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Cup-shaped ear is a common congenital auricle deformity. There are many specific surgical methods, such as V-Y method, Barsky method, Musgrave method, etc., but there is no unified treatment method. The authors used the outer helix reconstruction method for cup-shaped ear and achieved remarkable therapeutic effects.The authors performed the outer helix reconstruction on 30 patients with cup-shaped ear. The authors followed up the patients after the stage II operation. The authors used the SPSAU data science analysis platform (https://spssau.com/) for statistical analysis of the data.The mean follow-up time was 14.43±4.5 months. The mean preoperative perimeter of auricle was 8.19±0.56 cm. The mean postoperative perimeter of auricle was 10.82±0.49 cm. The mean perimeter of the healthy auricle was 10.89±0.44 cm. Through data analysis, the authors found that the comparison between preoperative and postoperative auricle perimeters was statistically significant (P0.05). The comparison between postoperative auricle perimeter and the perimeter of the healthy auricle was not statistically significant (P0.05). In terms of postoperative satisfaction of patients and their families, the satisfaction rate was 100%. In terms of postoperative complications, there were 1 case of incision dehiscence, 0 cases of incision infection, 2 cases of incision hematoma, and 0 cases of postoperative skin flap ischemia and necrosis.The outer helix reconstruction method is suitable for most cup-shaped ears, and the operation is simple and the effect is remarkable. It is worthy of promotion and application in plastic surgery clinical.

Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An easily scalable, sustainable, and cost-effective manufacturing strategy and long-term stability for storage are crucial for successful translation. Here, we report a system and method to instantly formulate NF achieved with a nanoscale polyelectrolyte coacervate-like system, consisting of anionic pseudopeptide poly(l-lysine isophthalamide) derivatives, polyethylenimine, and doxorubicin (Dox) via simple "mix-and-go" addition of precursor solutions in seconds. The coacervate-like nanosystem shows enhanced intracellular delivery of Dox to patient-derived multidrug-resistant (MDR) cells in 3D tumor spheroids. The results demonstrate the feasibility of an instant drug formulation using a coacervate-like nanosystem. We envisage that this technique can be widely utilized in the nanomedicine field to bypass the special requirement of large-scale production and elongated shelf life of nanomaterials.

A new individualized, cost-effective, modified semi-computer-assisted surgery (MSCAS) concept for free fibular flap mandibular reconstruction is reported and compared with the computer-assisted surgery (CAS) concept. Patients were divided into two groups and retrospectively reviewed. In the MSCAS and CAS groups, intraoperative guides were created using computer-aided design with manual fabrication and computer-aided design and manufacturing, respectively. Differences in specific linear and angular parameters on pre- and postoperative computed tomography scans were calculated for morphometric comparison, and clinical parameters and efficiency were analysed. RESULTS: Eighteen patients (CAS, 7; MSCAS, 11), were included. The morphometric comparison showed no significant differences between the groups. The mean deviation of the mandibular ramus length, body length, width 1 and width 2 was 0.82 ± 0.29 mm, 1.84 ± 0.43 mm, 1.89 ± 0.61 mm and 1.45 ± 0.61 mm in the CAS group versus 1.56 ± 0.54 mm, 1.72 ± 0.33 mm, 2.24 ± 0.55 mm and 2.36 ± 0.50 mm in the MSCAS group (p = 0.7804, p = 0.9997, p = 0.9814 and p = 0.6334). The mean deviation of the sagittal, axial and coronal mandibular angles was 1.56 ± 0.48°, 1.93 ± 0.50° and 2.15 ± 0.72° in the CAS group versus 2.19 ± 0.35°, 1.86 ± 0.35° and 1.94 ± 0.55° in the MSCAS group (p = 0.7594, p = 0.9996 and p = 0.9871). There were no significant differences in clinical parameters, efficiency or postoperative complications between the groups. CONCLUSION: The accuracy and operative efficiency of the MSCAS concept are comparable to those of the more expensive CAS concept. Therefore, in times of increasing clinical costs, this concept might be an adequate and inexpensive alternative to preoperative CAS.

Abstract: Protein-ligand interactions are necessary for majority protein functions. Adenosine- 5’-triphosphate (ATP) is one such ligand that plays vital role as a coenzyme in providing energy for cellular activities, catalyzing biological reaction and signaling. Knowing ATP binding residues of proteins is helpful for annotation of protein function and drug design. However, due to the huge amounts of protein sequences influx into databases in the post-genome era, experimentally identifying ATP binding residues is costineffective and time-consuming. To address this problem, computational methods have been developed to predict ATP binding residues. In this review, we briefly summarized the application of machine learning methods in detecting ATP binding residues of proteins. We expect this review will be helpful for further research.

Sepsis-associated encephalopathy(SAE) caused by infections outside the central nervous system always presents extensive brain damage.It is common in clinical practice and associated with a poor prognosis.There are problems in the assessing and diagnosing of SAE.Many factors,such as sedation and mechanical ventilation,make it difficult to assess SAE,while electrophysiological examination may play a role in the assessment.We reviewed the studies of electrophysiological techniques such as electroencephalography and somatosensory evoked potentials for monitoring SAE,hoping to provide certain evidence for the clinical evaluation and diagnosis of SAE.

Objective The aim of this study was to confirm the pathogenic variants, explore the genotype–phenotype correlation and characteristics of Chinese patients with Treacher Collins syndrome (TCS). Design Clinical details of 3 TCS family cases and 2 sporadic cases were collected and analyzed. Whole-exome sequencing and Sanger sequencing were conducted to detect causative variants. Setting Tertiary clinical care. Patients This study included 8 patients clinically diagnosed with TCS who were from 3 familial cases and 2 sporadic cases. Main Outcome Measures When filtering the database, variants were saved as rare variants if their frequency were less than 0.005 in the 1000 Genomes Project Database, the Exome Aggregation Consortium (ExAC) browser, and the Novogene database, or they would be removed as common ones. The pathogenic variants identified were verified by polymerase chain reaction. The sequencing results were analyzed by Chromas 2.1 software. Results Two novel pathogenic variants (NM_000356.3: c.537del and NM_000356.3: c.1965_1966dupGG) and 2 known pathogenic variants (NM_000356.3: c.1535del, NM_000356.3: c.4131_4135del) were identified within TCOF1 which are predicted to lead to premature termination codons resulting in a truncated protein. There was a known missense SNP (NM_015972.3: c.139G>A) within POLR1D. No phenotype–genotype correlation was observed. Instead, these 8 patients demonstrated the high genotypic and phenotypic heterogeneity of TCS. Conclusions This study expands on the pathogenic gene pool of Chinese patients with TCS. Besides the great variation among patients which is similar to international reports, Chinese patients have their own characteristics in clinical phenotype and pathogenesis mutations.

