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Few studies have assessed the efficacy and safety of reconstruction of sternal infection using a pectoralis muscle flap combined with a rectus abdominis muscle (RAM) sheath fasciocutaneous flap. We report here our experience with this procedure to reconstruct the sternal defect in patients (n = 46) with a deep sternal wound infection (DSWI) after cardiac surgery. After wound reconstruction, the proportion of prolonged mechanical ventilation use and intensive care unit (ICU) stay were 17.4% (n = 8) and 21.7% (n = 10), respectively. The 30-day all-cause mortality was 15.2%; recurrence rate was 17.4%; postoperative complications were 15.2%; and median hospital stay was 31 (0-157) days. Multivariate logistic regression analysis revealed that hypertension (β = 21.32, 95%CI 4.955-37.68, P = .014), drainage-tube use (β = 0.944, 95%CI 0.273-1.614, P = .008), and prolonged intensive care unit stay (β = 53.65, 95%CI 31.353-75.938, P .001) were significantly correlated with hospital stay. In conclusion, a procedure including surgical debridement, sternal reconstruction with bilateral PM and RAM sheath flap, long-term antibiotics, and adequate drainage is a beneficial technique in the reconstruction of deep sternal wound infection after cardiac surgery. Duration of drainage tube use may be as an index for a hospital stay or wound healing.

Kimura disease (KD) is a rare, chronic inflammatory disorder presenting with solitary or multiple masses. Treatment options include surgical excision, corticosteroids, and radiotherapy; however, optimal therapy remains to be established. Moreover, efficacy of a humanized monoclonal antibody, dupilumab (Dupixent), requires to be demonstrated. Here, we present a 36-year-old male patient with an enlarging mass in the left medial thigh and chronic eczema over the abdomen and lower legs. Kimura disease was diagnosed after surgical excision. Postoperative treatment with dupilumab was applied with an initial dose of 600 mg followed by 300 mg every 2 weeks for 8 months. No recurrence of KD was observed in the 1-year follow-up. The eczematous lesions improved greatly. To our knowledge, this is the first report of using dupilumab for treating KD.

Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph

Members of the PI3K signaling pathway, especially PIK3CA, the gene encoding the catalytic subunit of the PI3K complex, are highly mutated and amplified in various cancer types, including non-small cell lung cancer. Although PI3K inhibitors have been used in clinics for follicular lymphoma and chronic lymphocytic leukemia, no agents targeting PI3K aberrations in lung cancer have been approved by the FDA so far. In this study, we observed that PIK3CA-E545K, the most common mutation in lung cancer, harbored a modest induction of stem-like properties in lung epithelial cells, and drove development of adenocarcinoma autochthonously when paired with p53 loss in a murine mouse model. We also found that PIK3CA-mutant of amplified lung cancer cells were sensitive to EZH2 inhibition. EZH2 inhibition synergized with PI3K inhibition in human cancer cells in vitro and worked together efficiently in vivo. Mechanistically, EZH2 inhibition cooperated with PI3K inhibition to produce a more potent suppression of phospho-AKT downstream of PI3K. This study suggests a promising combination therapy to combat lung cancers with PIK3CA mutation or amplification. Both copanlisib, the PI3K inhibitor, and tazemetostat, the EZH2 inhibitor, are FDA-approved, which should enhance the clinical translation of this work.

Preeclampsia is one of the most serious pregnancy complications. It may be caused by immunological changes in the early placental microenvironment. The contents of small EVs may serve as biomarkers of pregnancy complications. Evidence suggests that the balance between T helper 17 (Th17) and regulatory T (Treg) cells are critical for preventing preeclampsia. The study recruited 39 pregnant women with preeclampsia and 127 healthy pregnant women. We assessed the levels of both Th17 and Treg cytokines (IL-10, IL-17, IL-21, IL-22, and TGF-β) in their plasma and small EVs. We found significant differences in the levels of all cytokines in the plasma between the two groups during the second trimester. We also observed significant differences between the two groups in the levels of EV-encapsulated cytokines IL-21, IL-22, and TGF-β, as well as in total small EVs, during the second trimester. The ROC analysis showed that the classification efficiency (AUC) of TGF-β in small EVs was 0.81. TGF-β had the best discriminant ability of all the single EV biomarkers tested, the cross-validation of the accuracy was 0.89. Th17 and Treg cytokines in plasma and small EVs may contribute to maternal immune activation and clarify the potential mechanisms of small EVs and cytokines in preeclampsia.

Metabolic reprogramming is critical for tumorigenesis. Pyruvate kinase M2 (PKM2) is overexpressed in lung carcinoma cells and plays a critical role in the Warburg effect, making the enzyme a research hotspot for anticancer drug development. Cynaropicrin (CYN), a natural sesquiterpene lactone compound from artichoke, has received increasing consideration due to its consumable esteem and pharmacological properties. Our data reveal that CYN not only inhibited the purified PKM2 activity but also decreased the cellular PKM2 expression in A549 cells. The inhibition of PKM2 leads to the upregulation of p53 and the downregulation of the DNA repair enzyme poly (ADP-ribose) polymerase (PARP), and subsequently causes the cell cycle arrest. Additionally, CYN inhibits the interaction of PKM2 and Nrf2, resulting in the impairment of cellular antioxidant capacity, induction of oxidative stress, and mitochondrial damages. Overexpression of PKM2 attenuates the CYN-induced DNA damage, mitochondrial fission, and cell viability. Thus, targeting PKM2 provides an original mechanism for understanding the pharmacological impact of CYN and assists in the further development of CYN as an anticancer agent.

Background Previous studies have assessed note quality and the use of electronic medical record (EMR) as a part of medical training. However, a generalized and user-friendly note quality assessment tool is required for quick clinical assessment. We held a medical record writing competition and developed a checklist for assessing the note quality of participants’ medical records. Using the checklist, this study aims to explore note quality between residents of different specialties and offer pedagogical implications. Methods The authors created an inpatient checklist that examined fundamental EMR requirements through six note types and twenty items. A total of 149 records created by residents from 32 departments/stations were randomly selected. Seven senior physicians rated the EMRs using a checklist. Medical records were grouped as general medicine, surgery, paediatric, obstetrics and gynaecology, and other departments. The overall and group performances were analysed using analysis of variance (ANOVA). Results Overall performance was rated as fair to good. Regarding the six note types, discharge notes (0.81) gained the highest scores, followed by admission notes (0.79), problem list (0.73), overall performance (0.73), progress notes (0.71), and weekly summaries (0.66). Among the five groups, other departments (80.20) had the highest total score, followed by obstetrics and gynaecology (78.02), paediatrics (77.47), general medicine (75.58), and surgery (73.92). Conclusions This study suggested that duplication in medical notes and the documentation abilities of residents affect the quality of medical records in different departments. Further research is required to apply the insights obtained in this study to improve the quality of notes and, thereby, the effectiveness of resident training.

To explore the clinical characteristics of early-onset preeclampsia (PE) combined with HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and to improve the capacity for early diagnosis and treatment.Pregnant women who received treatment at Women's Hospital, School of Medicine, Zhejiang University between March 2014 and October 2021 were retrospectively enrolled. There were two patient groups, the HELLP group consisting of 70 cases of early-onset PE combined with HELLP syndrome and the control group consisting of 140 cases of early-onset PE without HELLP syndrome. Patients in the two groups were matched by age. The general clinical data, characteristics of pathogenesis, and laboratory findings of the patients were collected and the perinatal outcomes of the two groups were compared and analyzed.1) There was no significant difference in gravidity, pre-delivery body mass index, years from the last delivery, and family history of diabetes mellitus and hypertension between the two groups. 2) The highest systolic blood pressure, highest diastolic blood pressure during the pregnancy, and the postpartum hospital length-of-stay (In comparison with early-onset PE patients without HELLP syndrome, patients with early-onset PE combined with HELLP syndrome are diagnosed for PE at an earlier gestational age, have higher blood pressure, are more prone to serious pregnancy complications, and have longer postpartum hospital length-of-stay and worse neonatal outcomes. Close monitoring of PLT counts of early-onset PE patients in the second trimester may help predict subsequent HELLP syndrome.

