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Some patients with endometrial cancer (EC) suffer from limited survival benefits after immunotherapy, suggesting that there may be a specific pattern associated with immunotherapy. Immune-related genes were extracted from The Cancer Genome Atlas databases. We analyzed the differences among immune subtypes (ISs) in the distribution of the tumor mutational burden, chemotherapy-induced immune response markers, immune checkpoint-related genes, immunotherapy, and chemotherapy. We applied dimensionality reduction and defined the immune landscape of EC. Then, we used the Weighted Gene Co-Expression Network Analysis package to identify the coexpression modules of these immune genes. Finally, hub genes were selected and detected by quantitative PCR and immunohistochemistry. We obtained three ISs. There were differences in the distribution of the tumor mutational burden, chemotherapy-induced immune response markers, and immune checkpoint–related genes among the ISs. Regarding immunotherapy and chemotherapy, the IS2 subtypes were more sensitive to programmed cell death protein 1 inhibitors. In addition, different positions in the immune landscape map exhibited different prognostic characteristics, providing further evidence of the ISs. The IS2 subtypes were significantly positively correlated with yellow module gene list, indicating a good prognosis with high score. SIRPG and SLAMF1 were identified as the final characteristic genes. The quantitative PCR and immunohistochemistry results showed that the expression levels of SIRPG and SLAMF1 were low in human EC tissue. In this study, we identified three reproducible ISs of EC. The immune landscape analysis further revealed the intraclass heterogeneity of the ISs. SIRPG and SLAMF1 were identified to be associated with progression, suggesting that they may be novel immune-related biomarkers of EC.

With the increased demands of human-machine interaction, haptic feedback is becoming increasingly critical. However, the high cost, large size and low efficiency of current haptic systems severely hinder further development. As a portable and efficient technology, cutaneous electrotactile stimulation has shown promising potential for these issues. This paper presents a review on and insight into cutaneous electrotactile perception and its applications. Research results on perceptual properties and evaluation methods have been summarized and discussed to understand the effects of electrotactile stimulation on humans. Electrotactile applications are presented in categories to understand the methods and progress in various fields such as prostheses control, sensory substitution, sensory restoration and sensorimotor restoration. State of the art has demonstrated the superiority of electrotactile feedback, its efficiency and its flexibility. However, the complex factors and the limitations of evaluation methods made it challenging for precise electrotactile control. Groundbreaking innovation in electrotactile theory is expected to overcome challenges such as precise perception control, information capacity increasing, comprehension burden reducing and implementation costs.

The purpose of this study was to clarify the differences in the diagnosis and treatment outcomes between radioactive iodine-induced sialadenitis (RAIS) and chronic obstructive parotitis (COP). The study cohort comprised 47 consecutive patients diagnosed with RAIS and 50 patients with COP. All patients were treated by interventional endoscopy. Clinical, sialography, and endoscopy characteristics and treatment outcomes were compared between the two groups. Compared with the COP group, the RAIS group included more females (male:female ratio 1:8.4 vs 1:2.1; P = 0.011) and had a younger onset age (42 vs 50 years; P = 0.001) and shorter disease duration prior to hospital visit (5.4 vs 34.8 months; P0.001). In the RAIS group, sialography revealed obliteration of the main duct (20.4% vs 0%; P0.001), non-visualization of the main gland (23.7% vs 0%; P0.001), and incomplete contrast filling of the main gland (19.4% vs 6.4%; P = 0.008), which were scarcely observed in the COP group. Endoscopy revealed a higher percentage of duct atresia in RAIS compared to COP (20.4% vs 0%; P0.001). During follow-up, a higher percentage of RAIS patients had duct atresia and gland atrophy (49.5% vs 1.1%, P0.001). Compared with COP, RAIS more commonly involves younger females and has a shorter disease duration. Atresia of the main duct and atrophy of the gland parenchyma occur more often despite the use of interventional endoscopy.

The objective of this study was to investigate the clinical manifestations and pathologic appearances of the submandibular gland (SMG) in Stevens-Johnson syndrome (SJS).Patients with autologous transplantation of SMG for treatment of severe dry eye between March 1998 and May 2018 were divided into the SJS group (70 cases) and non-SJS group (50 cases) according to the history of SJS. The SMG weight and computed tomography volume and salivary flow rate were measured. The concentration index and secretion index were estimated using scintigraphy with technetium-99m-pertechnetate. Histopathology studies of SMG tissues were conducted, and the acini parameters were measured using a digital image analyzer.A decreased computed tomography volume and weight was observed in 48.57% the SJS group and 2% in the non-SJS group (P.01). The rest whole, acid-stimulated whole, and SMG rest salivary flow rates decreased in the SJS group (P.05). The normal SMG concentration index (37.5% vs 96.67%, P.001) and secretion index (35% vs 96.67%, P.001) rates were lower in the SJS group than in the non-SJS group. The glandular parenchyma was reduced, the acinar space was widened, and the fat content was increased in the SJS group.SMG atrophic and degenerative changes occurred in the SJS group, with a decrease in salivary secretion function in more than half of the patients.

The prevalence of homologous recombination–DNA damage response (HR-DDR) genetic alterations is of therapeutic interest in gastroesophageal cancers. This study is a comprehensive assessment of HR-DDR mutation prevalence across gastroesophageal adenocarcinomas and squamous cell carcinomas. Here we investigate the association of HR-DDR mutations with known predictors for immune-checkpoint inhibition [deficiency in mismatch-repair (dMMRP), tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1)]. We confirmed HR-DDR mutations are present in a subset of gastroesophageal adenocarcinomas (23%) and gastroesophageal squamous cell carcinomas (20%). Biomarker expression of dMMRP (18% vs. 1%) and TMB-high with a cutoff of ≥10 mt/MB (27% vs. 9%) was significantly more prevalent in the DDR-mutated cohort compared with the non-DDR-mutated cohort. Mean combined positive score for PD-L1 in the total adenocarcinoma cohort was significantly higher in the DDR-mutated cohort compared with the non–DDR-mutated cohort (10.1 vs. 5.8). We demonstrated that alterations in ARID1A, BRCA2, PTEN, and ATM are correlated with dMMRP, TMB-high, and increased PD-L1 expression in gastroesophageal adenocarcinomas. Our findings show that a subset of gastroesophageal tumors harbor HR-DDR mutations correlated with established immune biomarkers. By better understanding the relationship between HR-DDR mutations and immune biomarkers, we may be able to develop better immunotherapy combination strategies to target these tumors.

The rapid growth and decreasing cost of Next-generation sequencing (NGS) technologies have made it possible to conduct routine large panel genomic sequencing in many disease settings, especially in the oncology domain. Furthermore, it is now known that optimal disease management of patients depends on individualized cancer treatment guided by comprehensive molecular testing. However, translating results from molecular sequencing reports into actionable clinical insights remains a challenge to most clinicians. In this review, we discuss about some representative systems that leverage artificial intelligence (AI) to facilitate some processes of clinicians’ decision making based upon molecular data, focusing on their application in precision oncology. Some limitations and pitfalls of the current application of AI in clinical decision making are also discussed.

Background Metastasis is the main cause of mortality in cervical cancer (CC). Circular RNAs (circRNAs) have been demonstrated to play a crucial role in carcinoma biology. However, the expression and function of circRNAs in cervical cancer metastasis are still unclear. Methods In the present study, we identified a circRNA with an N6-methyladenosine (m6A) modification, circCCDC134, whose expression was increased in CC tissues by circRNA-Seq and qPCR. CircCCDC134 upregulation in CC was fine-tuned by ALKBH5-mediated m6A modification, which enhanced its stability in a YTHDF2-dependent manner. The functional experiments illustrated that circCCDC134 enhanced tumour proliferation and metastasis in vitro and in vivo. For the comprehensive identification of RNA-binding proteins, circRNA pull-down and mass spectrometry (ChIRP-MS), chromatin immunoprecipitation-seq (Chip-seq), RNA binding protein immunoprecipitation (RIP) and luciferase reporter assays were used to perform mechanistic investigations. Results The results revealed that circCCDC134 recruited p65 in the nucleus and acted as a miR-503-5p sponge to regulate the expression of MYB in the cytoplasm, ultimately stimulating HIF1A transcription and facilitating CC growth and metastasis. Conclusion: These findings indicate that circCCDC134 is an important therapeutic target and provide new regulatory model insights for exploring the carcinogenic mechanism of circCCDC134 in CC.