QT interval length is an important risk factor for adverse cardiovascular outcomes; however, the genetic architecture of QT interval remains incompletely understood. We conducted a genome-wide association study of 76,995 ancestrally diverse Kaiser Permanente Northern California members enrolled in the Genetic Epidemiology Research on Adult Health and Aging cohort using 448,517 longitudinal QT interval measurements, uncovering 9 novel variants, most replicating in 40,537 individuals in the UK Biobank and Population Architecture using Genomics and Epidemiology studies. A meta-analysis of all 3 cohorts (n = 117,532) uncovered an additional 19 novel variants. Conditional analysis identified 15 additional variants, 3 of which were novel. Little, if any, difference was seen when adjusting for putative QT interval lengthening medications genome-wide. Using multiple measurements in Genetic Epidemiology Research on Adult Health and Aging increased variance explained by 163%, and we show that the ≈6 measurements in Genetic Epidemiology Research on Adult Health and Aging was equivalent to a 2.4× increase in sample size of a design with a single measurement. The array heritability was estimated at ≈17%, approximately half of our estimate of 36% from family correlations. Heritability enrichment was estimated highest and most significant in cardiovascular tissue (enrichment 7.2, 95% CI = 5.7–8.7, P = 2.1e−10), and many of the novel variants included expression quantitative trait loci in heart and other relevant tissues. Comparing our results to other cardiac function traits, it appears that QT interval has a multifactorial genetic etiology.

Immunotherapy has been proved to have a large effect on extensive-stage small cell lung cancer, but the role of immunotherapy in limited-stage small-cell lung cancer (LS-SCLC) is still unknown.A retrospective study of six patients with LS-SCLC who were treated with neoadjuvant chemoimmunotherapy (durvalumab plus etoposide combined with cisplatin) was performed. Patients were evaluated by the safety, feasibility and pathologic responses of neoadjuvant chemoimmunotherapy.Neoadjuvant durvalumab combined chemotherapy was associated with few immediate adverse events and did not delay planned surgery. All patients achieved partial pathologic response (pPR) instead of major pathologic response, or pathologic complete response. No association was observed between programmed death-ligand 1 expression in tumor specimens and the pathologic response. However, tumors with high expression of immune cells such as CD4+ T cells, CD8+ T cells and FoxP3+ Tregs tended to have better pathologic responses than tumors with low expression of immune cells.Neoadjuvant durvalumab combined chemotherapy could induce pPR with few side effects in resectable LS-SCLC. The immune cells in the tumor microenvironment might play an important role in neoadjuvant chemoimmunotherapy in resectable LS-SCLC.

This study aimed to investigate the efficacy of piezosurgery (PI) in promoting immediate clotting after flapless extraction in patients undergoing dual antiplatelet therapy (DAPT).In this randomized controlled trial, 80 DAPT patients were equally divided into the PI and turbine handpiece (TH) groups. Accordingly, flapless extraction of a single tooth using PI or TH was performed on each patient, and the immediate clotting status was evaluated. The results of the preoperative hematological examinations, surgery-related variables and postoperative complications were recorded for analysis.Both groups presented with low platelet aggregation and similar coagulation functions. The PI group exhibited a higher proportion of patients with normal intra-alveolar clotting (≤30 min) (70% vs. 40%, P = 0.007) and fewer intraoperative complications (25% vs. 47.5%, P = 0.036) than that in the TH group. Logistic regression analysis indicated that the applied instrument was an independent risk factor for prolonged immediate bleeding (odds ratio = 3.10, 95% confidence interval: 1.20-8.00, P = 0.019). Intergroup differences were insignificant in terms of the other surgery-related variables and postoperative complications, except for the longer surgical duration in the PI group.The application of PI may contribute to better immediate clotting in DAPT patients after flapless extraction compared with the use of TH.

Background Chemical exchange saturation transfer (CEST) is an emerging metabolic MRI technique to map creatine distribution in the myocardium. Purpose To investigate the feasibility of using a contrast-free CEST technique to evaluate cardiac involvement in amyloid light-chain (AL) amyloidosis. Study type Prospective. Population Forty patients with biopsy-proven AL amyloidosis (age 57.6 ± 9.1 years, 31 males) and 20 healthy controls (age 42.8 ± 13.8 years, 13 males). Field strength/sequence A 3.0 T, CEST imaging using a single-shot FLASH sequence, T1 mapping with a modified Look-Locker inversion recovery sequence and late gadolinium enhancement (LGE) imaging with a phase-sensitive inversion recovery gradient echo sequence. Assessment The average CEST was calculated in the basal short-axis slice of the entire left ventricle and septum. LGE was assessed subjectively (none/patchy/global) and extracellular volume (ECV), CEST and T1 maps generated. Statistical tests Comparison between patient groups and healthy controls was performed by one-way analysis of variance with post hoc Bonferroni correction. Correlation was assessed using the Pearson's r correlation or Spearman ρ correlation. Statistical significance was defined as P Results Global (0.09 ± 0.03 vs. 0.11 ± 0.02) and septal (0.09 ± 0.03 vs. 0.11 ± 0.03) basal short-axis CEST was significantly decreased in patients with AL amyloidosis compared to the controls. Global CEST correlated significantly with Mayo stage (ρ = -0.508), NYHA Class (ρ = -0.430), LVEF (r = 0.511), mass index (r = -0.373), LGE (ρ = -0.537), ECV (r = -0.544), and T2 (r = -0.396). Septal CEST correlated significantly with LVEF (r = 0.395), LGE (ρ = -0.330), and ECV (r = -0.391). Data conclusions This study highlights the potential of CEST MRI to identify cardiac involvement and evaluate disease burden and to give insight into cellular changes intermediary between function and structure in AL amyloidosis patients. Evidence level 2 TECHNICAL EFFICACY: Stage 2.

Aplastic anemia (AA) and myelodysplastic syndrome (MDS) are clonal diseases with hemopoietic stem cell (HSC) abnormalities,which are sometimes difficult to be distinguished from each other.The development of molecular detection techniques has facilitated our understanding of the molecular pathogenesis of the two diseases.This article reviewed the somatic mutation (SM) and cytogenetic changes of AA,and analyzed their molecular relationship with MDS and their roles in disease transformation.The most common somatic change in AA is the loss of PIGA and HLA alleles,which,along with trisomy 8 and del(13q),is related to the immune pathogenesis of AA.Among the 5 most common mutations in AA,PIGA and BCOR/BCORL1 mutations are related to a good prognosis,while DNMT3A and ASXL1 mutations are likely associated with clonal evolution and a poor prognosis.The risk factors for secondary MDS after AA include SM and cytogenetic changes such as del(7q) associated with poor prognosis,prolonged disease duration after diagnosis,onset age of AA,and leukocyte telomere attrition.Although role of SM in disease progression remains unclear because of its dynamic change and unknown significance,prognostic assessment based on the monitoring of SM and clinical features may guide the treatment.