BackgroundAdvances in tumor immunotherapy have been developed for patients with advanced recurrent or metastatic (R/M) HNSCC. However, the response of most HNSCC patients to immune checkpoint inhibitors (ICI) remains unsatisfactory. CD73 is a promising target for tumor immunotherapy, but its role in HNSCC remains insufficient. In this study, we aim to explore the function of CD73 in HNSCC.MethodsTranscriptomic and clinical data of TCGA-HNSC were downloaded from UCSC Xena for analysis of CD73 mRNA expression and prognosis. Immunohistochemical assay were performed to validate the expression of CD73 in tumor tissues and its relationship with CD8+ T cells. GSEA analysis was performed with the “clusterProfiler” R package. Immune infiltration analysis was calculated with ESTIMATE, CIBERSORT and MCP-counter algorithms. Single-cell transcriptomic data was originated from GSE103322. Cell clustering, annotation and CD73 expression were from the TISCH database. Correlation data between CD73 and tumor signatures were obtained from the CancerSEA database. Somatic mutation data were obtained from TCGA-HNSC and analyzed by “maftools” R package. Immune efficacy prediction was performed using TIDE algorithm and validated with the IMvigor210 cohort.ResultsCompared with normal tissues, both mRNA and protein expressions of CD73 were elevated in tumor tissues (P = 9.7×10-10, P = 7.6×10-5, respectively). Kaplan-Meier analysis revealed that patients with high expression of CD73 had worse overall survival (log-rank P = 0.0094), and CD73 could be used as a diagnostic factor for HNSCC (AUC = 0.778). Both bulk RNA-seq and single-cell RNA-seq analysis showed that high CD73 expression can promote EMT and metastasis, samples with high CD73 expression had reduced CD8+ T cells. Furthermore, it was found that CD73-high group was more prone to have mutations in TP53, HRAS and CDKN2A, and were negatively correlated with TMB (P = 0.0055) and MSI (P = 0.00034). Mutational signature analysis found that CD73 was associated with APOBEC signature. Immunotherapy efficacy analysis showed that CD73-high group was less sensitive to immune efficacy.ConclusionsOur results demonstrate that CD73 has an inhibitory effect on the tumor microenvironment, and is more likely to be unresponsive to ICI therapy. Collectively, targeting CD73 may provide new insights for tumor targeted therapy and/or immunotherapy.

Objective To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with SLE susceptibility, glucocorticoid (GC) efficacy and prognosis. Methods Our study was done in two stages. First, we performed whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and GC efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis. Results In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all PBH Conclusion We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GC efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GC efficacy. Our findings provide important information for future understanding of the occurrence and development of SLE.

AIMS Data regarding clinical pharmacokinetic/toxicodynamic (PK/TD) of polymyxin B is short of direct quantitative data. This study aims to investigate the risk factors of polymyxin B associated acute kidney injury (AKI) and to assess the relationship between polymyxin B plasma levels and its nephrotoxicity. METHODS A retrospective study was performed in adult patients treated with polymyxin B. Risk factors associated with AKI and plasma trough concentrations of polymyxin B were identified via medical record review. A multivariate logistic regression model was established and the risk of polymyxin B-associated AKI were predicted by a receiver operating characteristic curve, with maximal Youden index used to identify safety thresholds among the study population. RESULTS Fifty-four adult patients were included in the study. AKI was detected in 14 patients during polymyxin B treatment (25.9%, 14 out of 54). Cmin (odds ratio [OR] 2.071; 95% confidence interval [CI] 1.235-3.472) and baseline serum creatinine (OR 1.024; 95% CI 1.005-1.043) were significant independent risk factors for developing AKI. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was at maximum, the optimal cut-off point was 6.678 of the ROC curve. When Cmin ≥ 3.13 mg/L, the probability of AKI was more than 50%. CONCLUSION In this study, when the calculated combined predictor value was >6.678, there was an increased risk of AKI. Maintaining a polymyxin B Cmin level below 3.13 mg/L may be helpful in reducing the incidence of polymyxin B associated nephrotoxicity.

Radiation-induced emesis (RIE) is usually noted during abdominal-pelvic radiotherapy. In gynecological malignancies, it is usually noted in para-aortic but not whole-pelvic irradiation. Irradiated small bowel (SB) may be associated with RIE. The significance of SB dosimetry remains unclear. Dosimetric and non-dosimetric factors were evaluated and correlated with RIE in 45 patients with gynecological malignancies undergoing extended-field radiotherapy (EFRT) (median 45 Gy) from 2006 to 2021. Early-onset RIE (within 72 h after the first fraction of EFRT) was noted in 10 of 12 RIE patients. RIE was significantly associated with the SB mean dose. The RIE rates were 58.3% and 15.2% (p = 0.007) in patients with a low (&lt, 63%) and high (≥63%) SB mean dose. Logistic regression revealed that the SB mean dose remained the independent factor of overall RIE (p = 0.049) and early-onset RIE (p = 0.014). Therefore, constraint of the SB mean dose limited to less than 63% of the prescribed dose is suggested to decrease RIE.

Development of acquired resistance to lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor, severely limits the duration of clinical response in advanced HER2‐driven breast cancer patients. Although the compensatory activation of the PI3K/Akt survival signal has been proposed to cause acquired lapatinib resistance, comprehensive molecular mechanisms remain required to develop more efficient strategies to circumvent this therapeutic difficulty. In this study, we found that suppression of HER2 by lapatinib still led to Akt inactivation and elevation of FOX3a protein levels, but failed to induce the expression of their downstream pro‐apoptotic effector p27kip1, a cyclin‐dependent kinase inhibitor. Elevation of miR‐221 was found to contribute to the development of acquired lapatinib resistance by targeting p27kip1 expression. Furthermore, upregulation of miR‐221 was mediated by the lapatinib‐induced Src family tyrosine kinase and subsequent NF‐κB activation. The reversal of miR‐221 upregulation and p27kip1 downregulation by a Src inhibitor, dasatinib, can overcome lapatinib resistance. Our study not only identified miRNA‐221 as a pivotal factor conferring the acquired resistance of HER2‐positive breast cancer cells to lapatinib through negatively regulating p27kip1 expression, but also suggested Src inhibition as a potential strategy to overcome lapatinib resistance., The downregulation of p27kip1 by Src/NF‐κB axis‐induced miR‐221 expression as a novel mechanistic insight into lapatinib resistance. Targeting Src would be a promising strategy to overcome lapatinib resistance.

Objective Our present study intended to examine the associations of RPEL1 and miR-1307 gene polymorphisms (rs4917385 and rs7911488) with susceptibility, glucocorticoids (GCs) efficacy, anxiety, depression, and health-related quality of life (HRQoL) in Chinese systemic lupus erythematosus (SLE) patients. Methods Initially, 1000 participants (500 SLE cases and 500 controls) were recruited for the case–control study. Then, 429 cases who received GCs were followed through 12 weeks to explore GCs efficacy, depression, anxiety, and HRQoL. We selected the iMLDR technique for genotyping: RPEL1: rs4917385 (G/T) and miR-1307: rs7911488 (A/G). Results The minor G allele of rs7911488 reduced the risk of SLE ( p = .024). Four haplotypes consisting of rs4917385 and rs7911488 were associated with SLE susceptibility ( p < .025). Both rs4917385 and rs7911488 were associated with anxiety symptoms and physical function (PF) in SLE patients ( p < .025). The rs4917385 was associated with depression and its improvement. No statistical significance was found between RPEL1 and miR-1307 gene polymorphisms with GCs efficacy. Meanwhile, additive interaction analysis showed a significant association between RPEL1 and miR-1307 gene polymorphisms with tea consumption in anxiety. Conclusion RPEL1 and miR-1307 gene polymorphisms (rs4917385 and rs7911488) might be related to SLE susceptibility in Chinese population. Additionally, the two polymorphisms were possibly associated with depression, anxiety, and HRQoL in Chinese SLE population.

