongue leukoplakia. Methods Demographic data and pathological results of patients who underwent carbon dioxide laser surgery for tongue leukoplakia from 2002 to 2019 were retrospectively reviewed and analyzed statistically. Results Of the 111 patients enrolled, 80 were males and 31 females, with a mean age of 51.86 ± 11.84 years. The follow-up time was 3.74 ± 4.19 years. Fifteen patients had a postoperative recurrence (13.51%). Four (3.6%) patients developed malignant transformation. Annual transformation rate was 1.08%. There were no differences in the time to develop carcinoma (3.19 ± 1.94 vs. 3.51 ± 2.12 years, P = 0.83), overall cumulative malignant transformation rates (7.41% vs. 2.25%, P = 0.12), and annual transformation rates (2.32% vs. 0.64%, P = 0.099). The prevalence of the ventrolateral tongue leukoplakia was higher than that of the dorsal tongue leukoplakia (P P = 0.045). Conclusions Dorsal tongue leukoplakia is not as frequently encountered clinically as ventrolateral tongue leukoplakia. The response of the dorsal tongue and ventrolateral tongue leukoplakia to laser therapy of are comparable in postoperative recurrence and postoperative malignant transformation. Clinicians should take a more aggressive attitude toward oral tongue leukoplakia with higher grade of dysplasia.

IMPORTANCE: The majority of the patients with head and neck cancer (HNC) experience taste dysfunction (TD) during or after radiotherapy (RT). However, prospectively collected data for taste dysfunction have been limited, especially in the era of intensity-modulated RT (IMRT). OBJECTIVE: To evaluate the taste function in patients with HNC receiving IMRT by investigating the association between time course and recovery of TD in both acute and late phases. DESIGN, SETTING, AND PARTICIPANTS: From August 2017 to November 2020, patients treated at the Chang Gung Memorial Hospital with curative or postoperative IMRT for HNC were enrolled in this prospective cohort study. The data analysis was performed from March 2021 to January 2022. EXPOSURES: IMRT with and without concurrent chemotherapy. MAIN OUTCOMES AND MEASURES: Taste function was measured using the whole-mouth solution method for 4 tastes (salt, sweet, sour, and bitter). Subjective evaluations (National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03] and Subjective Total Taste Acuity scale) were used. Patient self-reported quality of life was evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module (EORTC QLQ-H&N35). RESULTS: A total of 87 patients (78 [90%] men and 9 [10%] women; mean [range] age, 58 [31-80] years) were enrolled. Overall TD rates were 79 of 86 (91.9%), 63 of 83 (75.9%), 27 of 81 (33.3%), 5 of 56 (8.9%), and 2 of 30 (6.7%) during RT, and 1 week, 3 months, 6 months, and 1 year after RT, respectively. Positive correlation occurred between objectively measured taste loss for the 4 taste qualities and subjective perception of taste loss. Only oral cavity mean dose 4000 cGy or greater predicted TD 3 months after RT. The mean oral cavity doses to the predicted 15% (D(15)), 25% (D(25)), and 50% (D(50)) probabilities were 25, 38, and 60 Gy at 3 months and 57, 60, and 64 Gy at 6 months, respectively. CONCLUSIONS AND RELEVANCE: In this cohort study, most patients still experienced TD during and at 3 months after RT. Only a few patients experienced long-term TD. A high oral cavity dose was associated with TD in patients with HNC receiving IMRT. Reducing oral cavity dose may promote early recovery of taste function after IMRT.

Cationic amphiphilic antihistamines have been shown to improve patient outcomes in immunogenic tumours, but whether they can augment and improve response to immunotherapy is unknown. We aim to evaluate the effect of cationic amphiphilic antihistamines in patients receiving immune checkpoint inhibitors (ICIs).We conducted a retrospective propensity score-matched cohort study at two tertiary referral centres in Taiwan between January 2015 and December 2021. Patients who received desloratadine, cyproheptadine, and ebastine were classified as cationic amphiphilic antihistamine users. The primary outcome was overall survival, and the secondary outcomes were progression-free survival and clinical benefit rate. Patients treated with cationic amphiphilic antihistamines were matched to patients who received non-cationic amphiphilic antihistamines based on variables including age, cancer type, stage, and history of allergic diseases.A total of 734 ICI-treated patients were included. After matching, 68 cationic amphiphilic antihistamine and non-cationic amphiphilic antihistamine users remained for analysis. Compared with non-cationic amphiphilic antihistamine users, patients who received cationic amphiphilic antihistamines had a significantly longer median overall survival (24.8 versus 10.4 months; Log-rank, p = 0.018) and progression-free survival (10.6 versus 4.93 months; Log-rank, p = 0.004). The use of cationic amphiphilic antihistamines was associated with an approximately 50% lower risk of all-cause mortality (HR, 0.55 [95% CI: 0.34-0.91]). Survival benefits were not seen in patients who received cationic amphiphilic antihistamines before immune checkpoint blockade. These survival benefits were observed regardless of the generation of cationic amphiphilic antihistamines.The use of cationic amphiphilic antihistamines was associated with improved survival among patients treated with immunotherapy.