Alzheimer's disease (AD) is a common neurodegenerative disease that contributes to 60-70% of dementia in elderly people and is currently incurable. Current treatments only relieve the symptoms of AD and slow its progression. Achieving effective neural regeneration to ameliorate cognitive impairment is a major challenge in the treatment of AD. For the first time, we alleviated symptoms of AD in APPswe/PS1dE9 mice (hereafter referred to as AD mice) by transplantation of olfactory mucosa mesenchymal stem cells (OM-MSCs). Our study demonstrated that OM-MSC transplantation promotes amyloid-β (Aβ) clearance, downregulates the inflammatory response, and increases the M2/M1 ratio; OM-MSCs promote the conversion of BV2 (microglia) from M1 to M2 and also Aβ clearance in SH-SY5Y

Background: The incidence of oral squamous cell carcinoma (OSCC) is increasing, with an estimated 369,000 new patients each year worldwide. Surgery is the primary treatment modality for early-stage OSCC, but there is scant evidence to prove the value of elective neck dissection (END) for relatively small early-stage OSCC. This study aimed to identify factors predicting survival for patients with clinical stage T1N0M0 (cT1N0M0) OSCC and whether up-front END improved survival. Patients and Methods: Patients with cT1N0M0 OSCC who underwent tumor resection with or without END were identified and extracted from the SEER database. Kaplan-Meier survival analysis was used to assess overall survival and disease-specific survival. Prognostic factors were determined using Cox regression analysis. Results: A total of 5,752 patients with cT1N0M0 OSCC were extracted, of whom 2,194 (38.1%) underwent tumor resection surgery with concurrent END and 3,558 (61.9%) underwent only tumor resection. In a multivariate Cox analysis, a relatively advanced age (>62 years) and relatively high pathologic grade were the significant negative predictors, but married status (hazard ratio, 0.709; P=.006) and undergoing END (hazard ratio, 0.708; PConclusions: Patients with cT1N0M0 OSCC gain significant overall and disease-specific survival benefit from END.

Background: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. Objective: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. Methods: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population–based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. Results: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P

Prostate cancer is the second most common malignant tumor in the world, with an incidence rate of 13.5% and a mortality rate of 6.7%. At present, treatment methods for prostate cancer include surgical treatment, endocrine therapy, chemotherapy, and radiotherapy. However, the efficacy of these treatments is not optimal, especially for advanced metastatic prostate cancer. Oncolytic virus has emerged as a novel therapeutic approach for cancer treatment due to its unique advantages such as high selectivity, high efficiency, and low toxicity. The replication ability of oncolytic virus in normal cells is low, while the virus can multiply specifically in tumor cells, which are lysed by the proliferation of the virus, and the induction of apoptosis. In addition, the released progeny virus can infect the surrounding tumor cells and eventually kill the tumor. In this review, we summarize the state-of-the-art progresses and propose new avenues in the development and application of oncolytic virus for the treatment of prostate cancer.

Papillary thyroid cancer (PTC) remains the most common endocrine malignancy, despite marked achieves in recent decades, and the mechanisms underlying the pathogenesis and progression for PTC are incompletely elucidated. Accumulating evidence show that γ-glutamylcyclotransferase (GGCT), an enzyme participating in glutathione homeostasis and is elevated in multiple types of tumors, represents an attractive therapeutic target. Using bioinformatics, immunohistochemistry, qRT-PCR, and Western blot assays, we found that GGCT expression was upregulated in PTC and correlated with more aggressive clinicopathological characteristics and worse prognosis. GGCT knockdown inhibited the growth and metastasis ability of PTC cells both in vitro and in vivo and reduced the expression of mesenchymal markers (N-cadherin, CD44, MMP2, and MMP9) while increasing epithelial marker (E-cadherin) in PTC cells. We confirmed binding of microRNA-205-5p (miR-205-5p) on the 3′-UTR regions of GGCT by dual-luciferase reporter assay and RNA-RNA pull-down assay. Delivery of miR-205-5p reversed the pro-malignant capacity of GGCT both in vitro and in vivo. Lastly, we found that GGCT interacted with and stabilized CD44 in PTC cells by co-immunoprecipitation and immunohistochemistry assays. Our findings illustrate a novel signaling pathway, miR-205-5p/GGCT/CD44, that involves in the carcinogenesis and progression of PTC. Development of miR-205-mimics or GGCT inhibitors as potential therapeutics for PTC may have remarkable applications.

Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction is one of the hallmarks of stroke-induced neuronal death, and maintaining mitochondrial function is essential in cell survival and neurological progress following ischemic stroke. Stem cell-mediated mitochondrial transfer represents an emerging therapeutic approach for ischemic stroke. Accumulating evidence suggests that mesenchymal stem cells (MSCs) can directly transfer healthy mitochondria to damaged cells, and rescue mitochondrial damage-provoked tissue degeneration. This review summarizes the research on MSCs-mediated mitochondrial transfer as a therapeutic strategy against ischemic stroke.

Here, we detected platelet extravasation from blood vessels in both mouse and human hepatocellular carcinoma (HCC) tissues. We show C‐X3‐C chemokine ligand 1 (CX3CL1) derived from HCC cells induces platelet infiltration through a CX3CR1/Syk/PI3K pathway and the infiltrated platelets promote the apoptosis of HCC cells. These findings confirm that platelets are important factors in tumor regulation., The mechanisms and biological functions of migrating platelets in cancer remain largely unknown. Here, we analyzed platelet infiltration in hepatocellular carcinoma. We detected platelet extravasation in both mouse and human HCC tissues. CX3CL1 directly induced platelet migration, and hypoxia enhanced platelet migration by upregulating CX3CL1 expression. Knocking down CX3CL1 in HCC cells reduced platelet migration in vitro, as well as infiltration of HCC tissue in an orthotopic HCC mouse model. Components of the CX3CR1/Syk/PI3K pathway were essential for CX3CL1‐induced platelet migration. Migrating platelets induced HCC cell apoptosis in vitro, as indicated by a reduced mitochondrial membrane potential and an increased percentage of apoptotic cells. In the orthotopic tumor implantation model, decreased platelet infiltration was associated with accelerated tumor growth. Taken together, our findings indicate that HCC cell‐derived CX3CL1 contributes to tumor infiltration by platelets, which in turn promotes apoptosis of HCC cells.

Ischemic stroke is one of the leading causes of death and long-term disability worldwide. As an important class of pervasive genes involved in many pathophysiological processes of ischemic stroke, non-coding RNAs (ncRNAs) have received attention in the past decades. ncRNAs are a class of functional RNAs that regulate gene expression in a post-transcriptional manner, and including microRNAs, long non-coding RNAs, and circular RNAs. Several studies have deciphered that ncRNAs have a key role in the ischemic stroke-induced neuroinflammation and cell death via different molecules and pathways. Thus, ncRNAs show great promise as novel molecular targets in ischemic stroke. In this article, we provide an updated review of the current state of our knowledge about the roles of different types of ncRNAs in neuroinflammation and cell death following ischemic stroke, which may facilitate the translation of ncRNAs research into clinical practice to improve the clinical outcome of stroke therapy.