Scars can cause pain, long-term physical dysfunction, and psychological harm. Botulinum toxin type A (BoNT-A) is one treatment choice for scars, but further evidence is needed to confirm its efficacy.This systematic review included randomized controlled trials that investigated the effectiveness of BoNT-A on scars. The mean and standard deviation for the Vancouver Scar Scale, Stony Brook Scar Evaluation Scale, visual analog scale for appearance evaluation, visual analog scale for scar pain evaluation, and scar width were extracted for subgroup analysis.Twenty-one randomized controlled trials were included. The BoNT-A group had a lower Vancouver Scar Scale score than the saline group (standardized mean difference, -0.73; 95 percent CI, -1.12 to -0.35; p = 0.0002) but a higher score than the steroid group (standardized mean difference, 0.85; 95 percent CI, 0.27 to 1.43; p = 0.004). The BoNT-A group exhibited a higher Stony Brook Scar Evaluation Scale grade than the saline group (standardized mean difference, 1.42; 95 percent CI, 0.83 to 2.00; p0.00001). The visual analog scale for appearance evaluation revealed higher scores in the BoNT-A group than in the saline group (standardized mean difference, 1.14; 95 percent CI, 0.69 to 1.60; p0.00001). As for pain evaluation, the BoNT-A group had a lower visual analog scale score than the steroid group (standardized mean difference, -2.57; 95 percent CI, -4.40 to -0.74; p = 0.006). Furthermore, scar width was significantly shorter in the BoNT-A group than in the control group (standardized mean difference, -1.11; 95 percent CI, -1.38 to -0.83; p0.00001).BoNT-A is more effective in treating scars than saline, although steroids may exhibit higher potency. Therefore, it can be considered an alternative in patients not amenable to steroid treatment.Therapeutic, II.

Updated and expert-quality knowledge bases are fundamental to biomedical research. A knowledge base established with human participation and subject to multiple inspections is needed to support clinical decision making, especially in the growing field of precision oncology. The number of original publications in this field has risen dramatically with the advances in technology and the evolution of in-depth research. Consequently, the issue of how to gather and mine these articles accurately and efficiently now requires close consideration. In this study, we present OncoPubMiner (https://oncopubminer.chosenmedinfo.com), a free and powerful system that combines text mining, data structure customisation, publication search with online reading and project-centred and team-based data collection to form a one-stop ‘keyword in–knowledge out’ oncology publication mining platform. The platform was constructed by integrating all open-access abstracts from PubMed and full-text articles from PubMed Central, and it is updated daily. OncoPubMiner makes obtaining precision oncology knowledge from scientific articles straightforward and will assist researchers in efficiently developing structured knowledge base systems and bring us closer to achieving precision oncology goals.

Encapsulating peritoneal sclerosis (EPS) is a catastrophic complication of peritoneal dialysis (PD) with high mortality. Our aim is to develop a novel noninvasive microRNA (miRNA) test for EPS.We collected 142 PD effluents (EPS: 62 and non-EPS:80). MiRNA profiles of PD effluents were examined by a high-throughput real-time polymerase chain reaction (PCR) array to first screen. Candidate miRNAs were verified by single real-time PCR. The model for EPS prediction was evaluated by multiple logistic regression and machine learning.Seven candidate miRNAs were identified from the screening of PCR-array of 377 miRNAs. The top five area under the curve (AUC) values with 5 miRNA-ratios were selected using 127 samples (EPS: 56 vs non-EPS: 71) to produce a receiver operating characteristic curve. After considering clinical characteristics and 5 miRNA-ratios, the accuracies of the machine learning model of Random Forest and multiple logistic regression were boosted to AUC 0.97 and 0.99, respectively. Furthermore, the pathway analysis of miRNA associated targeting genes and miRNA-compound interaction network revealed that these five miRNAs played the roles in TGF-β signaling pathway.The model-based miRNA expressions in PD effluents may help determine the probability of EPS and provide further therapeutic opinion for EPS.

Aims We aimed to evaluate the impact of the COVID-19 epidemic on emergency and cardiovascular disease–related calls in Hangzhou, China. Methods We conducted a single-center retrospective study, collecting data on emergency calls to the Hangzhou Emergency Center (HEC) during the COVID-19 epidemic (January 20, 2020, to March 15, 2020). Data were compared with the same period in 2019. Results Compared to 2019, the number of emergency calls has dropped by 21.63%, ambulance calls by 29.02%, rescue calls by 22.57%, and cardiovascular disease-related emergency calls by 32.86%. The numbers of emergency, ambulance, and rescue calls in 2020 were significantly lower than in 2019. Conclusions During the COVID-19 epidemic in Hangzhou, the numbers of emergency and cardiovascular disease–related calls have decreased significantly. These results point to a severe social problem that requires the attention of the medical community and the government.

This study aimed to investigate the research trend of traditional Chinese medicine(TCM) against premature ovarian fai-lure(POF) from 1989 to 2021 by bibliometrics and explore the research status, research hotspots, and advances in international co-operation, knowledge structure, and active topics.The research articles on POF published from database inception to December 28, 2021, were retrieved from Web of Science and China National Knowledge Infrastructure(CNKI) and visually analyzed for countries, journals, authors, institutions, and keywords by CiteSpace 5.8.R3.A total of 1 468 articles were included, including 217 in English and 1 251 in Chinese.Since 1989, there has been an overall upward trend in the number of articles, with China serving as the main contributor.The core authors of Chinese articles are from a cooperative team represented by FENG Yi-xuan, REN Yu-lan, LING Le-le, and TENG Xiu-xiang.BETTERLE C is the author with the highest number of published articles in this international research field.The articles are mainly published by TCM journals and universities, and Human Reproduction accounts for the highest proportion of publications in the international research(11 articles, 5.07%).In the retrieved research articles, the research contents mainly focus on the treatment methods, research methods, and mechanism of action of TCM in the treatment of POF, wherequot;Zuogui Pillsquot;quot;genequot;quot;cellquot;quot;modelquot;quot;expressionquot;, etc.are the current research hotspots.quot;Acupuncturequot;quot;data miningquot;quot;systematic reviewquot;quot;oxidative stressquot;quot;activationquot; may be the potential topics in the follow-up research development.Future development should focus on the scientific interpretation and analysis of the theory and practice of TCM by modern scientific and technological methods.The research on informatization, digitization, and knowledge of TCM theory and practice is pivotal to promoting the internationalization and modernization of TCM, which can help researchers explore new directions for future research and identify new perspectives for potential collaboration in the field.

Background To compare the safety and efficacy of tranexamic acid (TXA)-soaked absorbable Gelfoam and the retrograde injection of TXA through a drain with drain-clamping in degenerative cervical laminoplasty patients. Methods Patients were assigned into either TXA retrograde injection (TXA-RI), TXA-soaked absorbable Gelfoam (TXA-Gel), or control groups. The demographics, operative measurements, volume and length of drainage, length of hospital stay, complete blood cell count, coagulopathy, postoperative complications, and blood transfusion were recorded. Results We enrolled 133 patients, with 44, 44, and 45 in the TXA-RI, TXA-Gel, and control groups, respectively. The baseline characteristics did not differ significantly among the three groups. The TXA-RI group exhibited a lower volume and length of postoperative drainage compared to the TXA-Gel and control groups (126.60 ± 31.27 vs. 156.60 ± 38.63 and 275.45 ± 75.27 mL; 49.45 ± 9.70 vs 58.70 ± 10.46 and 89.31 ± 8.50 hours, all P P P P Conclusion Topical retrograde injection of TXA through a drain with drain-clamping at the conclusion of unilateral posterior cervical expansive open-door laminoplasty may effectively reduce postoperative blood loss and the length of hospital stays without increasing postoperative complications.