The success of sotorasib (AMG-510) and adagrasib (MRTX-849) has resolved the problem of non-availability of drugs for patients with KRASSotorasib (AMG-510) and adagrasib (MRTX-849) have changed the problem of non-availability of targeted drugs for patients with

BackgroundPeople in Taiwan enjoy comprehensive National Health Insurance coverage. However, under the global budget constraint, hospitals encounter enormous challenges. This study was designed to examine Taiwan medical centers' efficiency and factors that influence it.MethodsWe obtained data from open sources of government routine publications and hospitals disclosed by law to the National Health Insurance Administration, Ministry of Health and Welfare, Taiwan. The dynamic data envelopment analysis(DDEA) model was adopted to estimate all medical centers' efficiencies during 2015–2018. Beta regression models were used to model the efficiency level obtained from the DDEA model. We applied an input-oriented approach under both the constant returns-to-scale (CRS) and variable returns-to-scale (VRS) assumptions to estimate efficiency.ResultsThe findings indicated that 68.4% (13 of 19) of medical centers were inefficient according to scale efficiency. The mean efficiency scores of all medical centers during 2015–2018 under the CRS, VRS, and Scale were 0.85, 0.930, and 0.95,respectively. Regression results showed that an increase in the population less than 14 years of age, assets, nurse-patient ratio and bed occupancy rate could increase medical centers' efficiency. The rate of emergency return within 3-day and patient self-pay revenues were associated significantly with reduced hospital efficiency (p ConclusionsThe study results provide information for hospital managers to consider ways they could adjust available resources to achieve high efficiency.

Summary Background: The nivolumab-ipilimumab combination provides an overall response rate of 42% in first-line metastatic treatment of clear cell renal carcinoma (mccRCC). To date, there is no robust predictive biomarker of response to immune checkpoint inhibitor (ICI). In addition, severe autoimmune disorders occur more frequently with ICI combination than with ICI alone. The objective of this study is to compare the efficacy of ICI alone or in combination in patients according to tumor molecular characteristics. Methods: Using a 35-gene expression mRNA signature, patients were divided into 4 molecular groups (1 to 4). Patients in groups 1 and 4 were randomized to receive nivolumab alone (arms 1A and 4A) or nivolumab plus ipilimumab for 4 injections followed by nivolumab alone (arms 1B and 4B). Patients in groups 2 and 3 were randomized to receive nivolumab plus ipilimumab followed by nivolumab alone (arms 2B and 3B) or a tyrosine kinase inhibitor (sunitinib or pazopanib at the investigator’s choice (arms 2C and 3C)). The main objective is the overall response rate by treatment and molecular group. Discussion: BIONIKK is the first trial in mccRCC to study the personalization of treatment with ICI or TKI according to tumor molecular characteristics in mccRCC. This trial is the most appropriate to prospectively identify biomarkers of response to nivolumab used alone or in combination or TKI monotherapy in patients with mccRCC. NCT02960906.

Studies on biological functions of N6-methyladenosine (m6A) modification in mRNA have drawn significant attention in recent years. Here we describe the construction and characterization of a CRISPR–Cas13b-based tool for targeted demethylation of specific mRNA. A fusion protein, named dm6ACRISPR, was created by linking a catalytically inactive Type VI-B Cas13 enzyme from Prevotella sp. P5–125 (dPspCas13b) to m6A demethylase AlkB homolog 5 (ALKBH5). dm6ACRISPR specifically demethylates m6A of targeted mRNA such as cytochrome b5 form A (CYB5A) to increase its mRNA stability. It can also demethylate β-catenin-encoding CTNNB1 mRNA that contains multiple m6A sites to trigger its translation. In addition, the dm6ACRISPR system incurs efficient demethylation of targeted epitranscriptome transcripts with limited off-target effects. Targeted demethylation of transcripts coding for oncoproteins such as epidermal growth factor receptor (EGFR) and MYC can suppress proliferation of cancer cells. Together, we provide a programmable and in vivo manipulation tool to study mRNA modification of specific genes and their related biological functions.

EGFR inhibition is an effective treatment in the minority of non-small cell lung cancer (NSCLC) cases harboring EGFR-activating mutations, but not in EGFR wild type (EGFRwt) tumors. Here, we demonstrate that EGFR inhibition triggers an antiviral defense pathway in NSCLC. Inhibiting mutant EGFR triggers Type I IFN-I upregulation via a RIG-I-TBK1-IRF3 pathway. The ubiquitin ligase TRIM32 associates with TBK1 upon EGFR inhibition, and is required for K63-linked ubiquitination and TBK1 activation. Inhibiting EGFRwt upregulates interferons via an NF-κB-dependent pathway. Inhibition of IFN signaling enhances EGFR-TKI sensitivity in EGFR mutant NSCLC and renders EGFRwt/KRAS mutant NSCLC sensitive to EGFR inhibition in xenograft and immunocompetent mouse models. Furthermore, NSCLC tumors with decreased IFN-I expression are more responsive to EGFR TKI treatment. We propose that IFN-I signaling is a major determinant of EGFR-TKI sensitivity in NSCLC and that a combination of EGFR TKI plus IFN-neutralizing antibody could be useful in most NSCLC patients.

Objective To measure the factors that affect functional leg length of Crowe type IV Developmental dysplasia of the hip (DDH) patients and to review our own methods to balance leg length discrepancy (LLD) in Crowe type IV DDH patients. Methods This was a prospective observational study which started in June 2017 and ended in August 2019. Inclusion criteria included: (i) Crowe type I or Crowe type IV hip dysplasia patients who underwent total hip arthroplasty (THA) in the Department of Orthopaedics at our institution between July 2017 and June 2018; (ii) the patients were treated with our specific leg length balance strategy; and (iii) the related outcomes of patients were completely recorded. Finally, 18 consecutive Crowe type I patients (20 hips) and 14 consecutive Crowe type IV patients (18 hips) were selected and divided into two groups according to Crowe types. All patients received THA, and patients with a longer affected side and inferior anatomical acetabular positions in Crowe type IV group also received subtrochanteric osteotomy. During operation and after hip reduction, leg lengths were compared while two legs were in an extended position and the operative leg was on top of the non-operative one. Additional leg length adjustment was applied when leg length was considered to be unequal. Prior to surgery, subluxation height of the femoral head on the affected side, functional LLD, bony length of lower limbs, and distance from teardrops to the lowest point line of the sacroiliac joint were recorded. After surgery, cup sizes, functional LLD, and height of hip rotational centers were measured. Clinical evaluations, such as Harris Hip Score (HHS) and SF-12 scale, were also obtained before and after surgery for all patients. Results At the last follow-up, functional LLD and clinical measurements of both Crowe type IV group and Crowe type I group were significantly improved. Compared with Crowe type I patients, Crowe type IV patients had a significantly lower MCS, a significantly longer leg lengthening length and a significantly lower hip center height after surgery. Significant differences of tibia length, leg length, and teardrop position were found between affected side and healthy side of Crowe type IV patients. Only three of 14 Crowe type IV patients remained under 1 cm functional LLD. Five patients in the Crowe type IV group developed lower limb numbness immediately following surgery, and they all recovered within 6 months. The average follow-up period for either group was 14 months, and all patients were followed-up at 1, 3, 6, and 12 months then yearly after surgery until the final follow-up. Conclusion After detailed leg length balance process, THA combined with transverse sub-trochanter osteotomy could be an effective method to achieve equal function leg length with most Crowe type IV patients.