Objectives Carbapenem-resistant Enterobacteriaceae (CRE) are a major public-health threat. The most important mechanism of carbapenem resistance in CRE is carbapenemase production. Early identification of carbapenemase-producing Enterobacteriaceae (CPE) leads to improved clinical outcomes. This systematic review aimed to assess the accuracy and applicability of the modified Hodge test (MHT), the carbapenemase Nordmann–Poirel (Carba NP) test, the modified carbapenem inactivation method (mCIM) and matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF/MS) for CPE detection. Methods The meta-analysis included pooled sensitivity, specificity, diagnostic odds ratio, and summary receiver operating characteristic (SROC) curve and area under the curve (AUC). Results A total of 67 studies were included in the analysis. Pooled effect sizes (95% confidence interval) of the MHT, Carba NP, mCIM and MALDI-TOF/MS, respectively, were as follows: sensitivity, 92% (87–95%), 97% (94–98%), 99% (99–100%) and 99% (96–100%); specificity, 93% (86–97%), 100% (99–100%), 99% (96–100%) and 99% (96–100%); diagnostic odds ratio, 98.156 (48.175–199.995), 1277.710 (751.391–2172.692), 3597.352 (1287.575–10000) and 1781.360 (651.827–4868.228); and AUC, 0.97, 1, 1 and 1. Conclusion Carba NP, mCIM and MALDI-TOF/MS all demonstrated high accuracy in CPE detection, whereas the MHT is not recommended owing to some clear drawbacks. We recommend the selection of carbapenemase detection tests in the order of mCIM, Carba NP and MALDI-TOF/MS according to their simplicity, cost, and equipment and skills involved.

Mitochondrial dysfunction has long been implicated in the neurodegenerative disorder Parkinson's disease (PD); however, it is unclear how mitochondrial impairment and α-synuclein pathology are coupled. Using specific mitochondrial inhibitors, EM analysis, and biochemical assays, we report here that intramitochondrial protein homeostasis plays a major role in α-synuclein aggregation. We found that interference with intramitochondrial proteases, such as HtrA2 and Lon protease, and mitochondrial protein import significantly aggravates α-synuclein seeding. In contrast, direct inhibition of mitochondrial complex I, an increase in intracellular calcium concentration, or formation of reactive oxygen species, all of which have been associated with mitochondrial stress, did not affect α-synuclein pathology. We further demonstrate that similar mechanisms are involved in amyloid-β 1-42 (Aβ42) aggregation. Our results suggest that, in addition to other protein quality control pathways, such as the ubiquitin-proteasome system, mitochondria per se can influence protein homeostasis of cytosolic aggregation-prone proteins. We propose that approaches that seek to maintain mitochondrial fitness, rather than target downstream mitochondrial dysfunction, may aid in the search for therapeutic strategies to manage PD and related neuropathologies.

Transfer RNAs (tRNAs) are products of RNA polymerase III (Pol III) and essential for mRNA translation and ultimately cell growth and proliferation. Whether and how individual tRNA genes are specifically regulated is not clear. Here, we report that SOX4, a well-known Pol II-dependent transcription factor that is critical for neurogenesis and reprogramming of somatic cells, also directly controls, unexpectedly, the expression of a subset of tRNA genes and therefore protein synthesis and proliferation of human glioblastoma cells. Genome-wide location analysis through chromatin immunoprecipitation-sequencing uncovers specific targeting of SOX4 to a subset of tRNA genes, including those for tRNAi Met . Mechanistically, sequence-specific SOX4-binding impedes the recruitment of TATA box binding protein and Pol III to tRNA genes and thereby represses their expression. CRISPR/Cas9-mediated down-regulation of tRNAi Met greatly inhibits growth and proliferation of human glioblastoma cells. Conversely, ectopic tRNAi Met partially rescues SOX4-mediated repression of cell proliferation. Together, these results uncover a regulatory mode of individual tRNA genes to control cell behavior. Such regulation may coordinate codon usage and translation efficiency to meet the demands of diverse tissues and cell types, including cancer cells.

Rheumatoid arthritis (RA) is a classic autoimmune disease characterized by uncontrolled synovial proliferation, pannus formation, cartilage injury, and bone destruction. The specific pathogenesis of RA, a chronic inflammatory disease, remains unclear. However, both key glycolysis rate-limiting enzymes, hexokinase-II (HK-II), phosphofructokinase-1 (PFK-1), and pyruvate kinase M2 (PKM2), as well as indirect rate-limiting enzymes, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), are thought to participate in the pathogenesis of RA. In here, we review the latest literature on the pathogenesis of RA, introduce the pathophysiological characteristics of HK-II, PFK-1/PFKFB3, and PKM2 and their expression characteristics in this autoimmune disease, and systematically assess the association between the glycolytic rate-limiting enzymes and RA from a molecular level. Moreover, we highlight HK-II, PFK-1/PFKFB3, and PKM2 as potential targets for the clinical treatment of RA. There is great potential to develop new anti-rheumatic therapies through safe inhibition or overexpression of glycolysis rate-limiting enzymes.

Objective To compare the efficacy and safety of cyclosporin A(CsA)and CsA combined with recombined human erythropoietin(rhEPO)in the treatment of patients with chronic aplastic anemia(CAA).Methods Data of 79 patients with CAA treated at Department of Hematology,PUMC Hospital between January 2016 and June 2018 were collected for retrospective analysis.Forty-five patients were treated with CsA+rhEPO,and the other 34 patients with CsA alone.All the enrolled patients were treated for at least 1.5-2.0 years and followed for at least 1.0 year.The efficacy,side effects,long-term outcomes were compared between the two groups,and factors that may influence the efficacy were analyzed.Results The patients treated with CsA+rhEPO included 14 males and 31 females,with a median age of 43(19,73)years old.The median treatment duration of CsA and rhEPO was 26(12,38)and 4(3,6)months,respectively,and the median followed-up time was 24(12,42)months.The patients treated with CsA alone included 16 males and 18 females,with a median age of 36(16,85)years old.The median CsA treatment duration was 24(12,40)months and the median follow-up time was 25(12,40)months.There was no statistical difference in baseline characteristics between the two groups(all

Real-time evaluation of the fighting activities during a sudden unknown disaster like the COVID-19 pandemic is a critical challenge for control. This study demonstrates that the temporal variations of effluents from hospital sewage treatment facilities can be used as an effective indicator for such evaluation. Taking a typical infection-suffering city in China as an example, we found that there was an obvious decrease in effluent ammonia and COD concentrations in line with the start of city lockdown, and its temporal variations well indicated the major events happened during the pandemic control. Notably, the lagging period between the change point of effluent residual chlorine and the change points of COD and ammonia concentration coincided with a period in which there was a deficiency in local medical resources. In addition, the diurnal behavior of effluents from designated hospitals has varied significantly at different stages of the pandemic development. The effluent ammonia peaks shifted from daytime to nighttime after the outbreak of the COVID-19 pandemic, suggesting a high workload of the designated hospitals in fighting the rapidly emerging pandemic. This work well demonstrates the necessary for data integration at the wastewater-medical service nexus and highlights an unusual role of the effluents from hospital sewage treatment facilities in revealing the status of fighting the pandemic, which helps to control the pandemic.