Kidney stone is a disease with complex etiology and high incidence, and the most common chemical composition type of it is calcium oxalate stone. The formation of calcium oxalate stones includes crystal formation, crystal growth and aggregation, crystal interaction with renal tubular epithelial cells, and crystal invasion of renal interstitial extracellular matrix and so on. In these processes, crystal-cell interactions are essential for kidney crystal retention and kidney stone formation. Recently many studies have found that the interaction between crystal and renal tubular epithelial cells is closely related to various key binding molecules, endoplasmic reticulum stress of tubular cells, extracellular matrix proteins, and various lithotriptic drugs. Understanding the mechanism of crystal-cell interaction is of great significance for the prevention and early treatment of calcium oxalate stones.肾结石是一种病因复杂、发病率较高的疾病，其最常见的化学成分类型是草酸钙结石。草酸钙结石的形成过程包括结晶形成、晶体生长和聚集、晶体与肾小管上皮细胞相互作用、晶体入侵肾间质细胞外基质等，在这些过程中，晶体和肾小管上皮细胞的相互作用对于肾脏的晶体保留和肾结石形成非常重要。近年许多研究发现晶体和肾小管上皮细胞的相互作用与多种关键结合分子、肾小管上皮细胞内质网应激、细胞外基质蛋白及各类排石药物等关系密切。了解晶体-细胞相互作用的机制对草酸钙结石的预防和早期治疗具有重要意义。.

Dioscin is a natural product that possesses protective effects on multiple chronic injuries, but its effects on asthma are not fully understood. Herein, we evaluated its effects on asthmatic mice established by ovalbumin (OVA) sensitization and challenges and further explored the mechanism. Inflammatory cells in bronchoalveolar lavage fluids (BALFs) were analyzed using Diff-Quik staining. OVA-specific immunoglobulin E (IgE)/IgG1 in serum and inflammatory cytokines (interleukin 4[IL-4], IL-5, IL-13, and tumor necrosis factor-α) in BALFs and lung tissues were measured using Enzyme-Linked Immunosorbent Assay Kits. Hematoxylin and eosin, periodic acid-Schiff, and immunohistochemistry staining showed histopathological changes in lung tissues. Epithelial-mesenchymal transition (EMT) in human bronchial epithelial (16HBE) cells was assessed by immunofluorescence staining. Hydroxyproline content was used to evaluate collagen deposition. Polymerase chain reaction and Western blot were performed to measure messenger RNA and protein expression. We found that dioscin treatment (particularly at the dose of 80 mg/kg) significantly inhibited pulmonary inflammation in asthmatic mice, as evidenced by the decreased serum OVA-specific IgE/IgG1 and the reduced inflammatory cells and cytokines in BALFs and lung tissues. Moreover, dioscin effectively ameliorated the goblet cell hyperplasia, mucus hypersecretion, collagen deposition, and smooth muscle hyperplasia in the airways of asthmatic mice. Mechanistically, dioscin restrained the activated TGF-β1/Smad2/3 and protein kinase B (AKT) signal pathways in lung tissues and potently reversed the TGF-β1-induced EMT and phosphorylation of Smad2/3 and AKT in 16HBE cells. Collectively, dioscin displayed protective effects on OVA-induced asthmatic mice via adjusting TGF-β1/Smad2/3 and AKT signal pathways, supporting the fact that dioscin could be a candidate for chronic asthma prevention in the future.

Background No consensus exists about submandibular glands (SMGs) involvement in oral squamous cell carcinoma (OSCC) patients with cervical lymph node metastasis. We aimed to investigate the prevalence of SMG involvement in OSCC patients with positive lymph nodes. Methods Retrospective analysis of data of 302 study subjects with positive lymph nodes in OSCC operated between January 2002 and December 2012. Results Only 1/302 (0.3%) study subject had SMG involvement. The mode of spread was by direct extension of the primary carcinoma. Extracapsular spread of level IB lymph nodes was seen in 12/302 (4%) patients. Only one of these patients had involvement of the fibrous tissue around the SMG. Conclusion SMG involvement is very rare in OSCC patients with cervical lymph node metastasis. Preservation of the ipsilateral SMG during neck dissection might be oncologically safe when involvement by direct spread is unlikely.

Herein, an amphiphilic perylene derivative (denoted as PTC-DEDA) was explored as DNA intercalators endowed with an enhanced affinity and intense electrochemiluminescence (ECL) to construct a target-induced DNA hydrogel biosensing platform for the sensitive detection of microRNA let-7a (miRNA let-7a). Specifically, the DNA hydrogel with numerous dendritic DNA structures was in situ generated

SPTBN1 plays an anticancer role in many kinds of tumors and participates in the chemotherapeutic resistance of epithelial ovarian cancer (EOC). Here, we reported that lower SPTBN1 expression was significantly related to advanced EOC stage and shorter progression-free survival. SPTBN1 expression was also higher in less invasive EOC cell lines. Moreover, SPTBN1 decreased the migration ability of the EOC cells A2780 and HO8910 and inhibited the growth of EOC cells in vitro and tumor xenografts in vivo. SPTBN1 suppression increased the epithelial mesenchymal transformation marker Vimentin while decreasing E-cadherin expression. By analyzing TCGA data and immunohistochemistry staining of tumor tissue, we found that SPTBN1 and SOCS3 were positively coexpressed in EOC patients. SOCS3 overexpression or JAK2 inhibition decreased the proliferation and migration of EOC cells as well as the expression of p-JAK2, p-STAT3 and Vimentin, which were enhanced by the downregulation of SPTBN1, while E-cadherin expression was also reversed. It was also verified in mouse embryonic fibroblasts (MEFs) that loss of SPTBN1 activated the JAK/STAT3 signaling pathway with suppression of SOCS3. Our results suggest that SPTBN1 suppresses the progression of epithelial ovarian cancer via SOCS3-mediated blockade of the JAK/STAT3 signaling pathway.

PURPOSE Many targeted therapies are currently available only via clinical trials. Therefore, routine precision oncology using biomarker-based assignment to drug depends on matching patients to clinical trials. A comprehensive and up-to-date trial database is necessary for optimal patient-trial matching. METHODS We describe processes for establishing and maintaining a clinical trial database, focusing on genomically informed trials. Furthermore, we present OCTANE (Oncology Clinical Trial Annotation Engine), an informatics framework supporting these processes in a scalable fashion. To illustrate how the framework can be applied at an institution, we describe how we implemented an instance of OCTANE at a large cancer center. OCTANE consists of three modules. The data aggregation module automates retrieval, aggregation, and update of trial information. The annotation module establishes the database schema, implements data integration necessary for automation, and provides an annotation interface. The update module monitors trial change logs, identifies critical change events, and alerts the annotators when manual intervention may be needed. RESULTS Using OCTANE, we annotated 5,439 oncology clinical trials (4,438 genomically informed trials) that collectively were associated with 1,453 drugs, 779 genes, and 252 cancer types. To date, we have used the database to screen 4,220 patients for trial eligibility. We compared the update module with expert review, and the module achieved 98.5% accuracy, 0% false-negative rate, and 2.3% false-positive rate. CONCLUSION OCTANE is a general informatics framework that can be helpful for establishing and maintaining a comprehensive database necessary for automating patient-trial matching, which facilitates the successful delivery of personalized cancer care on a routine basis. Several OCTANE components are publically available and may be useful to other precision oncology programs.

Diabetes normally causes lipid accumulation and oxidative stress in the kidneys, which plays a critical role in the onset of diabetic nephropathy; however, the mechanism by which dysregulated fatty acid metabolism increases lipid and reactive oxygen species (ROS) formation in the diabetic kidney is not clear. As succinate is remarkably increased in the diabetic kidney, and accumulation of succinate suppresses mitochondrial fatty acid oxidation and increases ROS formation, we hypothesized that succinate might play a role in inducing lipid and ROS accumulation in the diabetic kidney. Here we demonstrate a novel mechanism by which diabetes induces lipid and ROS accumulation in the kidney of diabetic animals. We show that enhanced oxidation of dicarboxylic acids by peroxisomes leads to lipid and ROS accumulation in the kidney of diabetic mice via the metabolite succinate. Furthermore, specific suppression of peroxisomal β-oxidation improved diabetes-induced nephropathy by reducing succinate generation and attenuating lipid and ROS accumulation in the kidneys of the diabetic mice. We suggest that peroxisome-generated succinate acts as a pathological molecule inducing lipid and ROS accumulation in kidney, and that specifically targeting peroxisomal β-oxidation might be an effective strategy in treating diabetic nephropathy and related metabolic disorders.