Systemic lupus erythematosus (SLE) might increase deep neck infection (DNI) risk, but evidence supporting this hypothesis is limited. In this retrospective follow-up study, the SLE–DNI association was investigated using data from the Registry for Catastrophic Illness Patients, which is a subset of the Taiwan National Health Insurance Research Database. All patients newly diagnosed as having SLE in 1997–2011 were identified, and every SLE patient was individually matched to four patients without SLE according to sex, age, and socioeconomic status. The study outcome was DNI occurrence. DNI treatment modalities and prognoses in SLE and non-SLE patients, along with the association of steroid dose with DNI risk, were also studied. In total, 17,426 SLE and 69,704 non-SLE patients were enrolled. Cumulative DNI incidence was significantly higher in the SLE cohort than in the non-SLE cohort (p p p = 0.033). The between-group differences in tracheostomy use and hospitalisation duration were nonsignificant. In SLE patients, high steroid doses significantly increased DNI incidence (≥3 vs. p

Recent studies have suggested the suboptimal efficacy of liposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) in metastatic pancreatic ductal adenocarcinoma (mPDAC) patients previously treated with conventional irinotecan. This study investigated the effect of conventional irinotecan treatment in mPDAC patients receiving nal-IRI+5-FU/LV by analyzing a population-based dataset.We reviewed 667 consecutive mPDAC patients treated with nal-IRI+5-FU/LV between August 2018 and November 2020 at Taiwanese medical centers. Eighty-six patients previously treated with conventional irinotecan were matched to 86 patients not treated with conventional irinotecan, following propensity matching for age, sex, performance status, metastatic organ site, pre-treatment carbohydrate antigen 19-9 level, lines of prior chemotherapy treatment, and time from first-line treatment to nal-IRI+5-FU/LV therapy.The median overall survival and time-to-treatment failure were 4.8 and 2.6 vs 4.1 and 2.1 months, respectively, for patients who were and were not previously treated with conventional irinotecan. The tumor response and disease control rates were 5.8% and 32.6% vs 5.8% and 37.2%, respectively, for patients previously treated and not treated with conventional irinotecan. No significant differences were observed in survival times and tumor response rates between the two groups.Previous conventional irinotecan treatment does not compromise the efficacy of subsequent nal-IRI+5-FU/LV treatment in mPDAC patients.

Bromodomain-containing protein 4 (BRD4) is an emerging epigenetic drug target for intractable inflammatory disorders. The lack of highly selective inhibitors among BRD4 family members has stalled the collective understanding of this critical system and the progress toward clinical development of effective therapeutics. Here we report the discovery of a potent BRD4 bromodomain 1 (BD1)-selective inhibitor ZL0590 (52) targeting a unique, previously unreported binding site, while exhibiting significant anti-inflammatory activities in vitro and in vivo. The X-ray crystal structural analysis of ZL0590 in complex with human BRD4 BD1 and the associated mutagenesis study illustrate a first-in-class nonacetylated lysine (KAc) binding site located at the helix αB and αC interface that contains important BRD4 residues (e.g., Glu151) not commonly shared among other family members and is spatially distinct from the classic KAc recognition pocket. This new finding facilitates further elucidation of the complex biology underpinning bromodomain specificity among BRD4 and its protein–protein interaction partners.

Surgical removal is the treatment of choice for many neoplasms of the parotid gland. This meta-analysis aimed to evaluate the differences between parotidectomy using a modified facelift incision (MFI) and parotidectomy using a modified Blair incision (MBI). A systematic search of the available literature in PubMed, Embase and the Cochrane Library was performed. Studies of adult patients who underwent open parotidectomy with presumed benign parotid neoplasms based on preoperative examinations were reviewed. The surgical outcomes of the MFI and MBI groups were collected. Intraoperative and postoperative parameters, including operative time, tumor size, cosmetic satisfaction, and incidences of facial palsy, Frey’s syndrome and salivary complications, were compared. Dichotomous data and continuous data were analyzed by calculating the risk difference (RD) and the mean difference (MD) with the 95% confidence interval (CI), respectively. Seven studies were included in the final analysis. The pooled analysis demonstrated that the cosmetic satisfaction score was significantly higher in the MFI group (MD = 1.66; 95% CI 0.87–2.46). The operative duration in the MFI group was significantly longer than that in the MBI group (MD = 0.07; 95% CI 0.00–0.14). The MFI group exhibited a smaller tumor size (MD = − 2.27; 95% CI − 4.25 to − 0.30) and a lower incidence of Frey’s syndrome (RD = − 0.18; 95% CI − 0.27 to − 0.10). The incidence of postoperative temporary facial palsy (RD = − 0.05; 95% CI − 0.12 to 0.03), permanent facial palsy (RD = − 0.01; 95% CI − 0.06 to 0.03) and salivary complications (RD = − 0.00; 95% CI − 0.05 to 0.05) was comparable between the two groups. Based on these results, MFI may be a feasible technique for improving the cosmetic results of patients who need parotidectomy when oncological safety can be ensured.