This study aimed to compare the therapeutic effects of biplane skin dilator implantation with those of conventional skin dilator implantation in auricular reconstruction. A total of 137 patients with microtia who met the inclusion criteria from January 2020 to April 2021 were retrospectively selected. Sixty-three patients comprised the control group and were implanted with a skin expander using the conventional method. Seventy-four patients comprised the experimental group and were implanted with a skin expander using the biplane method. Non-parametric tests were used to compare the down-moving distance of the skin dilator between the experimental group and the control group. There was a statistically significant difference in the down-moving distance of the skin dilator between the experimental group and the control group (P P > 0.05). Moreover, there was no significant difference in the satisfaction rate of patients and their families between the experimental group and the control group (P > 0.05). In this study, the treatment effect of biplane skin dilator implantation was better than that of conventional skin dilator implantation.

Objective:The aim of the current study was to establish whether the neighbourhood food environment, characterised by the healthiness of food outlets, the diversity of food outlets and fast-food outlet density within a 500 m or 1000 m street network buffer around the home address, contributed to ethnic differences in diet quality.Design:Cross-sectional cohort study.Setting:Amsterdam, the Netherlands.Participants:Data on adult participants of Dutch, South-Asian Surinamese, African Surinamese, Turkish and Moroccan descent (n total 4728) in the HELIUS study were analysed.Results:The neighbourhood food environment of ethnic minority groups living in Amsterdam is less supportive of a healthy diet and of less diversity than that of participants of Dutch origin. For example, participants of Turkish, Moroccan and South-Asian Surinamese descent reside in a neighbourhood with a significantly higher fast-food outlet density (≤1000 m) than participants of Dutch descent. However, we found no evidence that neighbourhood food environment characteristics directly contributed to ethnic differences in diet quality.Conclusion:Although ethnic minority groups lived in less healthy food environments than participants of ethnic Dutch origin, this did not contribute to ethnic differences in diet quality. Future research should investigate other direct or indirect consequences of residing in less supportive food environments and gain a better understanding of how different ethnic groups make use of their neighbourhood food environment.

Background Long QT has been associated with ventricular dysrhythmias, cardiovascular disease (CVD) mortality, and sudden cardiac death. However, no studies to date have investigated the dynamics of within‐person QT change over time in relation to risk of incident CVD and all‐cause mortality in a real‐world setting. Methods and Results A cohort study among members of an integrated health care delivery system in Northern California including 61 455 people (mean age, 62 years; 60% women, 42% non‐White) with 3 or more ECGs (baseline in 2005–2009; mean±SD follow‐up time, 7.6±2.6 years). In fully adjusted models, tertile 3 versus tertile 1 of average QT corrected (using the Fridericia correction) was associated with cardiac arrest (hazard ratio [HR], 1.66), heart failure (HR, 1.62), ventricular dysrhythmias (HR, 1.56), all CVD (HR, 1.31), ischemic heart disease (HR, 1.28), total stroke (HR, 1.18), and all‐cause mortality (HR, 1.24). Tertile 3 versus tertile 2 of the QT corrected linear slope was associated with cardiac arrest (HR, 1.22), ventricular dysrhythmias (HR, 1.12), and all‐cause mortality (HR, 1.09). Tertile 3 versus tertile 1 of the QT corrected root mean squared error was associated with ventricular dysrhythmias (HR, 1.34), heart failure (HR, 1.28), all‐cause mortality (HR, 1.20), all CVD (HR, 1.14), total stroke (HR, 1.08), and ischemic heart disease (HR, 1.07). Conclusions Our results demonstrate improved predictive ability for CVD outcomes using longitudinal information from serial ECGs. Long‐term average QT corrected was more strongly associated with CVD outcomes than the linear slope or the root mean squared error. This new evidence is clinically relevant because ECGs are frequently used, noninvasive, and inexpensive.

Background TdP is a form of polymorphic ventricular tachycardia which develops in the setting of a prolonged QT interval. There are limited data describing risk factors, treatment, and outcomes of this potentially fatal arrhythmia. Objective Our goals were as follows: (1) to validate cases presenting with Torsade de Pointes (TdP), (2) to identify modifiable risk factors, and (3) to describe the management strategies used for TdP and its prognosis in a real‐world healthcare setting. Methods Case–control study (with 2:1 matching on age, sex, and race/ethnicity) nested within the Genetic Epidemiology Research on Aging (GERA) cohort. Follow‐up of the cohort for case ascertainment was between January 01, 2005 and December 31, 2018. Results A total of 56 cases of TdP were confirmed (incidence rate = 3.6 per 100,000 persons/years). The average (SD) age of the TdP cases was 74 (13) years, 55 percent were female, and 16 percent were non‐white. The independent predictors of TdP were potassium concentration 480 ms (OR = 4.4) and prior history of coronary artery disease (OR = 2.6). Exposure to furosemide and amiodarone was significantly greater in cases than in controls. The most common treatment for TdP was IV magnesium (78.6%) and IV potassium repletion (73.2%). The in‐hospital and 1‐year mortality rates for TdP cases were 10.7% and 25.0% percent, respectively. Conclusions These findings may inform quantitative multivariate risk indices for the prediction of TdP and could guide practitioners on which patients may qualify for continuous ECG monitoring and/or electrolyte replacement therapy.

The pyrroline-5-carboxylate reductase 1 (PYCR1) plays important roles in cancers, but its contribution to adenocarcinoma of the kidney (AK) and the potential mechanism remain to be clarified. In this study, we aimed to demonstrate the relationship between PYCR1 mRNA and AK based on The Cancer Genome Atlas database. PYCR1 mRNA in AK and normal tissues was compared using Wilcoxon rank sum test. The relationship between PYCR1 mRNA and clinicopathological characters was evaluated using logistic regression. The association between PYCR1 mRNA and survival rate was evaluated using Kaplan-Meier test and Cox regression of univariate and multivariate analysis. Additionally, Gene Set Enrichment Analysis was conducted to annotate the biological function of PYCR1 mRNA. Increased PYCR1 mRNA was found in AK tissues. Increased PYCR1 mRNA was related to high histologic grade, clinical stage, and lymph node and distant metastasis. Kaplan-Meier survival analysis and univariate analysis showed that AK patients with increased PYCR1 mRNA had worse prognosis than those without. PYCR1 mRNA remained independently associated with overall survival (HR: 1.34; 95% CI: 1.07–1.66; P = .009) in multivariate analysis. The Gene Set Enrichment Analysis suggested that ribosome, proteasome, inhibition of p53 signaling pathway, extracellular matrix receptor interaction, and homologous recombination were differentially enriched in increased PYCR1 mRNA phenotype. Increased PYCR1 mRNA is a potential marker in patients with AK. More importantly, p53 pathway, ribosome, proteasome, extracellular matrix receptor interaction, and homologous are differentially enriched in AK patients with increased PYCR1 mRNA.