Immunoglobulin A nephropathy (IgAN) is a highly prevalent autoimmune renal disease. Human IgA1 with galactose deficiency in the hinge region (HR) has been identified as an autoantigen for this disease. Therefore, analyzing IgA1 HR glycoforms in biofluids is important for biomarker discovery. Herein, an analytical method that includes one-pot sample preparation with unbiased plasma IgA purification, dual internal standard addition, and sensitive ultra-high-performance liquid chromatography-triple quadrupole tandem mass spectroscopy (UHPLC-QqQ-MS/MS) was developed. Targeted O-glycopeptides detection was performed in pooled plasma with the validation of theoretical retention times, enzymatic treatment outcomes, product ion scans, and signal repeatability. A total of 42 IgA1 O-glycopeptides with N-acetylgalactosamines, galactoses, and sialic acids were determined from 8 µL of plasma. The newly developed method was applied to plasma samples from 16 non-IgAN controls and 19 IgAN patients. Comparing the 42 targets, 16 IgA1 HR O-glycopeptides were statistically different between the two groups (p0.05). Decreased sialylation was identified in the IgA1 hinge region of IgAN patients, which was also correlated with the estimated glomerular filtration rate (eGFR). The developed method is sensitive and precise and can be used to identify plasma biomarkers for IgA nephropathy.

Although spirometry is a simple, portable test and recommended for the diagnosis of asthma and chronic obstructive pulmonary disease (COPD), it is not routinely used in the primary care setting. Minorities and underserved populations are less likely to have spirometry assessment, leading to both over and misdiagnosis of asthma and COPD. Because dyspnea is a common symptom across multiple diseases, use of spirometry as a diagnostic tool is important. Missed, delayed, or misdiagnosis of asthma and COPD, which are considered diagnostic errors (DE), can lead to poor quality of care, increased morbidity and mortality, and increased costs to patients and health systems. Barriers to the use of spirometry have been identified at clinician/clinic and health systems levels. The REDEFINE program is designed to overcome identified barriers to spirometry use in primary care by utilizing health promoters (HPs) who perform spirometry within primary care clinics and work collaboratively with clinicians to incorporate the results at the point of care without interrupting clinic workflow. The REDEFINE trial is a comparative effectiveness study comparing outcomes of the REDEFINE program with usual care (UC) in primary care patients determined to be at increased risk of DE for asthma and COPD. The primary outcome will be all-cause hospitalizations. The secondary outcomes will be the proportion of accurate diagnosis of COPD, asthma, or asthma-COPD overlap based on initial diagnosis and spirometry and all cause and respiratory-related acute outpatient care and emergency department visits. In this report, we describe the design and methods for the REDEFINE trial. Trial registration: NCT03137303https://clinicaltrials.gov/ct2/show/NCT03137303?term=REDEFINEdraw=2rank=1.

N6-methyladenosine (m6A) RNA methylation is an epigenetic modification that has emerged in the last few years and has received increasing attention as the most abundant internal RNA modification in eukaryotic cells. m6A modifications affect multiple aspects of RNA metabolism, and m6A methylation has been shown to play a critical role in the progression of multiple cancers through a variety of mechanisms. This review summarizes the mechanisms by which m6A RNA methylation induced peripheral cancer cell progression and its potential role in the infiltration of immune cell of the glioblastoma microenvironment and novel immunotherapy. Assessing the pattern of m6A modification in glioblastoma will contribute to improving our understanding of microenvironmental infiltration and novel immunotherapies, and help in developing immunotherapeutic strategies.

This study aimed to explore the role of mitochondrial DNA copy number (mtDNAcn) in the risk, glucocorticoid (GC) effectiveness, and prognosis of systemic lupus erythematosus (SLE) and its interactions with environmental factors and tumor necrosis factor receptor-associated protein 1 (TRAP1) genetic polymorphisms. We first conducted a case-control study of 1198 subjects (595 SLE patients and 603 healthy controls). Subsequently, we followed up with patients to assess the effectiveness of GC treatment and the prognosis of SLE. Real-time fluorescent quantitative PCR (qPCR) was used to quantify mtDNAcn. Associations were estimated using logistic regression, and prognosis analysis was performed using Kaplan-Meier analysis and Cox proportional hazards models. Interactions on multiplicative and additive scales were also evaluated. Individuals with low mtDNAcn had an increased risk of SLE (P lt; 0.001). Low mtDNAcn was associated with poor GC effectiveness in patients with spicy food consumption or with arthritis (P lt; 0.05). mtDNAcn was significantly related to the prognosis of SLE in the drinking subgroup (P = 0.018). Furthermore, we found significant interactions between mtDNAcn and environmental factors/TRAP1 genetic polymorphisms on the risk, GC effectiveness, and prognosis of SLE. Our data suggest that low mtDNAcn is associated with an increased risk of SLE. Alteration of mtDNAcn may be associated with GC effectiveness and prognosis in certain subgroups of SLE. The interactions between mtDNAcn, environmental factors, and TRAP1 gene polymorphisms may jointly affect the risk, GC effectiveness, and prognosis of SLE.

Sweat pH is a critical indicator for evaluating human health. With the extensive attention on the wearable and flexible biosensing devices, the technology for the monitoring of human sweat can be realized. In this study, a sensitive, miniaturized, and flexible electrochemical sweat pH sensor was developed for the continuous and real-time monitoring of the hydrogen-ion concentration in human sweat. A flexible electrode was fabricated on the poly(ethylene terephthalate) (PET) substrate by a simple and low-cost screen-printing technology, which was based on the integration of fluoroalkyl silane-functionalized Ti

STUDY OBJECTIVES: Positive airway pressure (PAP) treatment of obstructive sleep apnea reduces blood pressure (BP). Retrospective data suggest that African Americans (AA), a group at high-risk for hypertensive organ dysfunction, may have a greater BP response to PAP therapy than European Americans (EA). We examined the difference in 24-hour BP response to 3 months of PAP treatment between AA and EA. METHODS: Participants (n = 259, 161 AA and 98 EA) with apnea-hypopnea index ≥ 15 events/h from 2 prospective cohorts were included. t-Tests and multiple linear regression were used to examine BP outcomes in AA vs EA, adjusting for PAP adherence, socioeconomic status, and baseline characteristics. RESULTS: Participants were middle aged (mean ± SD, 53.8 ± 9.3 years), 86% (227) men, apnea-hypopnea index 35.6 ± 19.2 events/h, and PAP adherence of 3.36 ± 2.24 h/day. The reductions in 24-hour systolic and diastolic BP (mm Hg) were not different in AA vs EA (systolic = −1.13 ± 12.1 vs −0.61 ± 12.8, P = .80 and diastolic = −0.74 ± 7.9 vs −0.80 ± 7.4, P = .96), and race was not a predictor of 24-hour systolic or diastolic BP reduction (P = .75 and 0.54). Socioeconomic status and PAP adherence demonstrated a significant interaction; low socioeconomic status was associated with an increase in 24-hour systolic BP (β = 19.3, P = .03) in the absence of PAP use but a greater reduction in 24-hour systolic BP with higher PAP adherence (β = −3.96, P = .03). CONCLUSIONS: Twenty-four hour BP response to PAP treatment is similar in AA and EA. Adherence to PAP treatment is more effective in improving 24-hour systolic BP in those with low SES. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Race and CPAP Effectiveness (RACE); URL: https://clinicaltrials.gov/ct2/show/NCT01960465; Identifier: NCT01960465 and Registry: ClinicalTrials.gov; Name: The Effects of Treating Obese and Lean Patients with Sleep Apnea (PISA); URL: https://clinicaltrials.gov/ct2/show/NCT01578031; Identifier: NCT01578031. CITATION: Imayama I, Gupta A, Yen PS, et al. Socioeconomic status impacts blood pressure response to positive airway pressure treatment. J Clin Sleep Med. 2022;18(5):1287–1295.