Tissue repair engineering supported by nanoparticles and stem cells has been demonstrated as being an efficient strategy for promoting the healing potential during the regeneration of damaged tissues. In the current study, we prepared various nanomaterials including pure Pul, pure Col, Pul–Col, Pul–Au, Pul–Col–Au, and Col–Au to investigate their physicochemical properties, biocompatibility, biological functions, differentiation capacities, and anti-inflammatory abilities through in vitro and in vivo assessments. The physicochemical properties were characterized by SEM, DLS assay, contact angle measurements, UV-Vis spectra, FTIR spectra, SERS, and XPS analysis. The biocompatibility results demonstrated Pul–Col–Au enhanced cell viability, promoted anti-oxidative ability for MSCs and HSFs, and inhibited monocyte and platelet activation. Pul–Col–Au also induced the lowest cell apoptosis and facilitated the MMP activities. Moreover, we evaluated the efficacy of Pul–Col–Au in the enhancement of neuronal differentiation capacities for MSCs. Our animal models elucidated better biocompatibility, as well as the promotion of endothelialization after implanting Pul–Col–Au for a period of one month. The above evidence indicates the excellent biocompatibility, enhancement of neuronal differentiation, and anti-inflammatory capacities, suggesting that the combination of pullulan, collagen, and Au nanoparticles can be potential nanocomposites for neuronal repair, as well as skin tissue regeneration in any further clinical treatments.

Vocal fold nodules (VFNs) are the most frequent cause of hoarseness. The management comprised medical, surgical and physical therapy but the effectiveness is not always satisfactory. In this study, we try to figure out an alternative treatment from our clinical experience summary. We retrospectively reviewed VFNs patients who received traditional Chinese medicine (TCM) treatments from July 2018 to August 2020 and traced their Chinese Voice Handicap Index-10 (VHI-C10) and multidimensional voice program (MDVP) analysis results. For further evaluation, we conducted an inflammatory response of porcine vocal fold epithelial (PVFE) cells with 50 ng/mL TNF-alpha. The inflamed PVFE cells were separately cultured in the aqueous extract of Glycyrrhiza glabra (

A nanocomposite composed of polyethylene glycol (PEG) incorporated with various concentrations (~17.4, ~43.5, ~174 ppm) of gold nanoparticles (Au) was created to investigate its biocompatibility and biological performance in vitro and in vivo. First, surface topography and chemical composition was determined through UV-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), scanning electron microscopy (SEM), free radical scavenging ability, and water contact angle measurement. Additionally, the diameters of the PEG-Au nanocomposites were also evaluated through dynamic light scattering (DLS) assay. According to the results, PEG containing 43.5 ppm of Au demonstrated superior biocompatibility and biological properties for mesenchymal stem cells (MSCs), as well as superior osteogenic differentiation, adipocyte differentiation, and, particularly, neuronal differentiation. Indeed, PEG-Au 43.5 ppm induced better cell adhesion, proliferation and migration in MSCs. The higher expression of the SDF-1α/CXCR4 axis may be associated with MMPs activation and may have also promoted the differentiation capacity of MSCs. Moreover, it also prevented MSCs from apoptosis and inhibited macrophage and platelet activation, as well as reactive oxygen species (ROS) generation. Furthermore, the anti-inflammatory, biocompatibility, and endothelialization capacity of PEG-Au was measured in a rat model. After implanting the nanocomposites into rats subcutaneously for 4 weeks, PEG-Au 43.5 ppm was able to enhance the anti-immune response through inhibiting CD86 expression (M1 polarization), while also reducing leukocyte infiltration (CD45). Moreover, PEG-Au 43.5 ppm facilitated CD31 expression and anti-fibrosis ability. Above all, the PEG-Au nanocomposite was evidenced to strengthen the differentiation of MSCs into various cells, including fat, vessel, and bone tissue and, particularly, nerve cells. This research has elucidated that PEG combined with the appropriate amount of Au nanoparticles could become a potential biomaterial able to cooperate with MSCs for tissue regeneration engineering.

Since the start of the outbreak of coronavirus disease 2019 in Wuhan, China, there have been more than 150 million confirmed cases of the disease reported to the World Health Organization. The beta variant (B.1.351 lineage), the mutation lineages of SARS-CoV-2, had increase transmissibility and resistance to neutralizing antibodies due to multiple mutations in the spike protein. N501Y, K417N and E484K, in the receptor binding domain (RBD) region may induce a conformational change of the spike protein and subsequently increase the infectivity of the beta variant. The L452R mutation in the epsilon variant (the B.1.427/B.1.429 variants) also reduced neutralizing activity of monoclonal antibodies. In this study, we discovered that 300 μg/mL GB-2, from Tian Shang Sheng Mu of Chiayi Puzi Peitian Temple, can inhibit the binding between ACE2 and wild-type (Wuhan type) RBD spike protein. GB-2 can inhibit the binding between ACE2 and RBD with K417N-E484K-N501Y mutation in a dose-dependent manner. GB-2 inhibited the binding between ACE2 and the RBD with a single mutation (K417N or N501Y or L452R) except the E484K mutation. In the compositions of GB-2, glycyrrhiza uralensis Fisch. ex DC., theaflavin and (+)-catechin cannot inhibit the binding between ACE2 and wild-type RBD spike protein. Theaflavin 3-gallate can inhibit the binding between ACE2 and wild-type RBD spike protein. Our results suggest that GB-2 could be a potential candidate for the prophylaxis of some SARS-CoV-2 variants infection in the further clinical study because of its inhibition of binding between ACE2 and RBD with K417N-E484K-N501Y mutations or L452R mutation., Graphical Abstract ga1