Background Molecular testing for oncogenic mutations in fine‐needle aspiration has showed high predictive value in identifying malignant lesions from thyroid nodules with indeterminate cytology. Methods To figure out an efficient and economical gene panel for most medical institutions in China, we designed a five‐gene panel including BRAF/NRAS/KRAS/HRAS/TERT genes and conducted a retrospective study to evaluate the role of this five‐gene diagnostic panel in differential diagnosis of thyroid nodules. Results A total of 665 patients with 695 thyroid nodules were investigated in the current study. The fine‐needle aspiration biopsy and surgically separated thyroid tissue specimens were harvested to test BRAF, TERT, NRAS, KRAS, and HRAS mutations. We identified 261 mutations in 665 patients, including 177 V600E mutations in BRAF. Three hundred and sixty‐nine patients who underwent thyroid surgery after completion of the initial clinical and cytological evaluation were enrolled in the final analysis. The diagnostic sensitivity, specificity, and accuracy of the combination of FNAB cytology and five‐gene detection were 74.7%, 93.8%, and 84.8%, respectively. BRAF V600E and five‐gene panel could recognize 46.4% and 53.6% of papillary thyroid carcinoma in the patients with cytologically indeterminate nodules. Conclusion The five‐gene panel can effectively improve the sensitivity, negative predictive value, and accuracy of fine‐needle aspiration biopsy cytology, especially in the patients with cytologically indeterminate nodules., Our study focuses on the feasibility and utility of a five‐gene panel containing BRAF/RAS/TERT mutation detection in the improvement of fine‐needle aspiration biopsy (FNAB) cytology in differential diagnosis of thyroid nodules in China. Our results demonstrated that BRAF/five‐gene mutations detected in FNAB samples can effectively improve the sensitivity, negative predictive value (NPV), and accuracy of FNAB cytology, while kept the specificity and positive predictive value (PPV).

Lysine crotonylation has been discovered in histone and non-histone proteins and found to be involved in diverse diseases and biological processes, such as neuropsychiatric disease, carcinogenesis, spermatogenesis, tissue injury, and inflammation. The unique carbon–carbon π-bond structure indicates that lysine crotonylation may use distinct regulatory mechanisms from the widely studied other types of lysine acylation. In this review, we discussed the regulation of lysine crotonylation by enzymatic and non-enzymatic mechanisms, the recognition of substrate proteins, the physiological functions of lysine crotonylation and its cross-talk with other types of modification. The tools and methods for prediction and detection of lysine crotonylation were also described.

Aim: Alcohol intake alters DNA methylation profiles and methylation might mediate the association between alcohol and disease, but limited number of positive CpG sites repeatedly replicated. Materials & methods: In total, 57 monozygotic (MZ) twin pairs discordant for alcohol drinking from the Chinese National Twin Registry and 158 MZ and dizygotic twin pairs in the Swedish Adoption/Twin Study of Aging were evaluated. DNA methylation was detected using the Infinium HumanMethylation450 BeadChip. Results: Among candidate CpG sites, cg07326074 was significantly correlated with drinking after adjusting for covariates in MZ twins in both datasets but not in the entire sample or dizygotic twins. Conclusion: The hypermethylation of cg07326074, located in the tumor-promoting gene C16orf59, was associated with alcohol consumption.

We report an asymptomatic child who was positive for a coronavirus by reverse transcription PCR in a stool specimen 17 days after the last virus exposure. The child was virus positive in stool specimens for at least an additional 9 days. Respiratory tract specimens were negative by reverse transcription PCR.

Nature of exosome-secreting cells determines exosome content and function. ALIX, involved in exosome biogenesis, promotes cell degeneration. Here, ALIX was knocked out (iPSC-ALIX-/-) and overexpressed (iPSC-ALIX3+) in induced pluripotent stem cells (iPSCs) using CRISPR-Cas9 and lentiviral transduction, respectively, and the secreted exosomes were analyzed. Exosomes from iPSC-ALIX-/- (exosome-KO), iPSC-ALIX3+ (exosome-over), and their corresponding controls contained 176, 529, 431, and 351 proteins, respectively. Exosome-over showed increased protein levels, while exosome-KO contained fewer protein types without differing in total protein content. ALIX knockout did not affect exosome uptake by endothelial cells. Exosome-over more effectively promoted cell viability than exosome-GFP, in a dose-dependent manner. All exosomes were protective for endothelial cells injured by hydrogen peroxide or cisplatin, as demonstrated by promotion of cell viability, horizontal migration, angiogenic sprouting from aortic rings, and formation of capillary-like structures, inhibition of apoptosis, and maintenance of permeability of endothelial monolayer, although exosome-over and exosome-KO had stronger and weaker effects, respectively. SNX2 was important for ALIX-mediated exosomal function. Beneficial functions of the exosomes were independent of experimental models, targeted cell types, causes of injury, exosome-producing iPSC passages, clones of ALIX knockout, and transfection batches of ALIX overexpression. Thus, we present a novel strategy to manipulate iPSCs for production of exosomes with beneficial ALIX-regulated protein composition for varied exosome functions. KEY MESSAGES: ALIX knockout and overexpression regulate protein profile in iPSC-derived exosome. ALIX knockout decreases therapeutic function of iPSC-derived exosomes. ALIX overexpression increases therapeutic function of iPSC-derived exosomes. Manipulating iPSCs can produce exosomes with more beneficial protein content.

Background Preterm birth and feeding are the most important pathogenic factors of neonatal necrotizing enterocolitis (NEC). Metabonomic has been widely used in the diagnosis and treatment of other diseases, but there is no research on the related diseases of premature infants. Compared with full-term infants, the metabolism of preterm infants has its own specificity, so it can easily lead to NEC and other digestive tract inflammatory diseases. Metabonomic may be applied to the diagnosis of preterm related diseases, such as NEC. Methods The model was established with premature infant serum samples from 19 premature infants in our hospital, which was compared with the full-term infant control group. Serum was analyzed by gas chromatography-mass spectrometry (GC-MS), coupled with the analysis of serum metabolic characteristics. The variable important in projection, P value and Pearson correlation coefficient of samples were analyzed by using SIMCA, SPSS and other multivariate statistical analysis software. Results Compared to the term infants, premature infants had significantly higher levels of luteolin, and lower levels of xylose, O-succinyl-L-homoserine and lauric acid in the serum. There were some correlations among several different metabolites and clinically related indices (albumin, total bilirubin) for premature birth related diseases. Conclusions There are metabolic alterations in the serum of premature infants, which make contribution to the diagnosis of NEC.