Though physiological signal based human-machine interfaces (HMIs) have recently developed rapidly, their practical use is restricted by many real-world environmental factors, one of which is muscle fatigue. This paper explores the sensitivities between surface electromyography (sEMG) and A-mode ultrasound (AUS) sensing modalities subject to muscle fatigue in the context of hand gesture recognition tasks. Two metrics, mean classification accuracy ( mCA) and decline rate ( DR), are proposed to evaluate the accuracy and muscle fatigue sensitivity between sEMG and AUS based HMIs. Muscle fatigue inducing experiment was designed and eight subjects were recruited to participate in the experiment. The gesture recognition accuracies of sEMG and AUS under non-fatigue state and fatigue state are compared through Mahalanobis distance based classifier linear discriminant analysis (LDA). In addition, Mahalanobis distance based metrics, repeatability index ( RI) and separability index ( SI), are introduced to evaluate the changes in the feature distribution during muscle fatigue and reveal the cause of the fatigue sensitivity difference between sEMG and AUS signals. The experimental results demonstrate that the fatigue robustness of AUS signal is better than that of sEMG signal. Specifically, with the employment of the LDA classifier trained under non-fatigue state, the testing accuracy of the sEMG signal on the non-fatigue state is 94.96%, while reduce to 68.26% on the fatigue state. The testing accuracy of the AUS signal on the corresponding states is 99.68% and 91.24% respectively. AUS signal attains higher mCA and lower DR, indicating that it has advantages over sEMG signal in terms of both accuracy and muscle fatigue sensitivity. In addition, the RI and RI/SI analysis reveal that before and after muscle fatigue, the consistency of AUS feature distribution is better than that of sEMG. These research outcomes validate that AUS is more tolerant to feature migration caused by muscle fatigue than sEMG.

We evaluated the in vitro digestibility of apple polyphenols mimicking elderly and adult digestion models (dynamic and static systems). The digestibility of total apple polyphenols in small intestine was much higher in the adult dynamic system (62 μg/100 g fresh apple) compared to the static system (20 μg/100 g fresh apple) and elderly dynamic digestion conditions (33 μg/100 g fresh apple). Elderly in vitro static digestion showed better antioxidant activity than the adult system (OH and ABTS

PURPOSE: To compare submandibular gland (SMG) transplantation with minor salivary gland (MSG) transplantation for the treatment of different dry eye diseases (DED). DESIGN: Retrospective clinical cohort study. METHODS: A total of 73 refractory DED eyes were divided into 3 groups. Group A comprised 35 end-stage DED eyes that underwent SMG transplantation. Group B comprised 20 end-stage DED eyes with MSG transplantation. Group C comprised 18 non-end-stage DED eyes with MSG transplantation. Schirmer test (ST), tear break-up time (TBUT), corneal fluorescein staining (FL), and best-corrected visual acuity (BCVA) were measured before and after surgery. RESULTS: Hospital length of stay, length of operation, and hospital fee were significantly higher in group A than in group B or C. Eyes in group A showed the most severe DED disease, with preoperative ST, TBUT, FL, and BCVA of 0.36 mm per 5 minutes, 0.03 seconds, 10.97, and 0.11, respectively, which improved significantly to 20.23 mm per 5minutes, 1.74 seconds, 7.58, and 0.2 at >2-year follow-up. Group B had similar baseline data, and significant but limited improvement only in the ST (0.55 mm per 5 minutes to 3.79 mm per 5 minutes) and FL (11.10 to 9.58) after the operation. Group C had better baseline ST, TBUT, FL, and BCVA of 0.89 mm per 5min, 3.49 seconds, 1.83, and 0.81, respectively, which improved significantly (except for BCVA) to 9.35 mm per 5min, 9.08 s, 0.53, and 0.89 after MSG transplantation. CONCLUSION: SMG transplantation could be recommended to treat end-stage refractory DED. MSG transplantation may provide satisfying results for refractory DED with relatively less severe impairment of the eye.

Background: Lung cancer is one of the most common cancers, the symptoms and treatment of which can cause negative emotions like anxiety, depression, and cancer-related fatigue (CRF). Nonpharmacological interventions, serving as alternative therapies, can greatly alleviate CRF in lung cancer patients. Previous meta-analyses have reported nonpharmacological interventions of CRF in lung cancer patients, but the results may be conflicting, and the reporting and methodological qualities remain unknown. Moreover, there is limited evidence to identify efficient and safe non-pharmacological interventions of CRF in lung cancer patients. This study aims to assess the therapeutic efficacy of nonpharmacological interventions of CRF in lung cancer patients through a network meta-analysis. Methods: Relevant literatures reporting non-pharmacological interventions of CRF in lung cancer patients published before June 2021 will be searched in online databases, including Wanfang, VP Information Chinese Journal Service Platform, China National Knowledge Infrastructure, Chinese BioMedicine Literature Database, PubMed, Embase, Cochrane, and Web of science. Two reviewers will be independently responsible for study selection, quality appraisal, and data extraction. Data analysis will be performed using the STATA14.0 and GEMTC 0.14.3 software. Results: This meta-analysis will provide additional and stronger evidences for nonpharmacological interventions of CRF in lung cancer patients. Our findings will be conductive to make therapeutic decisions by clinicians. Conclusion: This study will provide a reliable evidence-based basis for non-pharmacological interventions of CRF in lung cancer patients. Ethics and dissemination: Ethical approval was not required for this study. The systematic review will be published in a peer-reviewed journal, presented at conferences, and shared on social media platforms. This review would be disseminated in a peer-reviewed journal or conference presentations. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/QRY42.

Background Metastatic cervical squamous cell carcinoma (CSCC) has poor prognosis and is recalcitrant to the current treatment strategies, which warrants the necessity to identify novel prognostic markers and therapeutic targets. Given that CSCC is a virus-induced malignancy, we hypothesized that the pattern recognition receptors (PRRs) involved in the innate immune response likely play a critical role in tumor development. Methods A bioinformatics analysis, qPCR, IHC, immunofluorescence, and WB were performed to determine the expression of NOD1/NOD2. The biological characteristics of overexpression NOD1 or NOD2 CSCC cells were compared to parental cells: proliferation, migration/invasion and cytokines secretion were examined in vitro through CCK8/colony formation/cell cycle profiling/cell counting, wound healing/transwell, and ELISA assays, respectively. The proliferative and metastatic capacity of overexpression NOD1 or NOD2 CSCC cells were also evaluated in vivo. FCM, mRNA and protein arrays, ELISA, and WB were used to identify the mechanisms involved, while novel pharmacological treatment were evaluated in vitro and in vivo. Quantitative variables between two groups were compared by Student’s t test (normal distribution) or Mann-Whitney U test (non-normal distribution), and one-way or two-way ANOVA was used for comparing multiple groups. Pearson χ2 test or Fisher’s exact test was used to compare qualitative variables. Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. P values of < 0.05 were considered statistically significant. Results NOD1 was highly expressed in CSCC with lymph-vascular space invasion (LVSI, P P P = 0.016). In vitro and in vivo functional assays revealed that the upregulation of NOD1 or NOD2 in CSCC cells promoted proliferation, invasion, and migration. Mechanistically, NOD1 and NOD2 exerted their oncogenic effects by activating NF-κb and ERK signaling pathways and enhancing IL-8 secretion. Inhibition of the IL-8 receptor partially abrogated the effects of NOD1/2 on CSCC cells. Conclusions NOD1/2-NF-κb/ERK and IL-8 axis may be involved in the progression of CSCC; the NOD1 significantly enhanced the progression of proliferation and metastasis, which leads to a poor prognosis. Anti-IL-8 was identified as a potential therapeutic target for patients with NOD1high tumor.