Background Electrical storm (ES) is a heterogeneous clinical emergency that can present with malignant ventricular arrhythmias such as ventricular fibrillation (VF), ventricular tachycardia (VT), requiring the need for cardiac defibrillation. ES is a life-threatening condition with a high mortality rate. Successfully managing ES in the setting of acute myocardial infarction (MI) is expected to be known by physicians on call to reduce in-hospital mortality. Case presentation A 57-year-old man presenting with acute onset chest pain was found to have an infero-posterior ST-segment elevation myocardial infarction (STEMI) complicated by acute right ventricular MI secondary to total occlusion of the proximal right coronary artery (RCA). The patient developed ES in the form of recurrent VF that was managed successfully with electrical defibrillation, antiarrhythmic therapy with amiodarone and esmolol, endotracheal intubation, sedation, electrolyte replacement, volume resuscitation, comfort care, psychological intervention, and percutaneous coronary intervention (PCI) of the occluded epicardial artery. With these interventions used in quick succession and with the aspiration of a massive RCA thrombus, the patient was reversed to hemodynamic stability, did not have further episodes of VF, and survived the index hospitalization. Conclusion ES is a rare but fatal complication of acute MI. Residents on night shifts should be better prepared and equipped to deal with this rare condition. We hope our successful experience can benefit physicians on call who take care of acute MI patients that deteriorate with ES.

To study the expression of B lymphocyte-induced mature protein-1 (BLIMP-1) in regulatory T cells (Tregs) of children with aplastic anemia (AA), and analyze its correlation with the number of Tregs and the levels of inhibitory cytokines interleukin (IL)-10 and transforming growth factor (TGF)-β in plasma.The peripheral blood samples of 10 newly diagnosed AA children and 10 healthy children were collected for experiment. qPCR was used to detect FOXP3 and PRDM1 mRNA expression levels. Flow cytometry was used to detect the proportion of Tregs, the expression of BLIMP-1 in Tregs, and the levels of cytokines such as IL-2, IL-17A, IL-6, interferon (IFN)-γ, IL-10 and TGF-β in plasma. Pearson correlation model was used to evaluate the relationship between the expression of BLIMP-1 in Treg and the number of Tregs, as well as the levels of IL-10 and TGF-β in plasma.Compared with control group, the proportion of Tregs in peripheral blood of AA children was decreased significantly (P0.001); The plasma levels of proinflammatory cytokines IL-2, IL-6 and IFN-γ in AA children were increased significantly (P=0.033, P=0.031, P=0.006), and IL-17A also was increased but the difference was not statistically significant (P=0.052), while anti-inflammatory cytokines IL-10 and TGF-β were significantly reduced (P=0.048, P=0.002). The relative expressions level of FOXP3 and PRDM1 mRNA in AA children were significantly lower than those in control group (P=0.037, P=0.016). The expression of BLIMP-1 protein in Tregs of AA children was significantly lower than that in control group (P0.001). The expression level of BLIMP-1 protein in Tregs was positively correlated with the percentage of Tregs in lymphocytes (r=0.671, P=0.001), and was also positively correlated with the levels of IL-10 and TGF-β in plasma (r=0.500, P=0.029; r=0.486, P=0.030).The expression of BLIMP-1 in Tregs of AA children is impaired, and the low expression of BLIMP-1 is related to the decrease of the number in Tregs and IL-10 and TGF-β expressions.BLIMP-1在再生障碍性贫血患儿Treg细胞中的表达及意义.研究B淋巴细胞诱导成熟蛋白-1（BLIMP-1）在再生障碍性贫血（AA）患儿Treg细胞中的表达并分析其与Treg细胞数量、血浆中抑制性细胞因子白介素（IL）-10和转化生长因子（TGF）-β水平的相关性.收集10例初诊AA患儿和10例健康儿童的外周血标本。采用qPCR法检测FOXP3、PRDM1的mRNA表达水平。采用流式细胞术检测Treg细胞比例、Treg细胞中BLIMP-1表达以及血浆中IL-2、IL-17A、IL-6、γ干扰素、IL-10和TGF-β等细胞因子水平。采用Pearson相关模型分析Treg细胞中BLIMP-1表达与Treg细胞数量、血浆中IL-10和TGF-β水平的相关性.与对照组相比，AA患儿外周血Treg细胞比例显著下降（P＜0.001）；AA患儿血浆中促炎细胞因子IL-2、IL-6、IFN-γ水平显著升高（P=0.033，P=0.031，P=0.006），IL-17A水平亦升高但不显著（P=0.052），而抑炎细胞因子IL-10和TGF-β水平明显降低（P=0.048，P=0.002）；AA患儿FOXP3和PRDM1 mRNA的相对表达量显著低于对照组（P=0.037，P=0.016）；AA患儿Treg细胞的BLIMP-1蛋白表达显著低于对照组（P＜0.001）。Treg细胞中BLIMP-1蛋白的表达水平与Treg细胞占淋巴细胞百分比呈正相关（r=0.671，P=0.001)，与血浆中IL-10和TGF-β水平亦呈正相关（r=0.500，P=0.029；r=0.486，P=0.030).AA患儿Treg细胞中BLIMP-1表达受损，且BLIMP-1表达低下与Treg细胞数量减少和IL-10、TGF-β水平减少具有相关性.

The epidermal growth factor receptor (EGFR) is a prime oncogene that is frequently amplified in glioblastomas. Here we demonstrate a new tumour-suppressive function of EGFR in EGFR-amplified glioblastomas regulated by EGFR ligands. Constitutive EGFR signalling promotes invasion via activation of a TAB1-TAK1-NF-κB-EMP1 pathway, resulting in large tumours and decreased survival in orthotopic models. Ligand-activated EGFR promotes proliferation and surprisingly suppresses invasion by upregulating BIN3, which inhibits a DOCK7-regulated Rho GTPase pathway, resulting in small hyperproliferating non-invasive tumours and improved survival. Data from The Cancer Genome Atlas reveal that in EGFR-amplified glioblastomas, a low level of EGFR ligands confers a worse prognosis, whereas a high level of EGFR ligands confers an improved prognosis. Thus, increased EGFR ligand levels shift the role of EGFR from oncogene to tumour suppressor in EGFR-amplified glioblastomas by suppressing invasion. The tumour-suppressive function of EGFR can be activated therapeutically using tofacitinib, which suppresses invasion by increasing EGFR ligand levels and upregulating BIN3.