Background Fine ambient particle matter (PM2.5) induces inflammatory lung injury; however, whether intratracheal administration of PM2.5 increases pulmonary polymorphonuclear leukocyte (PMN) infiltration, the mechanism of infiltration, and if these cells exacerbate PM2.5-induced lung injury are unknown. Methods Using 32,704 subjects, the association between blood PMNs and ambient PM2.5 levels on the previous day was retrospectively analyzed. Neutropenia was achieved by injecting mice with PMN-specific antibodies. Inhibition of PMN infiltration was achieved by pretreating PMNs with soluble vascular cell adhesion molecule-1 (sVCAM-1). The effects of PMNs on PM2.5-induced lung injury and endothelial dysfunction were observed. Result Short-term PM2.5 (> 75 μg/m3 air) exposure increased the PMN/white blood cell ratio and the PMN count in human peripheral blood observed during routine examination. A significant number of PM2.5-treated PMNs was able to bind sVCAM-1. In mice, intratracheally-instilled PM2.5 deposited in the alveolar space and endothelial cells, which caused significant lung edema, morphological disorder, increased permeability of the endothelial-alveolar epithelial barrier, and PMN infiltration with increased VCAM-1 expression. Depletion of circulatory PMNs inhibited these adverse effects. Replenishment of untreated PMNs, but not those pretreated with soluble VCAM-1, restored lung injury. In vitro, PM2.5 increased VCAM-1 expression and endothelial and epithelial monolayer permeability, and promoted PMN adhesion to, chemotaxis toward, and migration across these monolayers. PMNs, but not those pretreated with soluble VCAM-1, exacerbated these effects. Conclusion VCAM-1-mediated PMN infiltration was essential for a detrimental cycle of PM2.5-induced inflammation and lung injury. Results suggest that drugs that inhibit PMN function might prevent acute deterioration of chronic pulmonary and cardiovascular diseases triggered by PM2.5.

Background and Objective Due to the synergistic effects of drugs, drug combination is one of the effective approaches for treating complex diseases. However, the identification of drug combinations by dose-response methods is still costly. It is promising to develop supervised learning-based approaches to predict potential drug combinations on a large scale. Nevertheless, these approaches have the inadequate utilization of heterogeneous features, which causes the loss of information useful to classification. Moreover, they have an intrinsic bias, because they assume unknown drug pairs as non-combinations, of which some could be real drug combinations in practice. Methods To address above issues, this work first designs a two-layer multiple classifier system (TLMCS) to effectively integrate heterogeneous features involving anatomical therapeutic chemical codes of drugs, drug-drug interactions, drug-target interactions, gene ontology of drug targets, and side effects. To avoid the bias caused by labelling unknown samples as negative, it then utilizes the one-class support vector machines, (which requires no negative instance and only labels approved drug combinations as positive instances), as the member classifiers in TLMCS. Last, both a 10-fold cross validation (10-CV) and a novel prediction are performed to validate the performance of TLMCS. Results The comparison with three state-of-the-art approaches under 10-CV exhibits the superiority of TLMCS, which achieves the area under the receiver operating characteristic curve = 0.824 and the area under the precision-recall curve = 0.372. Moreover, the experiment under the novel prediction demonstrates its ability, where 9 out of the top-20 predicted combinative drug pairs are validated by checking the published literature. Furthermore, for each of the newly-validated drug combinations, this work analyses the combining mode of the member drugs and investigates their relationship in terms of drug targeting pathways. Conclusions The proposed TLMCS provides an effective framework to integrate those heterogeneous features and is trained by only positive samples such that the bias of taking unknown drug pairs as negative samples can be avoided. Furthermore, its results in the novel prediction reveal five types of drug combinations and three types of drug relationships in terms of pathways.

We established an efficient method for single-cell miRNA analysis by droplet microfluidics, which has high sensitivity of single molecule detection and high throughput. Single-cell analysis of multiple miRNAs in various cells shows that miRNA expression is closely related to cancer type. CTC analysis shows that the method is applicable for rare cell analysis.

This study used a three (animation types: educational, entertainment, and control groups) × four (age group: four-, five-, six-, and seven-year-olds) between-group experimental design to investigate the short-term effects of animation type and age on each component of children’s executive function (EF) (inhibitory control [IC], cognitive flexibility [CF], and working memory [WM]). One hundred twenty-six kindergarten and first-grade elementary school students in a city in Henan Province of China were selected for the experimental study. The results showed that briefly watching animation affected children’s EF. Specifically, watching entertainment cartoons weakened children’s IC and CF, while cartoons did not affect children’s WM. The moderating effect of age in the relationship between animation type and EFs was non-significant. This study suggests that researchers should focus on the uniqueness of each component of EF in children aged four to seven years, and parents should try to limit children’s viewing of animation, especially entertainment animation.

To explore prescription medication regularity in the treatment of Alzheimer's disease with traditional Chinese medicine(TCM). With Alzheimer's disease or senile dementia as the subject, collecting and sorting out the journal papers in CNKI were collected as the data source to establish the literature research database of Alzheimer's disease prescriptions, and then the association rule analysis, factor analysis and systematic cluster analysis on the included TCM were conducted. Among the 113 prescriptions included in the standard, the single herb Acori Tatarinowii Rhizoma was the most common. The herbs were mainly warm and flat among four pro-perties, mainly sweet, bitter and spicy among five flavors. The drugs were mainly distributed in five internal organs, and the most commonly used drugs were deficiency tonifying drugs as well as blood activating and stasis removing drugs. In the association rule analysis, it was found that there were 6 drug pairs with the highest association strength. Eight common factors were extracted from the factor analysis, and they were classified into 6 categories in the systematic cluster analysis. The results have shown that the overall principles in treating Alzheimer's disease with modern Chinese medicine are tonifying deficiency, invigorating circulation, activating blood and dispelling phlegm.

BACKGROUND: Bupropion, one of the dual norepinephrine and dopamine reuptake inhibitors (NDRIs), is an aminoketone derivative performed effect in improving cognitive function for depression. However, its therapeutic effect is unsatisfactory due to poor clinical response, and there are only few derivatives in pre-clinical settings. OBJECTIVE: This work attempted to elucidate the essential structural features for the activity and designed a series of novel derivatives with good inhibitive ability, pharmacokinetic and medicinal chemistry properties. METHODS: The field-based QSAR of aminoketone derivatives of two targets were established based on docking poses, and the essential structural properties for designing novel compounds were supplied by comparing contour maps. RESULTS: The selected two models performed good predictability and reliability with R2 of 0.8479 and 0.8040 for training set, Q2 of 0.7352 and 0.6266 for test set respectively, and the designed 29 novel derivatives performed no less than the highest active compound with good ADME/T pharmacokinetic properties and medicinal chemistry friendliness. CONCLUSIONS: Bulky groups in R1, bulky groups with weak hydrophobicity in R3, and potent hydrophobic substituted group with electronegative in R2 from contour maps provided important insights for assessing and designing 29 novel NDRIs, which were considered as candidates for cognitive dysfunction with depression or other related neurodegenerative disorders.