Objectives: This study examined the joint trajectories of behavioral risk factors (smoking, alcohol drinking, and body mass index) and their associations with cognitive function trajectories among older African Americans and white Americans. Methods: Data from the Health and Retirement Study (1998–2014) were used. Group-based mixture modeling and multinomial logistic regression analysis were performed. Results: Three joint trajectories of behavioral risk factors (overweight, smoking and drinking, and drinking and overweight) and three cognitive function trajectories (low, moderate, and high) were identified. A significantly higher percentage of African Americans were in the “overweight,” “smoking and drinking,” and “low” cognitive functioning groups as measured by the total cognition composite score compared to white Americans. After accounting for covariates, the “drinking and overweight” group was associated with the “moderate” or “high” cognitive functioning group. Discussion: Future interventions targeting the combinations of behavioral risk factors are needed to promote healthy aging among high-risk populations.

BACKGROUND CONTEXT: Perioperative ischemic optic neuropathy (ION) is a devastating complication of spinal fusion surgery. PURPOSE: To develop predictive models of this blinding condition using longitudinal medical administrative claims databases, which provide temporal sequence of perioperative ischemic optic neuropathy and potential risk factors. DESIGN: Nested case control study PATIENT SAMPLE: Participants in Cliniformatics® Data Mart medical claims database (2007–2017) with hospitalization involving lumbar or thoracic spinal fusion surgery and no history of ION. OUTCOME MEASURES: Peri-operative ION (or not) during hospitalization for lumbar or thoracic spinal fusion surgery. METHODS: 65 ION cases and 106,871 controls were identified. Matched controls (n=211) were selected based on year of surgery and zip code. Chronic and peri-operative variables were assigned based on medical claims codes. Least absolute shrinkage and selection (LASSO) penalized conditional logistic regression with ten-fold cross validation was used to select variables for the optimal predictive model from the subset of variables with p < 0.15 between cases and matched controls (unadjusted conditional logistic regression). Receiver operating characteristic (ROC) curves were generated for the strata-independent matched and full sample. RESULTS: The predictive model included age 57–65 years, male gender, diabetes with and without complications, chronic anemia, hypertension, heart failure, carotid stenosis, perioperative hemorrhage and perioperative organ damage in the predictive model. Area under ROC curve was 0.75 (95% CI: 0.68, 0.82) for the matched sample and 0.72 (95% CI: 0.66, 0.78) for the full sample. CONCLUSIONS: This predictive model for ION in spine fusion considering chronic conditions and perioperative conditions is unique to date in its use of longitudinal medical claims data, inclusion of ICD-10 codes and study of ophthalmic conditions as risk factors. Similar to other studies of this condition the multivariable model included age, male gender, peri-operative organ damage and peri-operative hemorrhage. Hypertension, chronic anemia and carotid artery stenosis were new predictive factors identified by this study.

Background Primary facial spasm accompanied by arrhythmia is a rare clinical phenomenon and has not been reported before. We describe this phenomenon and discuss its mechanism and treatment. Case presentation We herein present a rare case of a patient with left primary facial spasm and a third-degree atrioventricular block (III degree AVB), who was implanted with a temporary cardiac pacemaker to receive microvascular decompression (MVD) because of refusal of a permanent cardiac pacemaker. The symptoms of facial spasm disappeared after MVD. The temporary cardiac pacemaker was removed on the second day after surgery. Her ECG still showed the third-degree atrioventricular block after a follow-up period of 5 months. Conclusions We are the first to report a patient with facial spasm and arrhythmia who was implanted with a temporary cardiac pacemaker to receive MVD. This case report demonstrated that the concomitant presence of a III degree AVB maybe not a contraindication for MVD, and the etiology of this facial spasm was the actual vascular compression of the facial nerve entry zone that was not related to the atrioventricular block.

Smoker patients with non-small cell lung cancer (NSCLC) have poorer prognosis and survival than those without smoking history. However, the mechanisms underlying the low response rate of those patients to EGFR tyrosine kinase inhibitors (TKIs) are not well understood. Here we report that exposure to cigarette smoke extract enhances glycolysis and attenuates AMP-activated protein kinase (AMPK)-dependent inhibition of mTOR; this in turn reduces the sensitivity of NSCLC cells with wild-type EGFR (EGFRWT) to EGFR TKI by repressing expression of liver kinase B1 (LKB1), a master kinase of the AMPK subfamily, via CpG island methylation. In addition, LKB1 expression is correlated positively with sensitivity to TKI in patients with NSCLC. Moreover, combined treatment of EGFR TKI with AMPK activators synergistically increases EGFR TKI sensitivity. Collectively, the current study suggests that LKB1 may serve as a marker to predict EGFR TKI sensitivity in smokers with NSCLC carrying EGFRWT and that the combination of EGFR TKI and AMPK activator may be a potentially effective therapeutic strategy against NSCLC with EGFRWT.

BackgroundDuring the Coronavirus (COVID-19) pandemic, wearing masks became crucial for preventing infection risk and maintaining basic health. Therefore, it is necessary to understand the behavioral characteristics of the mask-wearing public to provide theoretical reference for the prevention and control of COVID-19.MethodsWe conducted a nationwide survey on the mask-wearing behavior of the public and their health literacy levels by distributing electronic questionnaires. Univariate and logistic regression analyses were performed to determine the factors influencing mask-wearing behavior. Pearson's correlation was used to analyze the correlation between mask-wearing behaviors and e-health literacy.ResultsA total of 1,972 valid questionnaires were collected; 99.8% of the public wore masks when going out and 59.2% showed good mask-wearing behavior. Most people choose to wear disposable medical masks (61.3%), followed by medical surgical masks (52.9%). All participants indicated that they had understood the information on how to use masks, and most obtained it through social media (61.8%). The average of the e-health literacy scores of those with good mask-wearing behavior was significantly higher than those with poor mask-wearing behavior (P < 0.05), and each item score of the former's e-health literacy was significantly higher than the latter (P < 0.05). Further, there was a positive correlation between mask-wearing behavior and e-health literacy (R = 0.550, P < 0.05). Logistic regression analysis showed that seven factors are related to mask-wearing behavior, including gender, place of residence, educational level, work or living environment, marital status, flu symptoms, and whether living with people in home quarantine (P < 0.01).ConclusionThe overall compliance of the public's mask-wearing behavior in China during COVID-19 is good. However, there are shortcomings regarding the selection, use, and precautions. The differences in mask-wearing behavior are related to factors including gender, place of residence, educational level, work or living environment, marital status, presence of flu symptoms, and whether living with people in home quarantine. Higher levels of e-health literacy indicated better mask-wearing behavior. Therefore, it is necessary to strengthen the public's popularization and education regarding the prevention and control of COVID-19.