Background: Adenosine monophosphate deaminase 3 (AMPD3) is an isoenzyme involved in the regulation of the energetic metabolism of mammalian cells. Cancer cells have a high demand for their energy supply. This experimental study aimed to illustrate the role of AMPD3 in human head and neck squamous cell carcinoma (HNSCC). Materials and Methods: Real-time quantitative reverse transcription-polymerase chain reaction was used to investigate the expression of the AMPD3 gene in human HNSCC tissues to assess the changes in cancerous and noncancerous parts and the correlation with different tumor behavior. The functions of AMPD3 were investigated using wound-healing and migration assays. Results: AMPD3 was significantly down-regulated in cancerous tissues of HNSCC (p=0.001) and this was correlated with more advanced tumor and clinical stages. Patients with high expression had better 5-year survival. AMPD3 knock-down in SCC-4 and SCC-25 cells demonstrated reduction of proliferation but increased migration and invasion. Conclusion: To our knowledge, this is the first report evidencing the expression pattern of AMPD3 in HNSCC and demonstrated that high AMPD3 expression might represent a good prognostic biomarker. AMPD3 may have an antiproliferative potential but its down-regulation may not contribute to reducing the migration and invasion of HNSCC cells.

Radiofrequency ablation (RFA) was first introduced for treating knee osteoarthritis (OA) in 2010 and has emerged as a minimally invasive treatment option. Three RFA techniques have been adopted for treating knee OA, including conventional, pulsed, and cooled RFA. However, the efficacy among different RFA techniques in the treatment of knee OA is still unclear. Three electronic databases were systematically searched for relevant articles, including PubMed, Embase, and Cochrane Library. A meta-analysis of articles that investigated the use of RFA techniques in the treatment of knee OA was conducted to pool the effect size in pain before and after treatment. A total of 20 eligible articles (including 605 patients) were included for our meta-analysis. After treatment, the patients had significant improvements in pain for all three RFA techniques when compared with the baseline level for the 1, 3-, and 6-month follow-ups (p &lt, 0.00001). However, there were no significant differences in the efficacy among the three RFA techniques for all follow-up visits (p &gt, 0.05). The three RFA techniques demonstrated a significant improvement in pain for up to 6 months after treatment. Comparing the efficacy of the three RFA techniques in the treatment of knee OA, our results showed that no significant differences in pain relief among the three RFA techniques were observed at the 1-, 3-, 6, and 12-month follow-up visits.

Gut microbiota has been proved to be involved in the occurrence and development of many diseases, such as type 2 diabetes, obesity, coronary heart disease, etcetera. It provides a new idea for the pathogenesis of polycystic ovary syndrome (PCOS). Our study showed that the gut microbial community of PCOS with high low-density lipoprotein cholesterol (LDLC) has a noticeable imbalance. Gut microbiota of PCOS patients was significantly changed compared with CON, and these changes were closely related to LDLC. Gut microbiota may affect the metabolic level of PCOS patients through multiple metabolic pathways, and lipid metabolism disorder may further aggravate the imbalance of gut microbiota. Actinomycetaceae, Enterobacteriaceae and Streptococcaceae had high accuracy in the diagnosis of PCOS and the differentiation of subgroups, suggesting that they may play an important role in the diagnosis and treatment of PCOS in the future. Also, the model we built showed good specificity and sensitivity for distinguishing PCOS from CON (including L_CON and L_PCOS, H_CON and H_PCOS). In conclusion, this is the first report on the gut microbiota of PCOS with high LDLC, suggesting that in the drug development or treatment of PCOS patients, the difference of gut microbiota in PCOS patients with different LDLC levels should be fully considered.

Danshen (Salvia miltiorrhiza Bunge) is broadly utilized in traditional Chinese medicine for lung cancer. However, it's exact effort and mechanism on lung cancer is fully unclear. In this study, we found that dihydroisotanshinone I (DT), a pure compound extracted from danshen, can inhibit the growth of A549 cells and H460 cells. DT also induced apoptosis and ferroptosis in these lung cancer cells. DT also blocking the protein expression of GPX4 (Glutathione peroxidase 4). For in vivo study, DT treatment can inhibit metastasis of A549 cells in the nude mice model without adverse effects on mice. In conclusion, DT inhibited the growth of lung cancer cells through apoptosis and ferroptosis and inhibited metastasis of A549 cells in the nude mice model. Further studies are warranted to validate the findings of this study.

To examine the association of laryngoplasty, voice therapy, and pneumonia rate in patients with unilateral vocal fold paralysis (UVFP).Population-based retrospective cohort study.Data were collected from the LHID2000 (Longitudinal Health Insurance Database 2000), containing the information of 1 million randomly selected patients in Taiwan.In the LHID2000, we identified 439 patients having new diagnoses of UVFP from 1997 to 2013. We grouped the aforementioned patients according to UVFP treatment and probed the occurrence of pneumonia: 305 patients underwent laryngoplasty or voice therapy, and 134 patients did not undergo treatment. Follow-up procedures were executed for the enrollees until death or December 31, 2013, representing the end of the study period. We assessed the association of UVFP treatment and pneumonia by executing Cox proportional hazards regression.The pneumonia cumulative incidence was significantly higher among enrolled patients without treatment than in those receiving treatment (Laryngoplasty was associated with a lower incidence of short- and long-term pneumonia in patients with UVFP. Physicians should encourage patients with UVFP at risk of aspiration to receive prompt evaluation as well as treatment.