Submandibular gland (SMG) transplantation improves the tear film and other ocular-surface features for patients with severe dry eye disease (DED). Using the dry eye-related quality of life (QOL) questionnaire, we aimed to evaluate whether DED patients' QOL would benefit from SMG transplantation and determine whether preoperative ophthalmologic and QOL measurements could predict which patients would be most satisfied with this surgery.This prospective study included DED patients with successful SMG transplantation. Using the Chinese version of the Dry Eye Related Quality of Life (CDERQOL) instrument, QOL was measured before and 1-year after surgery.The QOL data of 51 consecutive patients were analyzed. Before surgery, all the patients had a poor QOL. One year after surgery, all five QOL domains (Dry Eye Symptom Bother, Impact on Daily Activities, Emotional Impact, Impact on Work, and Satisfaction with Treatment) showed significant improvement (P 0.01). Unsuccessful treatment experience with cyclosporin eyedrops as well as pre-surgical low scores of visual acuity and all five QOL domains (except for "Satisfaction with Treatment") were found to significantly increase the post-surgical QOL scores (P 0.01); however, pre-surgical Schirmer's test, break-up times of tear-film, and corneal fluorescein staining measurements showed no effects or contradictory correlations with post-surgical QOL scores.The life quality and satisfaction of DED patients showed significant improvement after SMG transplantation. Patients with severe and refractory DED could reap the benefits of surgery. A subjective QOL questionnaire is very valuable for predicting and evaluating the treatment effect.

Purpose Whether the submandibular gland (SMG) can be preserved during neck dissection in the surgical treatment of oral squamous cell carcinoma (OSCC) is controversial. This study investigated the SMG involvement rate and provides a basis for preserving the SMG during neck dissection in appropriate cases of OSCC. Materials and Methods A comprehensive systematic review was conducted on the PubMed and MEDLINE, Embase, and Cochrane Library databases for studies on SMG involvement in OSCC published before December 2017 with a data analysis technique. Predictor variables were numbers of patients and resected SMGs, primary site, and tumor, node, and metastasis stage. Outcome variables were the number of involved SMGs and mode of involvement. Other variables, namely first author, publication year, mean age, and condition of neck lymph nodes at level Ib, also were extracted. A random-effects model was used to analyze the rate of SMG involvement in OSCC. Results Twelve studies involving 2,126 patients with OSCC who underwent neck dissection were included in the study. Fifty-two SMGs were involved, and the pooled involvement rate was 2% (I2 = 73%; 95% confidence interval [CI], 1-3). Forty-eight SMGs were involved through direct spread from the primary site or extracapsular spread of positive lymph nodes, and the pooled involvement rate was 1.9% (I2 = 72%; 95% CI, 0.9-3.1). Except for direct spread, 4 SMGs were involved through the intraglandular lymph node or carcinoma growing along Wharton ducts, and the pooled involvement rate was only 0.1% (I2 = 0%; 95% CI, 0-0.2). Conclusions The rate of SMG involvement in OSCC is very low, and the most common mode of involvement is by direct spread. The SMG might be preserved during neck dissection in OSCC when it is unlikely to be involved through direct spread.

EZH2, the catalytic subunit of PRC2, catalyzes histone H3 lysine 27 (H3K27) trimethylation to induce the agglutination of chromosomes and in turn represses the transcription of the target genes. Numerous reports indicate that EZH2 is overexpressed in a variety of malignant tumor tissues. Therefore, targeting EZH2 protein is a promising strategy for cancer treatment. So far, many small molecule EZH2 specific inhibitors have entered clinical trials, but many of them harbored limited clinical efficacy. New technologies and methods are imperative to enhance the anticancer activity of EZH2. In this review, the structure and biological functions of EZH2 protein will be reviewed. The internal relationship between EZH2 and various diseases will be expounded. The development status of specific inhibitors for EZH2, and the latest progress of new strategies such as drug combination, dual-target inhibitors, targeted protein degradation technology and protein-protein interactions (PPI) inhibitors will be emphatically summarized and analyzed.

Hepatic fat accumulation is associated with diabetes and hepatocellular carcinoma (HCC). Here, we characterize the metabolic response that high-fat availability elicits in livers before disease development. After a short term on a high-fat diet (HFD), otherwise healthy mice showed elevated hepatic glucose uptake and increased glucose contribution to serine and pyruvate carboxylase activity compared with control diet (CD) mice. This glucose phenotype occurred independently from transcriptional or proteomic programming, which identifies increased peroxisomal and lipid metabolism pathways. HFD-fed mice exhibited increased lactate production when challenged with glucose. Consistently, administration of an oral glucose bolus to healthy individuals revealed a correlation between waist circumference and lactate secretion in a human cohort. In vitro, palmitate exposure stimulated production of reactive oxygen species and subsequent glucose uptake and lactate secretion in hepatocytes and liver cancer cells. Furthermore, HFD enhanced the formation of HCC compared with CD in mice exposed to a hepatic carcinogen. Regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism to those identified in fat exposed nontransformed mouse livers, however, particular lipid species were elevated in HFD tumor and nontumor-bearing HFD liver tissue. These findings suggest that fat can induce glucose-mediated metabolic changes in nontransformed liver cells similar to those found in HCC. Significance: With obesity-induced hepatocellular carcinoma on a rising trend, this study shows in normal, nontransformed livers that fat induces glucose metabolism similar to an oncogenic transformation.

Purpose This study examined the role of the CSF1/CSF1Raxis in the crosstalk between choroidal vascular endothelial cells (CVECs) and macrophages during the formation of choroidal neovascularization (CNV). Methods Quantitative reverse transcriptase (QRT)-PCR, Western blot and ELISA measured the production and release of CSF1 from human choroidal vascular endothelial cells (HCVECs) under hypoxic conditions. Western blot detected CSF1 released from HCVECs under hypoxic conditions that activated the PI3K/AKT/FOXO1 axis in human macrophages via binding to CSF1R. Transwell migration assay, qRT-PCR, and Western blot detected the effect of CSF1 released from HCVECs on macrophage migration and M2 polarization via the CSF1R/PI3K/AKT/FOXO1 pathway. Incorporation of 5-ethynyl-20-deoxyuridine, transwell migration, and tube formation assays detected the effects of CSF1/CSF1R on the behaviors of HCVECs. Fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), and immunofluorescence detected the effect of blockade of CSF1/CSF1R on mouse laser-induced CNV. Color fundus photograph, ICGA, and FFA detected CNV lesions in neovascular AMD (nAMD) patients. ELISA detected CSF1 and CSF1R in the aqueous humor of age-related cataract and nAMD patients. Results CSF1 released from HCVECs under hypoxic conditions activated the PI3K/AKT/FOXO1 axis in human macrophages via binding to CSF1R, promoting macrophage migration and M2 polarization via up-regulation of the CSF1R/PI3K/AKT/FOXO1 pathway. Human macrophages promoted the proliferation, migration, and tube formation of HCVECs in a CSF1/CSFR1-dependent manner under hypoxic conditions. CSF1/CSF1R blockade ameliorated the formation of mouse laser-induced CNV. CSF1 and CSF1R were increased in the aqueous humor of nAMD patients. Conclusions Our results affirmed the crucial role of CSF1/CSF1R in boosting the formation of CNV and offered potential molecular targets for the treatment of nAMD.

This study aimed to evaluate the long-term outcome and quality of life of IgG4-related sialadenitis (IgG4-RS) patients after submandibular gland (SMG) excision without immunomediate therapy.This retrospective review included patients with IgG4-RS who did not undergo further treatment following SMG excision. All patients diagnosed with IgG4-RS between January 1955 and December 2012 at the Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, were enrolled. The main outcome measures included postoperative IgG4-RS progression rate and differences between patients with and without recurrent disease. The degree of subjective oral dryness was evaluated using the summated xerostomia inventory (SXI); the objective secretory function was assessed by whole saliva flow rate measurements. Serological findings were analyzed during the follow-up.SMG excision was adopted in all of the 83 patients. The median follow-up period was 108 (range 7-396) months. Clinical progression was observed in 54.2% of cases. Patients with other organ involvement (OOI) indicated higher progression rate to a significant extent (P = 0.015, HR = 2.108). The annual progression rate was 20.7% in the group with OOI and was 14.1% in the group without OOI. All cases showed higher levels of serum IgG4; the level was in positive correlation with follow-up time when no therapy was added. 82.4% of cases experienced xerostomia after the surgery, and the degree of dry mouth in patients underwent bilateral resection was significantly more severe than those in unilateral resection.Surgical excision of involved SMG cannot control the disease progression, which is not recommended for treatment of IgG4-RS. Differential diagnosis is crucial in order to prevent irreversible organ loss and relevant salivary gland dysfunction. Key Points • Surgical excision of involved SMG cannot control progression of IgG4-RS.