From the first illustrations of neuronal morphology by Ramon y Cajal to the recent three-dimensional reconstruction of synaptic connections, the development of modern neuroscience has greatly benefited from breakthroughs in imaging technology. This also applies specifically to the study of neurodegenerative diseases. Much of the research into these diseases relies on the direct visualisation of intracellular structures and their dynamics in degenerating neural cells, which cannot be fully resolved by diffraction-limited microscopes. Progress in the field has therefore been closely linked to the development of super-resolution imaging methods. Their application has greatly advanced our understanding of disease mechanisms, ranging from the structural progression of protein aggregates to defects in organelle morphology. Recent super-resolution studies have specifically implicated the disruption of inter-organelle interactions in multiple neurodegenerative diseases. In this article, we describe some of the key super-resolution techniques that have contributed to this field. We then discuss work to visualise changes in the structure and dynamics of organelles and associated dysfunctions. Finally, we consider what future developments in imaging technology may further our knowledge of these processes.

BackgroundSomatic mutations are involved in hepatocellular carcinoma (HCC) progression, but the genetic mechanism associated to hepatocarcinogenesis remains poorly understood. We report that Eyes absent homolog 2 (EYA2) suppresses the HCC progression, while EYA2(A510E) mutation identified by exome sequencing attenuates the tumor-inhibiting effect of EYA2.MethodsWhole-exome sequencing was performed on six pairs of human HCC primary tumors and matched adjacent tissues. Focusing on EYA2, expression level of EYA2 in human HCC samples was evaluated by quantitative real-time PCR, western blot and immunohistochemistry. Loss- and gain-of-function studies, hepatocyte-specific deletion of EYA2 (Eya2−/−) in mice and RNA sequencing analysis were used to explore the functional effect and mechanism of EYA2 on HCC cell growth and metastasis. EYA2 methylation status was evaluated using Sequenom MassARRAY and publicly available data analysis.ResultsA new somatic mutation p.Ala510Glu of EYA2 was identified in HCC tissues. The expression of EYA2 was down-regulated in HCC and associated with tumor size (P = 0.001), Barcelona Clinic Liver Cancer stage (P = 0.016) and tumor differentiation (P = 0.048). High level of EYA2 was correlated with a favorable prognosis in HCC patients (P = 0.003). Results from loss-of-function and gain-of-function experiments suggested that knockdown of EYA2 enhanced, while overexpression of EYA2 attenuated, the proliferation, clone formation, invasion, and migration of HCC cells in vitro. Delivery of EYA2 gene had a therapeutic effect on inhibition of orthotopic liver tumor in nude mice. However, EYA2(A510E) mutation led to protein degradation by unfolded protein response, thus weakening the inhibitory function of EYA2. Hepatocyte-specific deletion of EYA2 in mice dramatically promoted diethylnitrosamine-induced HCC development. EYA2 was also down-regulated in HCC by aberrant CpG methylation. Mechanically, EYA2 combined with DACH1 to transcriptionally regulate SOCS3 expression, thus suppressing the progression of HCC via SOCS3-mediated blockade of the JAK/STAT signaling pathway.ConclusionsIn our study, we identified and validated EYA2 as a tumor suppressor gene in HCC, providing a new insight into HCC pathogenesis.

Kidney cancer is the third most common malignancy of the urinary system, of which, kidney renal clear cell carcinoma (KIRC) accounts for the vast majority. Runt-related transcription factors (RUNX) are involved in multiple cellular functions. However, the diverse expression patterns and prognostic values of RUNX genes in kidney cancer remained to be elucidated. In our study, we mined the DNA methylation, transcriptional and survival data of RUNX genes in patients with different kinds of kidney cancer through Oncomine, Gene Expression Profiling Interactive Analysis, UALCAN, Kaplan–Meier Plotter, cBioPortal and LinkedOmics. We found that RUNX1 and RUNX3 were upregulated in KIRC tissues compared with those in normal tissues. The survival analysis results indicated a high transcription level of RUNX1 was associated with poor overall survival (OS) in KIRC patients. Furthermore, KIRC tumor tissues had significantly lower levels of RUNX1 promoter methylation than that in paracancerous tissues, with decreased DNA methylation of RUNX1 notably associated with poor OS in KIRC. In conclusion, our results revealed that RUNX1 may be a potential therapeutic target for treating KIRC, and RUNX1 promoter methylation level shows promise as a novel diagnostic and prognostic biomarker, which laid a foundation for further study.

Background and Purpose: Hematoma expansion is closely associated with adverse functional outcomes in patients with intracerebral hemorrhage (ICH). Prediction of hematoma expansion would therefore be of great clinical significance. We therefore attempted to predict hematoma expansion using a dual-modal machine learning (ML) strategy which combines information from non-contrast computed tomography (NCCT) images and multiple clinical variables. Method: We retrospectively identified 140 ICH patients (57 with hematoma expansion) with 5,616 NCCT images of hematoma (2,635 with hematoma expansion) and 10 clinical variables. The dual-modal ML strategy consists of two steps. The first step is to derive a mono-modal predictor from a deep convolutional neural network (DCNN) using solely NCCT images. The second step is to achieve a dual-modal predictor by combining the mono-modal predictor with 10 clinical variables to predict hematoma growth using a multi-layer perception (MLP) network. Result: For the mono-modal predictor, the best performance was merely 69.5% in accuracy with solely the NCCT images, whereas the dual-modal predictor could boost the accuracy greatly to be 86.5% by combining clinical variables. Conclusion: To our knowledge, this is the best performance from using ML to predict hematoma expansion. It could be potentially useful as a screening tool for high-risk patients with ICH, though further clinical tests would be necessary to show its performance on a larger cohort of patients.

Soybean, as a major oil crop, is one of the most widely planted crops in the world. Fusarium oxysporum causes soybean root rot, leading to great economic losses to soybean planting every year globally. Chemical fungicide for controlling soybean F. oxysporum diseases may cause environmental problems and has human health risks. Biological control methods avoid these shortcomings; however, few studies have focused on biocontrol of soybean diseases caused by F. oxysporum. Aiming at this problem, we obtained biocontrol bacteria against soybean F. oxysporum by plate confrontation method. The type of the strain with the highest biocontrol activity was identified by molecular biological methods, and then its biocontrol effects were verified through greenhouse experiments. One of our isolated strain named BS06 strain had the highest activity, which was identified as Bacillus subtilis. Our study showed that BS06 strain could effectively control soybean F. oxysporum disease and significantly reduce F. oxysporum to infect soybean roots. Compared with control and carbendazim treatments, BS06 treatment had higher root biomass, plant height, leaf chlorophyll content, stem base diameter and control efficiency. Our results indicated that BS06 could effectively protect soybean root (BS06 strain might produce substances to inhibit F. oxysporum), which was potentially useful for soybean planting.