BACKGROUND Given the lower incidence of lymphoma-related death but higher background mortality in patients with early-stage mucosa-associated lymphoid tissue (MALT) lymphoma, it is critically important to examine how age affects a treatment’s survival benefit. METHODS 9,467 patients with early-stage MALT lymphoma in the Surveillance, Epidemiology, and End Results (SEER) database treated between 2000-2015 were extracted and analyzed. Primary therapy was classified as radiotherapy (n = 3,407), chemotherapy (n = 1,294), and other/unknown treatments including observation (n = 4,766). Inverse probability of treatment weighting (IPTW) was conducted to balance baseline characteristics between groups. Relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression were conducted to compare survival differences between treatment modalities by controlling for the background mortality. Radiotherapy–age interaction was examined.RESULTS Across age-groups, early-stage MALT lymphoma patients were at lower risk of lymphoma-related death than death due to other causes. The 10-year overall survival (OS, 73.8%) and RS (96.6%) rates were significantly higher, and the SMR (1.14) significantly lower, with radiotherapy than with chemotherapy (OS, 61.7%; RS, 86.4%; SMR, 1.54; P < 0.001) or other/unknown treatments (OS, 61.1%; RS, 87.2%; SMR, 1.41; P < 0.001). By multivariable analysis and IPTW, radiotherapy remained an independent predictor of better RS (HR 0.81, 95%CI, 0.73-0.89; P < 0.001). A significant interaction between age and radiotherapy was identified for both RS (Pinteraction = 0.016) and OS (Pinteraction = 0.024), indicating greater benefit in young adults.CONCLUSION Radiotherapy can provide significant survival benefit in early-stage MALT lymphoma, especially in young adults.

RNA-sequencing (RNA-seq) is a versatile, high-throughput technology that is being widely employed for screening differentially expressed genes (DEGs) in various diseases. Echinococcosis, a globally distributed zoonosis, has been reported to impose a heavy disease burden in pastoral areas of China. Herein we aimed to explore the molecular mechanisms underlying echinococcosis. In this study, peripheral blood samples were collected from six patients with alveolar echinococcosis (AE), six patients with cystic echinococcosis (CE), and six healthy controls. RNA-Seq (mRNA) was performed to detect gene transcript and expression levels, and DEGs were subjected to bioinformatic analyses. In comparison with healthy controls, 492 DEGs (270 upregulated, 222 downregulated) were found in the AE group and 424 DEGs (170 upregulated, 254 downregulated) were found in the CE group (|log2 (fold change)| > 1 and P < 0.05). Further, 60 genes were upregulated and 39 were downregulated in both the AE and CE groups. Gene ontology enrichment analysis indicated that DEGs were mainly involved in molecular functions, including extracellular space, extracellular region, organ and system development, and anatomical structure development. Protein–protein interaction (PPI) networks were constructed to depict the complex relationship between DEGs and interacting proteins.

Previous studies identified risk factors for ischemic optic neuropathy (ION) after cardiac surgery; however, there is no easy-to-use risk calculator for the physician to identify high-risk patients for ION before cardiac surgery. The authors sought to develop and validate a simple-to-use predictive model and calculator to assist with preoperative identification of risk and informed consent for this rare but serious complication.Retrospective case-control study.Hospital discharge records.A total of 5,561,177 discharges in the National Inpatient Sample18 years of age, with procedure codes for coronary artery bypass grafting, heart valve repair/replacement, or left ventricular assist device insertion.All patients had undergone cardiac surgery.Known preoperative risk factors for ION after cardiac surgery were assessed to develop a risk score and prediction model. This model was validated internally using the split-sample method. There were 771 cases of ION among 5,561,177 patients in the National Inpatient Sample. The risk factors for ION used in the model were carotid artery stenosis, cataract, diabetic retinopathy, macular degeneration, glaucoma, male sex, and prior stroke; whereas uncomplicated diabetes decreased risk. With the internal validation, the predictive model had an area under the receiver operating characteristic curve of 0.66. A risk score cutoff ≥3 had 98.4% specificity.This predictive model, based on previously identified preoperative factors, predicted risk of perioperative ION with a fair area under the receiver operating characteristic curve. This predictive model could enable screening to provide a more accurate risk assessment for ION, and consent process for cardiac surgery.

The maintenance of uric acid levels is crucial for the human body. In this study, the feasibility of using portable ultraviolet (UV) spectrophotometry to measure the uric acid of spot urine without the need to add reagents has been demonstrated for the first time. UV spectral analysis has been used to inspect the uric acid concentration in urine. It is found that the absorption spectrum of urine has a high correlation with the concentration of uric acid at a wavelength of around 290–300 nm. Uric acid levels measured with a spectral analyzer compared to uric acid concentrations measured with a traditional biochemical analysis showed good agreement. The portable prototype is label-free and capable of displaying the inspection result of each measurement within 10 s. In the long run, this device can assist people in checking uric acid levels of spot urine with higher frequency and can adjust diet or medication in real time for more efficient health management.

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The pulmonary embolism severity index (PESI) and simplified PESI (sPESI) are recommended to recognize patients with acute pulmonary thromboembolism (PTE) with low prognosis risk, which is of great significance for treatment. This study aims to verify the influence of hypocalcaemia on the prognosis of patients with PTE and to establish a new prognosis assessment model.This is an observational, multicentre study enrolling patients with PTE from February 2010 to June 2020 across 12 Chinese hospitals. Variables in PESI, serum calcium levels and patient survival status as of 5 July 2020 were collected. The area under the curve of the receiver operating characteristic curve, sensitivity, specificity and Youden index were used to evaluate model performance.In the cohort of 4196 patients with PTE, independent associations existed between hypocalcaemia and mid- and long-term mortalities (p 0.05). By including hypocalcaemia, the new 30-day death risk prediction rule, Peking Union Medical College Hospital rule (PUMCH rule), showed significantly higher specificity (0.622 [0.582, 0.661]; p 0.001) than the PESI (0.514 [0.473, 0.554]) and sPESI (0.484 [0.444, 0.525]) and similar sensitivity (0.963 [0.810, 0.999]; p = 0.161) with PESI (0.889 [0.708, 0.976]) and sPESI (0.963 [0.810, 0.999]) in the internal validation cohort. Well-performing predictive validity was also verified on a constructed external validation cohort.Hypocalcaemia is independently associated with mid- and long-term PTE mortalities. The PUMCH rule showed significantly higher specificity than the PESI and sPESI and similar sensitivity, which may be used as a prognostic assessment tool for patients with acute PTE.

To analyze correlations between the realistic surgical difficulty of LaLIF and anatomic characteristics in radiographic images, in order to develop a simple classification to provide guiding information for case selection and evaluate the potential risks of the technique. Ninety-six consecutive cases who underwent LaLIF surgeries at the L4-5 level with MR T2-weighted images were analyzed. A novel classification based on the anatomic relationships among the disk, great vessels, and psoas muscle was used for grouping. Clinical outcomes and realistic surgical difficulty parameters were recorded, and comparisons were made among different types of classifications. Of the 96 analyzed cases, the time of surgical exposure was significantly longer for type C than for type B, and both of these were longer than that of type A. The VAS and ODI were significantly improved at a 1-year follow-up. There was no statistically significant difference among the three types. Type C had the highest incidence of complications, while Type A had the lowest. Analyses of another 304 MRI cases obtained in outpatient clinics showed that the distribution of the three types among these cases was consistent with that of the surgical cohort. Our novel and simple classification provides useful information for case selection. Type A provided the best indication and is most appropriate for a beginner in this technique. Type C includes the most challenging situations, which may have a high incidence of complications and require sophisticated surgical skills to achieve satisfactory outcomes and avoid approach-related complications.