OBJECTIVE To investigate the association between rheumatoid arthritis (RA) and deep neck infection (DNI). STUDY DESIGN Retrospective cohort study. METHODS Patients newly diagnosed with RA between 2000 and 2011 were identified from the National Health Insurance Research Database in Taiwan. Moreover, patients without RA were randomly selected and matched at a 1:4 ratio by age, sex, urbanization level, income, and diabetes mellitus. The patients were followed up until death or the end of the study period (December 31, 2013). The primary outcome was the occurrence of DNI. RESULTS In total, 30,207 patients with RA and 120,828 matched patients without RA were enrolled. Patients with RA had a significantly higher cumulative incidence of DNI than those without RA (P

Aims/Introduction To investigate the clinical and genetic characteristics of Chinese patients with a phenotype consistent with maturity‐onset diabetes of the young type 2 and explore the pathogenic mechanism of their hyperglycemia. Materials and Methods We studied 12 probands and their extended families referred to our center for screening mutations in the glucokinase gene (GCK). Clinical data were collected and genetic analysis was carried out. The recombinant wild‐type and mutant glucokinase were generated in Escherichia coli. The kinetic parameters and thermal stability of the enzymes were determined in vitro. Results In the 12 families, 11 GCK mutations (R43C, T168A, K169N, R191W, Y215X, E221K, M235T, R250H, W257X, G261R and A379E) and one variant of uncertain significance (R275H) were identified. R191W was detected in two unrelated families. Of the 11 GCK mutations, three mutations (c.507G>C, K169N; c.645C>A, Y215X; c.771G>A, W257X; NM_000162.3, NP_000153.1) are novel. Basic kinetics analysis explained the pathogenicity of the five mutants (R43C, K169N, R191W, E221K and A379E), which showed reduced enzyme activity with relative activity indexes between ~0.001 and 0.5 compared with the wild‐type (1.0). In addition, the thermal stabilities of these five mutants were also decreased to varying degrees. However, for R250H and R275H, there was no significant difference in the enzyme activity and thermal stability between the mutants and the wild type. Conclusions We have identified 11 GCK mutations and one variant of uncertain significance in 12 Chinese families with hyperglycemia. For five GCK mutations (R43C, K169N, R191W, E221K and A379E), the changes in enzyme kinetics and thermostability might be the pathogenic mechanisms by which mutations cause hyperglycemia.

The mechanistic action of bromodomain-containing protein 4 (BRD4) in cancer motility, including epithelial-mesenchymal transition (EMT), remains largely undefined. We found that targeted inhibition of BRD4 reduces migration, invasion, in vivo growth of patient-derived xenograft (PDX), and lung colonization of breast cancer (BC) cells. Inhibition of BRD4 rapidly decreases the expression of Snail, a powerful EMT transcription factor (EMT-TF), via diminishing its protein stability and transcription. Protein kinase D1 (PRKD1) is responsible for BRD4-regulated Snail protein stability by triggering phosphorylation at Ser11 of Snail and then inducing proteasome-mediated degradation. BRD4 inhibition also suppresses the expression of Gli1, a key transductor of Hedgehog (Hh) required to activate the transcription of SNAI1, in BC cells. The GACCACC sequence (−341 to −333) in the SNAI1 promoter is responsible for Gli1-induced transcription of SNAI1. Clinically, BRD4 and Snail levels are increased in lung-metastasized, estrogen receptor-negative (ER-), and progesterone receptor-negative (PR-) breast cancers and correlate with the expression of mesenchymal markers. Collectively, BRD4 can regulate malignancy of breast cancer cells via both transcriptional and post-translational regulation of Snail.

Background: Chronic kidney disease exhibits a prominent premature aging phenotype in many different organ systems, including the brain. Nevertheless, a comprehensive characterization of brain aging in non-demented patients with end-stage renal disease (ESRD) is lacking and it remains unclear if the collective changes of cognitive functions and brain structures in ESRD is compatible with aging. Methods: We compared 56 non-demented, independently living dialysis patients (mean age 59.4 ± 11.0 years; mean dialysis vintage of 5.9 years) and 60 non-dialysis controls on a battery of neuropsychological tests, brain MRI T1 imaging and diffusion tensor imaging. Participants with diagnosis of dementia, Mini-Mental State Examination

Lineage commitment and tumorigenesis, traits distinguishing stem cells, have not been well characterized and compared in mesenchymal stem cells derived from human dental pulp (DP-MSCs) and bone marrow (BM-MSCs). Here, we report DP-MSCs exhibit increased osteogenic potential, possess decreased adipogenic potential, form dentin pulp-like complexes, and are resistant to oncogenic transformation when compared to BM-MSCs. Genome-wide RNA-seq and differential expression analysis reveal differences in adipocyte and osteoblast differentiation pathways, bone marrow neoplasm pathway, and PTEN/PI3K/AKT pathway. Higher PTEN expression in DP-MSCs than in BM-MSCs is responsible for the lineage commitment and tumorigenesis differences in both cells. Additionally, the PTEN promoter in BM-MSCs exhibits higher DNA methylation levels and repressive mark H3K9Me2 enrichment when compared to DP-MSCs, which is mediated by increased DNMT3B and G9a expression, respectively. The study demonstrates how several epigenetic factors broadly affect lineage commitment and tumorigenesis, which should be considered when developing therapeutic uses of stem cells., Mesenchymal stem cells derived from dental pulp (DP-MSCs) differ in oncogenesic and developmental potential compared to those from bone marrow. Here, the authors show that decreased DNA methylation and histone H3K9Me2 enrichment along with higher PTEN activation in DP-MSCs promotes osteogenesis and reduces oncogenesis.