There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. To compare the effectiveness of a novel genetically engineered recombinant super-compound interferon (rSIFN-co) with traditional interferon-alpha added to baseline antiviral agents (lopinavir–ritonavir or umifenovir) for the treatment of moderate-to-severe COVID-19. In this multicenter randomized (1:1) trial, patients hospitalized with moderate-to-severe COVID-19 received either rSIFN-co nebulization or interferon-alpha nebulization added to baseline antiviral agents for no more than 28 days. The primary endpoint was the time to clinical improvement. Secondary endpoints included the overall rate of clinical improvement assessed on day 28, the time to radiological improvement and virus nucleic acid negative conversion. A total of 94 patients were included in the safety set (46 patients assigned to rSIFN-co group, 48 to interferon-alpha group). The time to clinical improvement was 11.5 days versus 14.0 days (95% CI 1.10 to 2.81, p = .019); the overall rate of clinical improvement on day 28 was 93.5% versus 77.1% (difference, 16.4%; 95% CI 3% to 30%); the time to radiological improvement was 8.0 days versus 10.0 days (p = .002), the time to virus nucleic acid negative conversion was 7.0 days versus 10.0 days (p = .018) in the rSIFN-co and interferon alpha arms, respectively. Adverse events were balanced with no deaths among groups. rSIFN-co was associated with a shorter time of clinical improvement than traditional interferon-alpha in the treatment of moderate-to-severe COVID-19 when combined with baseline antiviral agents. rSIFN-co therapy alone or combined with other antiviral therapy is worth to be further studied.Key messagesThere are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus.In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir–ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents. There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus. In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir–ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents.

Background COVID-19 has caused a global pandemic and the death toll is increasing. However, there is no definitive information regarding the type of clinical specimens that is the best for SARS-CoV-2 detection, the antibody levels in patients with different duration of disease, and the relationship between antibody level and viral load. Methods Nasopharyngeal swabs, anal swabs, saliva, blood, and urine specimens were collected from patients with a course of disease ranging from 7 to 69 days. Viral load in different specimen types was measured using droplet digital PCR (ddPCR). Meanwhile, anti-nucleocapsid protein (anti-N) IgM and IgG antibodies and anti-spike protein receptor-binding domain (anti-S-RBD) IgG antibody in all serum samples were tested using ELISA. Results The positive detection rate in nasopharyngeal swab was the highest (54.05%), followed by anal swab (24.32%), and the positive detection rate in saliva, blood, and urine was 16.22%, 10.81%, and 5.41%, respectively. However, some patients with negative nasopharyngeal swabs had other specimens tested positive. There was no significant correlation between antibody level and days after symptoms onset or viral load. Conclusions Other specimens could be positive in patients with negative nasopharyngeal swabs, suggesting that for patients in the recovery period, specimens other than nasopharyngeal swabs should also be tested to avoid false negative results, and anal swabs are recommended. The antibody level had no correlation with days after symptoms onset or the viral load of nasopharyngeal swabs, suggesting that the antibody level may also be affected by other factors.

C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adipokine involved in diverse biological processes. However, its role in salivary glands remains unknown. Here, we demonstrated that CTRP6 was mainly distributed in the nuclei, apicolateral membranes, and cytoplasm of human submandibular glands (SMGs), serous cells of parotid glands, and ducts and apicolateral membranes of serous cells in rats and mice. CTRP6 inhibited the apoptosis rate and reversed the increased levels of cleaved caspase 3, caspase 8, caspase 9, and cytochrome C and the decreased Bcl-2 expression induced by tumor necrosis factor (TNF)-α in both SMG-C6 cells and cultured human SMG tissues. Microarray analysis identified 43 differentially expressed microRNAs (miRNAs) in the SMGs of nonobese diabetic mice. miR-34a-5p was selected due to its upregulation by TNF-α, which was abolished by CTRP6. The miR-34a-5p inhibitor promoted whereas the miR-34a-5p mimic suppressed the effects of CTRP6 on TNF-α-induced apoptosis. CTRP6 increased AMP-activated protein kinase (AMPK) phosphorylation and reversed TNF-α-induced SIRT1 downregulation in salivary cells. AraA, an AMPK inhibitor, reversed the effects of CTRP6 on TNF-α-induced alterations in the levels of SIRT1, miR-34a-5p, Bcl-2, and cleaved caspase 3 in vitro and ex vivo, whereas activating AMPK by AICAR reversed the decrease in SIRT1 expression and increase in miR-34a-5p expression induced by TNF-α. Inhibition of SIRT1 by EX527 suppressed the effects of CTRP6 on TNF-α-induced changes in miR-34a-5p and apoptosis-related proteins. Our findings indicate that salivary glands are novel sites for CTRP6 synthesis and secretion. CTRP6 protects acinar cells against TNF-α-induced apoptosis via AMPK/SIRT1-modulated miR-34a-5p expression.

Background Siraitia grosvenorii (binomial name Siraitia grosvenorii (Swingle) C. Jeffrey ex Lu et Z. Y. Zhang), also called Arhat Fruit or Monk’s Fruit, is a dried ripe fruit belonging to the Cucurbitaceae Family. S. grosvenorii has a long history of being used for constipation treatment in folk medicine. However, there are few studies where the laxative effect, related mechanisms, and active constituents of S. grosvenorii were investigated. This research explores the relationship between the common components and the laxative effect of aqueous extracts of S. grosvenorii from different habitats in China. Methods The fingerprints of S. grosvenorii aqueous extracts from different habitats were established by HPLC. The constipation mice model was used to investigate the laxative effect of S. grosvenorii aqueous extracts. The motilin (MTL) level in mice serum, and the water content of the large and small intestines in mice were determined. The profile-effect relationship of S. grosvenorii aqueous extracts was preliminarily clarified using gray correlation analysis. Results Nine common peaks were identified from the fingerprint of aqueous extracts of S. grosvenorii. The aqueous extracts obviously shortened the incubation period of defecation, and significantly increased the number of defecations, and the wet and dry weight of defecation in constipated mice. The profile-effect relationship indicated that seven common peaks were highly correlated with the effect of the incubation period of defecation, the number of defecations, and the wet and dry weight of defecation in mice. Conclusion This work provides a promising method for the fingerprint establishment, pharmacodynamic evaluation, and quality control of S. grosvenorii on the basis of its profile-effect relationship.

Background: Magnetic Resonance Imaging (MRI) is frequently employed for the assessment of therapy in head and neck squamous cell carcinoma patients. Nonetheless, this technique has its limitations, the most apparent being the inability to differentiate between after therapy effects and the reoccurrence of tumor cells. Objective: This review was carried out to demonstrate the role of operative MRI in the treatment of head and neck squamous cell carcinoma patients, as well as the analysis of various methods like diffusion, perfusion, and spectroscopy when used in conjugation. Main Findings: Techniques such as diffusion-weighted imaging can augment the reliability of the detection of the main tumor site and local lymphatic nodes post-treatment. It was observed that diffusion is the most facile of the methods in question and can be easily implemented in follow-up sessions after therapy, though the evidential information is sometimes insufficient to validate. Perfusion factors may become elevated in the proliferation of tumors or their reoccurrence, but they are not employed for their accuracy in clinical settings. Spectroscopy methods pose some potential, but the case is the same as diffusion; insufficient data cannot be deemed enough to validate its application. Conclusion: These operative MRI methods can significantly help in the initial discernment of disease, thereby resulting in an improved therapeutic approach in patients. Prospective studies are necessary to layout standard specifications for using operative MRI in routine clinical applications.