Objectives : To explore the associations of FKBP4 and FKBP5 gene polymorphisms with disease susceptibility, glucocorticoid (GC) efficacy, anxiety, depression, and health-related quality of life (HRQOL) in systemic lupus erythematosus (SLE) patients. Methods : All subjects were collected from the First and the Second Affiliated Hospital of Anhui Medical University in Hefei, China, during 2011 to 2015. In the case–control study, 541 SLE patients and 543 controls were recruited. In the follow-up study, 466 patients completed the 12-week follow-up and then were divided into GC-sensitive and GC-insensitive groups. Genotyping was determined using Multiplex SNaPshot technique. Data were analyzed using chi-square test and univariate and multivariate logistic regression analyses. Results : rs4713904, rs9368878, and rs7757037 of FKBP5 were associated with depression in SLE patients (rs4713904, PBH = 0.037; rs9368878, PBH = 0.001; rs7757037, PBH = 0.003). Moreover, rs4713904 was associated with GC efficacy in males with SLE (PBH = 0.011). The rs755658 of FKBP5 was associated with improvement in social function (PBH = 0.022) and mental component summary (PBH = 0.028). The rs4713907 of FKBP5 was related to improvement in total score of SF-36, bodily pain, and mental component summary score (all PBH = 0.018). Furthermore, the rs12582595 of FKBP4 was correlated with general health improvement (PBH = 0.033). No associations were seen between FKBP4/FKBP5 gene polymorphisms and SLE susceptibility and anxiety. Conclusions : FKBP5 gene polymorphisms may be associated with depression and GC efficacy of SLE patients. Meanwhile, the genetic polymorphisms of FKBP4 and FKBP5 genes may be associated with HRQOL improvement in SLE patients.Key Points• FKBP5 gene polymorphisms were associated with depression of SLE patients.• FKBP5 gene polymorphisms were associated with GC efficacy of SLE patients.• FKBP5 gene polymorphisms were associated with HRQOL improvement in SLE patients.• FKBP4 gene polymorphisms were associated with HRQOL improvement in SLE patients.

Advances in high-throughput profiling of RNA binding proteins (RBPs) have resulted in CLIP-seq datasets coupled with transcriptome profiling by RNA-seq. However, analysis methods that integrate both types of data are lacking. We describe SURF, Statistical Utility for RBP Functions, for integrative analysis of large collections of CLIP-seq and RNA-seq data. We demonstrate SURF’s ability to accurately detect differential alternative transcriptional regulation events and associate them to local protein-RNA interactions. We apply SURF to ENCODE RBP compendium and carry out downstream analysis with additional reference datasets. The results of this application are browsable at http://www.statlab.wisc.edu/shiny/surf/.

We investigated the prognostic significance of Nudix hydrolase 1 (NUDT1) in hepatocellular carcinoma (HCC). NUDT1 mRNA and protein levels were significantly higher in HCC tissues than normal liver tissues. The level of NUDT1 expression correlated with tumor grade, stage, size, differentiation, degree of vascular invasion, overall survival (OS), and disease-free survival (DFS) in HCC patients. Multivariate analysis showed that NUDT1 expression was an independent prognostic factor for OS and DFS in HCC patients. We constructed a prognostic nomogram with NUDT1 expression, AFP levels, vascular invasion, Child-Pugh classification, age, sex, AJCC staging, and tumor differentiation as variables. This nomogram was highly accurate in predicting the 5-year OS of HCC patients (c-index= 0.709; AUC= 0.740). NUDT1 silencing in HCC cells significantly reduced their survival, colony formation, migration, and invasiveness. Gene set enrichment analysis showed that biological pathways related to cell cycle, fatty acid metabolism, bile acid and bile salt metabolism, and PLK1 signaling were associated with NUDT1, as were the gene ontology terms "DNA binding transcription activator activity," "RNA polymerase II," "nuclear division," and "transmembrane transporter activity." Our study thus demonstrates that NUDT1 is a prognostic biomarker with therapeutic potential in HCC patients.

Oral cavity cancer is a common cancer type that presents an increasingly serious global problem. Oral squamous cell carcinoma (OSCC) accounts for90% oral cancer cases. No biomarker tests are currently available for management of this cancer type in clinical practice. Previously, we validated matrix metalloproteinase-1 (MMP1) as one of the most promising salivary biomarkers for OSCC detection. Development of a convenient, rapid and high-throughput assay should further facilitate application of salivary MMP1 measurement for early detection of OSCC. The present study aimed to develop a workflow comprising dry saliva spot (DSS) sampling and immunoenrichment-coupled MALDI-TOF MS (immuno-MALDI) analysis to quantify salivary MMP1. We generated recombinant MMP1 protein and anti-peptide antibodies against MMP1, which were used to optimize the procedures of the entire workflow, including DSS sampling, on-paper protein digestion and elution, KingFisher magnetic particle processor-assisted immuno-enrichment and MALDI-TOF MS analysis. The established workflow was applied to measure salivary MMP1 levels in DSS samples from 5 healthy donors and 9 OSCC cases. The newly developed workflow showed good precision (intra-day and inter-day variations10%) and accuracy (80-100%) in quantification of MMP1 in DSS samples, with the limit of quantification at 3.07 ng/ml. Using this assay, we successfully detected elevated salivary MMP1 levels (ranging from 5.95 to 242.52 ng/ml) in 7 of 9 OSCC cases while MMP1 was not detectable in samples from the 5 healthy donors. In comparison, the traditional immunoassay was not effective in measuring MMP1 in DSS samples, highlighting the significant advantage of our immuno-MALDI assay. The DSS sampling format confers high flexibility and convenience of collection, storage and delivery of saliva specimens and the KingFisher-assisted immuno-MALDI analysis renders the assay as suitable for high-throughput screening. By combining the two features, the workflow developed in this study should facilitate improvement of molecular diagnostic tests for OSCC using salivary MMP1 as a biomarker.

The role of immune mediators, including proinflammatory cytokines in chemotherapy-induced peripheral neuropathy (CIPN), remains unclear. Here, we studied the contribution of interleukin-20 (IL-20) to the development of paclitaxel-induced peripheral neuropathy. Increased serum levels of IL-20 in cancer patients with chemotherapy were accompanied by increased CIPN risk. In mouse models, proinflammatory IL-20 levels in serum and dorsal root ganglia fluctuated with paclitaxel treatment. Blocking IL-20 with the neutralizing antibody or genetic deletion of its receptors prevented CIPN, alleviated peripheral nerve damage, and dampened inflammatory responses, including macrophage infiltration and cytokine release. Mechanistically, paclitaxel upregulated IL-20 through dysregulated Ca homeostasis, which augmented chemotherapy-induced neurotoxicity. Importantly, IL-20 suppression did not alter paclitaxel efficacy on cancer treatment both in vitro and in vivo. Together, targeting IL-20 ameliorates paclitaxel-induced peripheral neuropathy by suppressing neuroinflammation and restoring Ca homeostasis. Therefore, the anti-IL-20 monoclonal antibody is a promising therapeutic for the prevention and treatment of paclitaxel-induced neuropathy.

Vascular diseases are commonly observed in patients with autosomal dominant polycystic kidney disease (ADPKD). We aim to investigate the differences in the risk for arteriovenous fistula or graft (AVF/AVG) dysfunction in haemodialysis (HD) patients with and without ADPKD. 557 ADPKD and 1671 non-ADPKD patients were enrolled in the study after propensity score matching. The primary outcome measure is the incidence rate of AVF/AVG dysfunction. The incidence rates and risks of AVF/AVG dysfunction (per 100 person-years) for ADPKD and non-ADPKD patients were (1) 38.83 and 48.99 [SHR = 0.79, P = 0.137], respectively, for within 90 days, (2) 45.85 and 51.31 [SHR = 0.90, P = 0.300], respectively, for within 180 days, (3) 44.42 and 41.40 [SHR = 1.08, P = 0.361], respectively, for within the first year, (4) 27.38 and 24.69 [SHR = 1.09, P = 0.168], respectively, for within 5 years, (5) 17.35 and 13.80 [SHR = 1.19, P = 0.045], respectively, for between the 1st and 10th year, and (6) 25.40 and 21.22 [SHR = 1.14, P = 0.031], respectively, for all periods. ADPKD patients had lower incidence rates of AVF/AVG dysfunction within the first 180 days than non-ADPKD patients, but presented a higher incidence rate after 1 year of AVF/AVG creation and onwards.