Keloids are wounding-induced fibroproliferative human tumor-like skin scars of complex genetic makeup and poorly defined pathogenesis. To reveal dynamic epigenetic and transcriptome changes of keloid fibroblasts, we performed RNA-seq and ATAC-seq analysis on an early passage keloid fibroblast cell strain and its paired normal control fibroblasts. This keloid strain produced keloid-like scars in a plasma clot-based skin equivalent humanized keloid animal model. RNA-seq analysis reveals gene ontology terms including hepatic fibrosis, Wnt-β-catenin, TGF-β, regulation of epithelial-mesenchymal transition (EMT), STAT3 and adherens junction. ATAC-seq analysis suggests STAT3 signalling is the most significantly enriched gene ontology term in keloid fibroblasts, followed by Wnt signalling (Wnt5) and regulation of the EMT pathway. Immunohistochemistry confirms that STAT3 (Tyr705 phospho-STAT3) is activated and β-catenin is up-regulated in the dermis of keloid clinical specimens and keloid skin equivalent implants from the humanized mouse model. A non-linear dose-response of cucurbitacin I, a selective JAK2/STAT3 inhibitor, in collagen type I expression of keloid-derived plasma clot-based skin equivalents implicates a likely role of STAT3 signalling in keloid pathogenesis. This work also demonstrates the utility of the recently established humanized keloid mouse model in exploring the mechanism of keloid formation.

Skin evolves essential appendages and indispensable types of cells that synergistically insulate the body from environmental insults. Residing in the specific regions in the skin such as epidermis, dermis and hair follicle, melanocytes perform an array of vital functions including defending the ultraviolet radiation and diversifying animal appearance. As one of the adult stem cells, melanocyte stem cells in the hair follicle bulge niche can proliferate, differentiate, and keep quiescence to control and coordinate tissue homeostasis, repair, and regeneration. In synchrony with hair follicle stem cells, melanocyte stem cells in the hair follicles undergo cyclic activation, degeneration, and resting phases, to pigment the hairs and to preserve the stem cells. Disorder of melanocytes results in severe skin problems such as canities, vitiligo, and even melanoma. Here, we compare and summarize recent discoveries about melanocyte in the skin, particularly in the hair follicle. A better understanding of the physiological and pathological regulation of melanocyte and melanocyte stem cell behaviors will help to guide the clinical applications in regenerative medicine.

Objective In individuals with epiglottitis, chronic obstructive pulmonary disease (COPD) is a common comorbidity; however, the impact of COPD under such circumstances is not well documented. Therefore, we performed this population-based study to determine whether, in adults, COPD is a risk factor for epiglottitis. Methods In this retrospective matched-cohort study, data obtained from the Taiwan National Health Insurance Research Database were analyzed. We identified all patients newly diagnosed as having COPD in 2000–2011 and performed frequency matching and propensity-score matching for every patient with COPD individually to another patient without a COPD diagnosis. We used epiglottitis occurrence as the study endpoint, and we investigated the hazard ratio of epiglottitis by using the Cox proportional hazards model after adjustment for potential confounders. Results In the frequency matching, the cumulative epiglottitis incidence was significantly higher (p = 0.005) in the COPD cohort. According to the adjusted Cox proportional hazard model, COPD exhibited a significant association with elevated epiglottitis incidence (adjusted hazard ratio: 1.76; 95% confidence interval: 1.15–2.70, p = 0.009). Similar trend was observed in the propensity-score matching analysis (adjusted hazard ratio: 1.50; 95% confidence interval: 0.99–2.29, p = 0.057). Our subgroup analysis revealed COPD to be an epiglottitis risk factor in male patients and those aged 40–64 years. Conclusions This is the first nationwide matched-cohort research to examine the association of COPD with epiglottitis. Our results revealed that COPD may be a potential risk factor for epiglottitis; thus, clinicians should be mindful of the potential increased risk of epiglottitis following COPD.

To investigate the safety of replacing doxorubicin with tirapazamine in conventional transarterial chemoembolization (TACE) in an Asian population with hepatocellular carcinoma (HCC), and to determine the optimal tirapazamine dose for phase II studies.This was a phase I, 3 + 3 dose-escalation study for patients with unresectable early- and intermediate-stage HCC who received 5, 10, or 20 mg/mSeventeen patients were enrolled, 59% of whom had progression from a prior HCC therapy and 35% of whom had progression or recurrence after TACE. All patients tolerated the tirapazamine TACE well without any DLT or serious adverse event. Using the modified Response Evaluation Criteria in Solid Tumors, the complete response (CR) rate was 47%, and the CR + partial response rate was 65%. The median duration of response was not reached. The median time to progression was 12.6 months (95% confidence interval, 5.1-not reached). The median overall survival was 29.3 months. The selected phase II dose was set at a fixed dose of 35 mg of IA tirapazamine.IA tirapazamine with transarterial embolization was well tolerated and showed promising efficacy signals in intermediate-stage HCC, justifying pursuit of a phase II study.

Acquired mutations in the ligand-binding domain (LBD) of the gene encoding estrogen receptor α (ESR1) are common mechanisms of endocrine therapy resistance in patients with metastatic ER+ breast cancer. The ESR1 Y537S mutation, in particular, is associated with development of resistance to most endocrine therapies used to treat breast cancer. Employing a high-throughput screen of nearly 1,200 Federal Drug Administration-approved (FDA-approved) drugs, we show that OTX015, a bromodomain and extraterminal domain (BET) inhibitor, is one of the top suppressors of ESR1 mutant cell growth. OTX015 was more efficacious than fulvestrant, a selective ER degrader, in inhibiting ESR1 mutant xenograft growth. When combined with abemaciclib, a CDK4/6 inhibitor, OTX015 induced more potent tumor regression than current standard-of-care treatment of abemaciclib + fulvestrant. OTX015 has preferential activity against Y537S mutant breast cancer cells and blocks their clonal selection in competition studies with WT cells. Thus, BET inhibition has the potential to both prevent and overcome ESR1 mutant-induced endocrine therapy resistance in breast cancer.