Patients with cancer demonstrate particularly poor outcomes from COVID-19. To provide information essential for understanding the biologic underpinnings of this association, we analyzed whole-transcriptome RNA expression data obtained from a large cohort of cancer patients to characterize expression of ACE2, TMPRSS2, and other proteases that are involved in viral attachment to and entry into target cells. We find substantial variability of expression of these factors across tumor types and identify subpopulations expressing ACE2 at very high levels. In some tumor types, especially in gastrointestinal cancers, expression of ACE2 and TMPRSS2 is highly correlated. Furthermore, we found infiltration with T-cell and natural killer (NK) cell infiltration to be particularly pronounced in ACE2-high tumors. These findings suggest that subsets of cancer patients exist with gene expression profiles that may be associated with heightened susceptibility to SARS-CoV-2 infection, in whom malignant tumors function as viral reservoir and possibly promote the frequently detrimental hyper-immune response in patients infected with this virus.

AimsTo use minor salivary glands’ flow rate (MSGFR) measurement in minor salivary glands (MSGs) autotransplantation for the treatment of severe dry eye disease (DED).MethodsMSGs autotransplantations were performed in 18 eyes (17 patients) with severe DED. MSGFR were measured before operation. The upper or lower lip with higher MSGFR was selected as the donor site. Buccal mucosa was the back-up in cases labial MSGs showing markedly decreased MSGFRs. Two pieces of salivary lobules with the covering mucosa were harvested and transplanted to the recipient beds prepared in both upper and lower lids.ResultsThe donor sites included lower lip in 12 eyes, upper lip in 5 eyes and buccal mucosa in 1 eye. Postoperative follow-up confirmed viable grafts in all cases. The overall subjective relief rate of DED symptoms was 58.8%, with Schirmer test values increasing from 0 mm to 4 mm (p2. ROC analysis indicated an outstanding discrimination power for preoperative MSGFR to predicate postoperative relief of DED symptoms (area under the curve (AUC)=0.948, p2. Patients with preoperative MSGFR >1.785 µL/min/cm2 showed greater improvement of Schirmer test values after surgery than those with MSGFR ≤1.785 µL/min/cm2 (pConclusionMSGs transplantation proved to be useful for treating severe DED. The amount of postoperative lubrication and the treatment effect were positively correlated with preoperative MSGFR. MSGFR measurement and donor-site selection should be critical steps before the operation.

Purpose Genomic analysis of individual patients is now affordable, and therapies targeting specific molecular aberrations are being tested in clinical trials. Genomically-informed therapy is relevant to many clinical domains, but is particularly applicable to cancer treatment. However, even specialized clinicians need help to interpret genomic data, to navigate the complicated space of clinical trials, and to keep up with the rapidly expanding biomedical literature. To quantitate the cognitive load on treating clinicians, we attempt to quantitate the rate of change in potential treatment options for patients considering genomically-relevant and genomically-selected therapy for cancer. Materials and methods To this end, we analyzed patient-specific reports generated by a precision oncology decision support team (PODS) at a large academic cancer center. Two types of potential treatment options were analyzed: FDA-approved genomically-relevant and genomically-selected therapies and therapies available via clinical trials. We focused on two clinically-actionable alterations: ERBB2 (Her2/neu; amplified vs. non-amplified) and BRAF mutation (V600 vs. non-V600). To determine changes in available treatment options, we grouped patients into similar groups by disease site (ERBB2: breast, gastric and “other”; BRAF: melanoma, non-melanoma). Results A total of 2927 reports for 2366 unique patients were generated 8/2016-12/2018. Reports included 9902 gene variants and 150 disease classifications. BRAF mutation and ERBB2 amplification were annotated with therapeutic options in 270 reports (225 unique patients). The median survival time of a therapeutic option was nine months. Conclusion When compared to “traditional” clinical practice guideline recommendations, treatment options for personalized cancer therapy change seven times more rapidly; partly due to change in knowledge and partly due to logistics such as clinical trial availability.

Objective: The association between acylcarnitine metabolites and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM) remains uncertain. This study aimed to investigate associations between acylcarnitines and CVD in Chinese patients with T2DM. Methods: A cross-sectional study was conducted from May 2015 to August 2016. Medical records of 741 patients with T2DM were retrieved from the main electronic database of Liaoning Medical University First Affiliated Hospital. CVD was defined as having either coronary artery disease (CAD) or heart failure (HF) or stroke. Mass Spectrometry was utilized to measure levels of 25 acylcarnitine metabolites in fasting plasma. Factor analysis was used to reduce the dimensions and extracted factors of the 25 acylcarnitine metabolites. Multivariable binary logistic regression was used to obtain odds ratios (OR) of the factors extracted from the 25 acylcarnitine metabolites and their 95% confidence intervals (CI) for CVD. Results: Of the 741 patients with T2DM, 288 had CVD. Five factors were extracted from the 25 acylcarnitines and they accounted for 65.9% of the total variance. Factor 1 consisted of acetylcarnitine, butyrylcarnitine, hydroxylbutyrylcarnitine, glutarylcarnitine, hexanoylcarnitine, octanoylcarnitine, and tetradecanoyldiacylcarnitine. Factor 2 consisted of decanoylcarnitine, lauroylcarnitine, myristoylcarnitine, 3-hydroxyl-tetradecanoylcarnitine, tetradecenoylcarnitine, and 3-hydroxypalmitoylcarnitine. After adjusting for potential confounders, increased factor 1 and 2 were associated with increased risks of CVD in T2DM (OR of factor 1: 1.45, 95% CI: 1.03-2.03; OR of factor 2: 1.23, 95% CI: 1.02-1.50). Conclusions: Elevated plasma levels of some acylcarnitine metabolites, i.e., those extracted into factor 1 and 2, were associated with CVD risk in T2DM.

Nanomaterial-based enzyme mimics (nanozymes) are attracting increasing attention because of their low production cost, high stability against denaturation, and resistance to high concentrations of substrates. Here, carbon nanoparticles doped with a small amount (5 mol%) of Pt (denoted as PtCNPs) are synthesized via a facile, cost-effective hydrothermal treatment of p-phenylenediamine (PPD) and K

Recent studies have shown that after traumatic brain injury (TBI), the number of autophagosomes is markedly increased in brain cells surrounding the wound; however, whether autophagy is enhanced or suppressed by TBI remains controversial. In our study, we used a controlled cortical impact system to establish models of mild, moderate and severe TBI. In the mild TBI model, the levels of autophagy-related protein 6 (Beclin1) and autophagy-related protein 12 (ATG12)-autophagy-related protein 5 (ATG5) conjugates were increased, indicating the enhanced initiation of autophagy. Furthermore, the level of the autophagic substrate sequestosome 1 (SQSTM1) was decreased in the ipsilateral cortex. This result, together with the results observed in tandem mRFP-GFP-LC3 adeno-associated virus (AAV)-infected mice, indicates that autophagosome clearance was also increased after mild TBI. Conversely, following moderate and severe TBI, there was no change in the initiation of autophagy, and autophagosome accumulation was observed. Next, we used chloroquine (CQ) to artificially impair autophagic flux in the injured cortex of the mild TBI model and found that the severity of trauma was obviously exacerbated. In addition, autophagic flux and trauma severity were significantly improved in adenosine A2A receptor (A2AR) knockout (KO) mice subjected to moderate TBI. Thus, A2AR may be involved in regulating the impairment of autophagic flux in response to brain injury. Our findings suggest that whether autophagy is increased after TBI is associated with whether autophagic flux is impaired, and the impairment of autophagic flux exacerbates the severity of trauma. Furthermore, A2AR may be a target for alleviating the impairment in autophagic flux after TBI.

Choroidal neovascularization (CNV), a feature of neovasular age-related macular degeneration (AMD), acts as a leading cause of vision loss in the elderly. Shikonin (SHI), a natural bioactive compound extracted from Chinese herb radix arnebiae, exerts anti-inflammatory and anti-angiogenic roles and also acts as a potential pyruvate kinase M2 (PKM2) inhibitor in macrophages. The major immune cells macrophages infiltrate the CNV lesions, where the production of pro-angiognic cytokines from macrophage facilitates the development of CNV. PKM2 contributes to the neovascular diseases. In this study, we found that SHI oral gavage alleviated the leakage, area and volume of mouse laser-induced CNV lesion and inhibited macrophage infiltration without ocular cytotoxicity. Moreover, SHI inhibited the secretion of pro-angiogenic cytokine, including basic fibroblast growth factor (FGF2), insulin-like growth factor-1 (IGF1), chemokine (C-C motif) ligand 2 (CCL2), placental growth factor and vascular endothelial growth factor (VEGF), from primary human macrophages by down-regulating PKM2/STAT3/CD163 pathway, indicating a novel potential therapy strategy for CNV.