The effective accumulation at tumor sites and endocytosis by tumor cells for anticancer agents in carriers are essential in successful cancer therapy, and both of the processes are affected by the surface charge of drug carriers. In this study, vitamin C (VC) was employed as an "exogenous switch" to trigger the surface charge conversion of DOX-loaded micelles to obtain a better antitumor effect. T micelles formed by poly(ε-caprolactone)

PURPOSE: To evaluate the relationship between microperimetric (MP) sensitivity and retinal thickness measured at co-registered retinal locations in individuals who have mild or no diabetic retinopathy. METHODS: Fifty non-diabetic control subjects and 50 type-2 diabetic subjects participated (25 had no clinically apparent DR [NDR] and 25 had mild nonproliferative DR [MDR]). MP sensitivity was measured at 36 retinal locations that were arranged in three concentric rings centered on the fovea (radii of 3°, 6°, and 12°). Optical coherence tomography (OCT) images were obtained and total retinal thickness (TRT), inner retinal thickness (IRT), and outer retinal thickness (ORT) were quantified from the OCT images at locations that matched the MP measures. Linear quantile mixed models (LQMMs) and linear quantile models (LQMs) were used to compare MP and thickness values for the three subject groups and to quantify structure-function relationships. RESULTS: The statistical models indicated significant TRT and IRT reductions in the NDR and MDR groups, relative to the controls, that were most apparent in the 3° ring. By contrast, ORT was not reduced significantly for either diabetic group. MP sensitivity was reduced significantly within each ring and for both diabetic groups. Despite reductions in both thickness and sensitivity, the structure-function associations were generally weak with borderline statistical significance. For example, a TRT or IRT reduction of approximately 27 μm was predicted to result in approximately 1 dB of MP sensitivity loss for the MDR group (p = 0.03 and 0.05, respectively). CONCLUSIONS: The results support previous findings of early retinal neurodegeneration in diabetics who have NDR or MDR. Interestingly, the structural and functional deficits appear to be only weakly associated, suggesting that mechanisms in addition to retinal thinning underlie the functional defects in early stage DR.

Purpose To investigate the role of Anti-Citrullinated Protein autoantibodies (ACPAs) in the pathology of dry eye disease (DED) and the therapeutic potential of pooled human immune globulin-eye drops in these patients. Methods We investigated the presence of citrullinated proteins and ACPAs in ocular surface wash (OSW) and conjunctival impressions from patients with DED and determined the pathological consequences of OSW with high ACPA using in vitro experiments and in vivo murine models. We performed a randomized, double-masked, pilot clinical trial to determine the safety, tolerability and preliminary efficacy of using pooled human immune globulin-eye drops to treat DED patients with ACPAs in OSW. Results We found that neutrophils are a source of citrullinated proteins on the ocular surface of DED patients. We detected significantly higher immunoglobulin amount and presence of several species of ACPAs in OSW from DED patients. We also found that OSW with high ACPA contributes to production of NETs, and that ACPAs cause ocular surface disease in murine eyes, both of which are reduced with addition of Immune globulins. As compared to Vehicle treatment, pooled human immune globulin-eye drops (IVIG 4 mg/mL) twice a day for 8 weeks caused significant reduction in signs and symptoms of DED with no difference in tolerability or adverse events. Conclusions This is the first report demonstrating ACPAs in OSW of DED patients and their contribution to ocular surface disease. The first-in-human clinical trial suggests that pooled immune globulin-eye drops are a potential new class of biologic therapies for Dry Eye patients.

The assessment of myocardial motion plays a promising role in the evaluation of cardiac function. This study aims to propose a novel framework of global estimation of the myocardial motion using radio-frequency (RF) data. The framework consists of B-mode image reconstruction, displacement estimation, myocardium extraction, and image fusion. The RF data of murine heart in parasternal long-axis (PLAX) view were collected for B-mode image reconstruction and displacement estimation. The vectorized normalized cross-correlation (VNCC) approach was proposed to globally estimate the displacements of the RF frames, while a sum-table based normalized cross-correlation (STNCC) was performed as reference algorithm. The bimodal fusion images were obtained to visualize the motion and anatomical structure of myocardium by an improved fast mapping algorithm (IFMA). In comparison with STNCC, the computation time of displacement using VNCC reduced by approximate 10s. The myocardial motions of anterior wall and posterior wall during one cardiac cycle were similarly tracked by VNCC as that of STNCC. The averaged absolute error in displacement between the two methods ranges from 1 to 3μm. The obtained myocardial elastographic images using VNCC intuitively present the morphological and mechanical changes during the contraction period of left ventricle. The results demonstrate that the proposed framework is an efficient tool for the estimation of myocardial motion reflecting cardiac systolic function. This approach has potentials to provide visualized information of myocardium for diagnosis and prognosis of cardiovascular diseases (CVDs).

Objective: Golgi alpha-mannosidase II (GM II) is one of the crucial enzymes in the process of N-glycan processing. The aim of our study was to examine the clinical significance of GM II in patients with clear cell renal cell carcinoma (ccRCC). Methods: Quantitative reverse transcription polymerase chain reaction analysis and immunohistochemical staining were used to analyze GM II expression in patients with ccRCC. The clinical data of 62 patients with ccRCC were collected to analyze the clinical significance of GM II. The clinical significance among GM II expression, clinicopathological staging, and histological grade of ccRCC was explored. Survival analyses were performed to identify the relevance between the expression of GM II and the overall survival of patients with ccRCC. A uni-/multivariate Cox regression model was used to detect risk factors affecting the prognosis of patients with ccRCC. Subsequently, the proliferation and migration of ccRCC cells were detected after transfecting with GM II-short hairpin RNA (shRNA). Results: The results of these comparisons suggested that GM II expression of ccRCC tissues was dramatically higher than that of para-carcinoma tissues (p < 0.05). GM II expression in the high-differentiation group was lower than that in the median- and low-differentiation groups (p < 0.05). GM II expression in stage I and II tissues was lower than that in stage III and IV tissues (p < 0.05). The expression levels of GM II in the group without lymph node metastasis were lower than those in the group with lymph node metastasis (p < 0.05). Survival analysis indicated that patients with ccRCC with high GM II expression generally had decreased overall survival. Uni-/multivariate Cox model analyses further suggested an association between GM II expression and prognosis of patients with breast cancer. High GM II expression is a potential and independent prognostic biomarker in ccRCC. The inhibition of GM II by transfecting with GM II-shRNA could reduce the proliferation and migration of ccRCC. Conclusion: GM II expression in human ccRCC tissues was upregulated compared with that found in normal human renal tissue, and GM II may promote the progression and migration of ccRCC. Furthermore, the GM II gene may be used as a promising tumor marker for the diagnosis and prognosis of ccRCC.

Perineural invasion (PNI) is a typical feature of pancreatic ductal adenocarcinoma (PDAC), which occurs in most cases. The embryonic protein Nodal plays a critical role in embryonic neural development and is overexpressed in human pancreatic cancer. In this study, we explored the contribution of Nodal to pancreatic cancer PNI and progression. We evaluated the function of Nodal in PNI by coculturing rat dorsal root ganglia and pancreatic cancer cells in vitro and performing cellular and molecular biology assays. The results illustrate that Nodal upregulates NGF (nerve growth factor), BDNF (brain-derived neurotrophic factor), and GDNF (glial cell line-derived neurotrophic factor) expression in pancreatic cancer cells and promotes cancer cell migration/invasion. Furthermore, in the in vitro 3D PNI model, Nodal enhances nerve outgrowth to pancreatic cancer cell colonies. Our study indicates that Nodal participates in tumor invasion by mediating neural and tumor cell signaling interactions, and inhibiting the expression of Nodal represents a potential strategy for targeting PNI in pancreatic cancer therapy.