Background C1q/tumour necrosis factor-related protein 3 (CTRP3) plays important roles in metabolism and inflammatory responses in various cells and tissues. However, the expression and function of CTRP3 in salivary glands have not been explored. Methods The expression and distribution of CTRP3 were detected by western blot, polymerase chain reaction, immunohistochemical and immunofluorescence staining. The effects of CTRP3 on tumour necrosis factor (TNF)-α-induced apoptosis and barrier dysfunction were detected by flow cytometry, western blot, co-immunoprecipitation, and measurement of transepithelial resistance and paracellular tracer flux. Results CTRP3 was distributed in both acinar and ductal cells of human submandibular gland (SMG) and was primarily located in the ducts of rat and mouse SMGs. TNF-α increased the apoptotic rate, elevated expression of cleaved caspase 3 and cytochrome C, and reduced B cell lymphoma-2 (Bcl-2) levels in cultured human SMG tissue and SMG-C6 cells, and CTRP3 further enhanced TNF-α-induced apoptosis response. Additionally, CTRP3 aggravated TNF-α-increased paracellular permeability. Mechanistically, CTRP3 promoted TNF-α-enhanced TNF type I receptor (TNFR1) expression, inhibited the expression of cellular Fas-associated death domain (FADD)-like interleukin-1β converting enzyme inhibitory protein (c-FLIP), and increased the recruitment of FADD with receptor-interacting protein kinase 1 and caspase 8. Moreover, CTRP3 was significantly increased in the labial gland of Sjogren's syndrome patients and in the serum and SMG of nonobese diabetic mice. Conclusions These findings suggest that the salivary glands are a novel source of CTRP3 synthesis and secretion. CTRP3 might promote TNF-α-induced cell apoptosis through the TNFR1-mediated complex II pathway.

High-throughput genomic and molecular profiling of tumors is emerging as an important clinical approach. Molecular profiling is increasingly being used to guide cancer patient care, especially in advanced and incurable cancers. However, navigating the scientific literature to make evidence-based clinical decisions based on molecular profiling results is overwhelming for many oncology clinicians and researchers. The Personalized Cancer Therapy website (www.personalizedcancertherapy.org) was created to provide an online resource for clinicians and researchers to facilitate navigation of available data. Specifically, this resource can be used to help identify potential therapy options for patients harboring oncogenic genomic alterations. Herein, we describe how content on www.personalizedcancertherapy.org is generated and maintained. We end with case scenarios to illustrate the clinical utility of the website. The goal of this publicly available resource is to provide easily accessible information to a broad oncology audience, as this may help ease the information retrieval burden facing participants in the precision oncology field. Cancer Res; 77(21); e123–6. ©2017 AACR.

Background A reliable anterior facial vein (AFV, donor vein) is cardinal for the success of submandibular gland (SMG) transplantation. This study determined the impact of computed tomographic (CT) venography in identifying AFV variations for SMG transplantation. Methods CT venography was performed in consecutive patients with severe dry eye prior to SMG transplantation in order to identify disadvantageous AFV variations for vascular anastomosis, namely, AFVs that did not drain the SMG and those that did not match the superficial temporal vein (STV, recipient vein; AFV:STV caliber ratio, ≥3). The CT results were compared with the intraoperative findings for the diagnostic accuracy. Results Forty-two donors were included. Compared with the intraoperative findings, the CT results accurately identified AFV–STV caliber mismatches ( P = 1.00; sensitivity and specificity, 100%). In the identification of AFVs not draining the SMG, CT showed 94.7% sensitivity and 100% specificity ( P = 0.25). According to the CT findings, 10 contralateral SMGs with AFVs (23.8%), instead of ipsilateral donors, were selected for transplantations (conventionally ipsilateral donor was the first choice). The surgical success rate was 95.2% (40/42). Conclusion CT venography is valuable in determining disadvantageous AFV variations for anastomosis and choosing a reliable donor for SMG transplantation.

Background To develop the Chinese version of quality of life scale for dry eye patients based on the Impact of Dry Eye on Everyday Life (IDEEL) questionnaire and to assess the reliability and validity of the developed scale. Methods The original IDEEL was adapted cross-culturally to Chinese language and further developed following standard procedures. A total of 100 Chinese patients diagnosed with dry eye syndrome were included to investigate the psychometric properties of the Chinese version of scale. Psychometric tests included internal consistency (Cronbach’s ɑ coefficients), construct validity (exploratory factor analysis), and known-groups validity (the analysis of variance). Results The Chinese version of Dry Eye Related Quality of Life (CDERQOL) Scale contains 45 items classified into 5 domains. Good to excellent internal consistency reliability was demonstrated for all 5 domains (Cronbach’s ɑ coefficients range from 0.716 to 0.913). Construct validity assessment indicated a consistent factorial structure of the CDERQOL scale with hypothesized construct, with the exception of “Dry Eye Symptom-Bother” domain. All domain scores were detected with significant difference across three severity groups of dry eye patients (P

The diagnostic utility of labial salivary gland (LSG) biopsy for IgG4-related sialadenitis remains undetermined. The purpose of the present study was to determine whether submandibular gland biopsy could be replaced by LSG biopsy for diagnosing IgG4-RS. Medical records of two groups of patients were reviewed. Group A contained 45 patients suspected to have IgG4-RS who underwent both SMG and LSG biopsies. Group B contained 25 patients who were clinically and pathologically diagnosed with Sjogren syndrome (SS). Biopsy samples were stained using hematoxylin and eosin (HE) and immunohistochemical techniques and observed under an optical microscope. Relevant data describing histopathological characteristics were collected and analyzed. SMG of IgG4-RS patients presented typical histopathological characteristics of fibrosis and IgG4-positive plasmacytic infiltration, while LSG showed varied characteristics. The sensitivity and accuracy of SMG for diagnosing IgG4-RS were greater than those of LSG (100% and 100% versus 55.3% and 75.7%, respectively, P

Genomic testing has become a part of routine oncology care and plays critical roles in diagnosis, prognostic assessment, and treatment selection. Thus, in parallel, the variety of genomic testing providers and sequencing platforms has grown exponentially. Selection of the best-fit panel for each case can be daunting, with many factors to consider. Among them is whether alteration interpretation and therapy/clinical trial matching are included and/or sufficient. In this article, we review some common commercially available sequencing platforms for the genes and types of alterations tested, samples needed, and reporting content provided. We review publicly available resources for a do-it-yourself approach to alteration interpretation when it is not provided or when supplemental research is needed, along with resources to identify genomically matched treatment options that are approved and/or investigational. However, with both commercially provided interpretation and publicly available resources, there are still caveats and limitations that can stem from insufficient or ambiguous nomenclature as well as from the presentation of information. Use cases in which clinical decision making was affected are discussed. After treatment options are identified, it is important to assess the level of evidence for use within the patient’s tumor type and molecular profile. However, numerous level-of-evidence scales have been published in recent years, so we provide a publicly available tool to facilitate interoperability. The level of evidence, along with other factors, such as allelic frequency and copy number, can be used to prioritize treatment options when multiple are identified.

Red-emitting carbon dots (CDs) have attracted tremendous attention due to their wide applications in areas including imaging, sensing, drug delivery, and cancer therapy. However, it is still highly challenging for red-emitting CDs to simultaneously achieve high quantum yields (QYs), nucleus targeting, and super-resolution fluorescence imaging (especially the stimulated emission depletion (STED) imaging). Here, it is found that the addition of varied metal ions during the hydrothermal treatment of

Our purpose was to provide a pathological basis for preservation of the submandibular glands during neck dissection for oral squamous cell carcinoma (SCC) by investigating whether intraglandular lymph nodes exist in submandibular glands, and the modes of involvement of submandibular glands in oral SCC. We studied the records of 95 patients with oral SCC (other than that in the floor of the mouth) treated at our hospital from January 2017 to June 2018. The specimens of submandibular glands discarded after neck dissection were analysed, and serially sectioned. Sections 5μm thick were obtained at 0.5mm intervals and stained with haematoxylin and eosin for examination under light microscopy. A total of 116 specimens were obtained from the 95 patients, and about 5000 slides were evaluated. No intraglandular lymph nodes were detected in the submandibular glands. In the subgroup of patients whose primary tumours had extended into the floor of the mouth, four submandibular glands were involved by direct spread of the primary tumour. In the subgroup with metastases to level Ib lymph nodes, four submandibular glands were involved by extranodal extension from the metastatic nodes. No intraglandular lymph nodes or micrometastases were detected. We conclude that no intraglandular lymph nodes are present in submandibular glands, which may be involved by direct extension of the primary carcinoma or metastatic cervical lymph nodes with extranodal extension. Preservation of the submandibular glands during neck dissection seems to be feasible and safe in selected patients with oral SCC.

Objective Optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation remains controversial. The present study is an assessment of efficacy and safety of short-term (≤6 months) DAPT after DES implantation in patients with coronary artery disease, especially in important subgroups. Methods PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched for randomized, controlled trials comparing short-term and long-term (>6 months) DAPT after DES implantation. Primary efficacy outcome was stent thrombosis (ST). Primary safety outcome was major bleeding. Pooled relative risks (RRs) with 95% confidence interval (CI) were calculated using random- or fixed-effects models as appropriate. Results Total of 7 trials involving 15870 patients were included in the study. Short-term DAPT significantly reduced major bleeding by 49% compared with long-term DAPT (RR: 0.51; 95% CI: 0.32-0.80; p=0.003) without increasing risk of ST (RR: 1.28; 95% CI: 0.83-1.97; p=0.266). In addition, no differences were observed in all-cause mortality, myocardial infarction (MI), cardiac mortality, or cerebrovascular accidents. Moreover, no significant difference in composite of cardiovascular events, bleeding, and mortality was found in important clinical subgroups. Conclusion Short-term DAPT is associated with lower bleeding risk compared with long-term DAPT. Number of ST and MI was higher with short-term DAPT without reaching statistical significance. Comprehensive clinical judgment is necessary to weigh benefits and risks in the individual patient.

// Reva K. Basho 1,* , Debora de Melo Gagliato 2,* , Naoto T. Ueno 2 , Chetna Wathoo 3 , Huiqin Chen 4 , Maryam Shariati 5 , Caimiao Wei 4,6 , Ricardo H. Alvarez 2,7 , Stacy L. Moulder 2 , Aysegul A. Sahin 8 , Sinchita Roy-Chowdhuri 8 , Mariana Chavez-MacGregor 2,9 , Jennifer K. Litton 2 , Vincent Valero 2 , Raja Luthra 8 , Jia Zeng 3 , Kenna R. Shaw 3 , John Mendelsohn 3,10 , Gordon B. Mills 3,11 , Debu Tripathy 2 and Funda Meric-Bernstam 3,5,12 1 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA 6 Pfizer, Inc, New York, NY, USA 7 The Cancer Treatment Centers of America, Chicago, IL, USA 8 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 9 Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 10 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 11 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 12 Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA * These authors have contributed equally to this work Correspondence to: Funda Meric-Bernstam, email: // Keywords : metastatic breast cancer, genomics, TP53, PIK3CA Received : April 06, 2016 Accepted : October 13, 2016 Published : October 28, 2016 Abstract BACKGROUND: Identifying the clinical impact of recurrent mutations can help define their role in cancer. Here, we identify frequent hotspot mutations in metastatic breast cancer (MBC) patients and associate them with clinical outcomes. PATIENTS AND METHODS: Hotspot mutation testing was conducted in 500 MBC patients using an 11 gene ( N = 126) and/or 46 or 50 gene ( N = 391) panel. Patients were stratified by hormone receptor (HR) and human epidermal growth factor 2 (HER2) status. Clinical outcomes were retrospectively collected. RESULTS: Hotspot mutations were most frequently detected in TP53 (30%), PIK3CA (27%) and AKT1 (4%). Triple-negative breast cancer (TNBC) patients had the highest incidence of TP53 (58%) and the lowest incidence of PIK3CA (9%) mutations. TP53 mutation was associated with shorter relapse-free survival (RFS) (median 22 vs 42months; P < 0.001) and overall survival (OS) from diagnosis of distant metastatic disease (median 26 vs 51months; P < 0.001). Conversely, PIK3CA mutation was associated with a trend towards better clinical outcomes including RFS (median 41 vs 30months; P = 0.074) and OS (52 vs 40months; P = 0.066). In HR-positive patients, TP53 mutation was again associated with shorter RFS (median 30 vs 46months; P = 0.017) and OS (median 30 vs 55months; P = 0.001). When multivariable analysis was performed for RFS and OS, TP53 but not PIK3CA mutation remained a significant predictor of outcomes in the overall cohort and in HR-positive patients. CONCLUSIONS: Clinical hotspot sequencing identifies potentially actionable mutations. In this cohort, TP53 mutation was associated with worse clinical outcomes, while PIK3CA mutation did not remain a significant predictor of outcomes after multivariable analysis.

Poor secretion of transplanted submandibular glands (SMGs) during the latent period may cause duct obstruction and affects the surgical outcome. The objective of this study was to investigate the efficacy and systemic side effects of carbachol on transplanted SMG secretion. Twenty-seven patients who underwent SMG transplantation for severe keratoconjunctivitis sicca were treated with subcutaneous injections of 0.2mg/2ml carbachol at 10 days, 1 month, and/or 3 months after surgery. The effect on secretion was evaluated by Schirmer test and technetium 99m ((99m)Tc) scintigraphy. Systemic side effects were evaluated subjectively using a questionnaire. The results showed that the time to onset varied from 4 to 9min and the duration of action from 50 to 110min after carbachol administration. The secretion at each time point after drug administration was significantly higher than the pre-administration value (all P

We explored the effects of repeated plateletpheresis on the platelet P-selectin expression and soluble P-selectin (sP-selectin) concentrations in platelet donors.Totally 289 platelet donors and 97 first-time whole blood (WB) donors were enrolled from the blood donor registry at the Fujian provincial blood center, China. The accumulative numbers of plateletpheresis in the last 2 y for participants were recorded, and the basal concentrations of platelet count, sP-selectin and total platelet P-selectin (pP-selectin) were determined.Platelet donors had significantly higher basal concentrations of sP-selectin compared to WB donors (24.12±7.33ng/mL vs. 20.74±5.44ng/mL, P0.0001), with no difference in platelet count and pP-selectin concentrations. Increased numbers of platelet donation were correlated with a steady increase of sP-selectin (r=0.18, P=0.002). Multivariate regression analysis identified that the frequency of plateletpheresis is an independent factor for the rise of the sP-selectin concentration (t=2.64, P=0.009) while no association was found for pP-selectin and platelet count.Repeated plateletpheresis could result in an increased basal concentration of sP-selectin in blood donors whereas not an alteration in the concentrations of total platelet P-selectin. It remains to be determined whether this might be a consequence of endothelial activation or platelet activation or some other phenomenon.

Introduction Genomic profiling information is frequently available to oncologists, enabling targeted cancer therapy. Because clinically relevant information is rapidly emerging in the literature and elsewhere, there is a need for informatics technologies to support targeted therapies. To this end, we have developed a system for Automated Identification of Molecular Effects of Drugs, to help biomedical scientists curate this literature to facilitate decision support. Objectives To create an automated system to identify assertions in the literature concerning drugs targeting genes with therapeutic implications and characterize the challenges inherent in automating this process in rapidly evolving domains. Methods We used subject-predicate-object triples (semantic predications) and co-occurrence relations generated by applying the SemRep Natural Language Processing system to MEDLINE abstracts and ClinicalTrials.gov descriptions. We applied customized semantic queries to find drugs targeting genes of interest. The results were manually reviewed by a team of experts. Results Compared to a manually curated set of relationships, recall, precision, and F2 were 0.39, 0.21, and 0.33, respectively, which represents a 3- to 4-fold improvement over a publically available set of predications (SemMedDB) alone. Upon review of ostensibly false positive results, 26% were considered relevant additions to the reference set, and an additional 61% were considered to be relevant for review. Adding co-occurrence data improved results for drugs in early development, but not their better-established counterparts. Conclusions Precision medicine poses unique challenges for biomedical informatics systems that help domain experts find answers to their research questions. Further research is required to improve the performance of such systems, particularly for drugs in development.