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Background: The incidence of melanoma has been increasing over the last 30 years. The most common treatments, such as surgery, chemotherapy, and radiotherapy, frequently cause serious damage to the body. It is therefore critical to develop a new therapeutic strategy for the treatment of melanoma. Objectives: This research aims to evaluate the anti-tumor effect of Neochamaejasmine A (NCA) on B16F10 melanoma cells and the underlying molecular mechanisms. Methods: The CCK-8 kit was utilized to assay the influence of NCA on the vitality of B16F10 cells. Modifications in B16F10 cells morphology were observed using a phase-contrast microscope. Apoptosis of B16F10 melanoma cells was assessed by Hoechst 33258, Annexin V and propidium iodide staining. Cell cycle was detected using a commercial kit by flow cytometry. The mRNA and protein expression levels associated with apoptosis and cell cycle arrest were detected by RT-PCR and Western blot. The expression level of pathway proteins was assessed using Western blot. Result: It was found that the proliferation of B16F10 cells was inhibited by NCA in concentration- and time-dependent manners. NCA promoted apoptosis by halting the cell cycle at the G2/M phase. After treatment with NCA, cell apoptosis was confirmed by Hoechst 33258 staining. NCA triggered the cell cycle to seize at the G2/M stage by downregulating cyclin B1 and cyclin-dependent kinase 2 (CDC2) expression. Moreover, the mRNA and protein expression of cleaved caspase- 9 and Bcl-2-associated X-protein (Bax) were increased, whereas there was a decline in the expression of B-cell lymphoma 2 (Bcl-2). The p-p38/p38 and phosphorylated c-Jun N-terminal kinase (p-JNK/JNK) ratio were also elevated by NCA. The apoptosis and G2/M cell cycle arrest were inhibited in cells co-treated with the p38 inhibitor SB203580 and JNK inhibitor SP600125. The expression of apoptosis-related proteins Bax was decreased, and Bcl-2 was increased. Conclusion: The findings of this study showed that NCA could induce apoptosis and cell cycle arrest in B16F10 melanoma cells by activating JNK and p38 MAPK signaling pathway.

Decidualization of the endometrial stromal cells (ESCs) is essential for successful embryo implantation. It involves the transformation of fibroblastic cells into epithelial-like cells that secrete cytokines, growth factors, and proteins necessary for implantation. Previous studies have revealed altered expression of miR-375 in the endometrium of patients with recurrent implantation failure and the ectopic stromal cells of patients with endometriosis. However, the exact molecular mechanisms, particularly the role of microRNAs (miRNAs) in the regulation of decidualization, remain elusive. In this study, we investigated whether decidualization is affected by miR-375 and its potential target(s). The findings demonstrated the downregulation of the expression of miR-375 in the secretory phase compared to its expression in the proliferative phase of the endometrium in normal donors. In contrast, it was upregulated in the secretory phase of the endometrium in infertility patients. Furthermore, during decidualization of ESCs in vitro, overexpression of miR-375 significantly reduced the transcript-level expression of forkhead box protein O1 (FOXO1), prolactin (PRL), and insulin-like growth factor binding protein-1 (IGFBP1), the well-known decidual cell markers. Overexpression of miR-375 also resulted in reduced decidualization-derived intracellular and mitochondrial reactive oxygen species (ROS) levels. Using the luciferase assay, we confirmed that NADPH oxidase 4 (NOX4) is a direct target of miR-375. Collectively, the study showed that the miR-375-mediated NOX4 downregulation reduced ROS production and attenuated the decidualization of ESCs. It provides evidence that miR-375 is a negative regulator of decidualization and could serve as a potential target for combating infertility.

Context The symptom burden associated with heart failure (HF) remains high despite improvements in therapy and calls for the integration of palliative care into traditional HF care. Little is also known about how patients with HF perceive palliative care and patient-level characteristics associated with the need for palliative care, which could influence the utilization of palliative care in HF management. Objectives To identify characteristics of HF patients associated with perceived need for palliative care. Methods We analyzed data from the Hopeful Heart Trial, which studied the efficacy of a collaborative care intervention for treating both systolic HF and depression. Palliative care preferences were collected during routine study follow-up. We assessed the association of perceived need for palliative care during study follow-up and baseline data on sociodemographics, clinical measures, and patient-centered outcomes. We then used descriptive statistics and logistic regression to analyze our data. Results Participants were on average 64 years old, male, and reported severe HF symptoms and poor to below average quality of life (. Most had unfavorable impressions of palliative care, but many still perceived a need for palliative care. Factors associated with perceived need for palliative care included depression, non-white race, more severe HF symptoms, and lower mental & physical health-related quality of life. Conclusion HF patients’ beliefs about palliative care may affect utilization of palliative care. Specific characteristics can help identify patients with HF who may benefit from palliative care involvement. Education targeted towards patients with selected attributes may help incorporate palliative care into HF management.

Chromosomal instability (CIN) is a driving force for cancer development. The most common causes of CIN include the dysregulation of the spindle assembly checkpoint (SAC), which is a surveillance mechanism that prevents premature chromosome separation during mitosis by targeting anaphase-promoting complex/cyclosome (APC/C). DAB2IP is frequently silenced in advanced prostate cancer (PCa) and is associated with aggressive phenotypes of PCa. Our previous study showed that DAB2IP activates PLK1 and functions in mitotic regulation. Here, we report the novel mitotic phosphorylation of DAB2IP by Cdks, which mediates DAB2IP’s interaction with PLK1 and the activation of the PLK1-Mps1 pathway. DAB2IP interacts with Cdc20 in a phosphorylation-independent manner. However, the phosphorylation of DAB2IP inhibits the ubiquitylation of Cdc20 in response to SAC, and blocks the premature release of the APC/C-MCC. The PLK1-Mps1 pathway plays an important role in mitotic checkpoint complex (MCC) assembly. It is likely that DAB2IP acts as a scaffold to aid PLK1-Mps1 in targeting Cdc20. Depletion or loss of the Cdks-mediated phosphorylation of DAB2IP destabilizes the MCC, impairs the SAC, and increases chromosome missegregation and subsequent CIN, thus contributing to tumorigenesis. Collectively, these results demonstrate the mechanism of DAB2IP in SAC regulation and provide a rationale for targeting the SAC to cause lethal CIN against DAB2IP-deficient aggressive PCa, which exhibits a weak SAC.

LEOPARD syndrome (OMIM #151,100) caused by a germline PTPN11 mutation are characterized as multisystemic anomalies and variable marked phenotypes such as multiple lentigines and cafe´-au-lait spots, electrocardiographic conduction abnormalities, ocular hypertelorism/obstructive cardiomyopathy, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness. Phenotype overlap complicates clinical discrimination within RASopathies, making the diagnosis of LEOPARD more confusing and challenging. Besides, LEOPARD patients do not usually present with all these typical clinical features, increasing the possibility of underdiagnosis or misdiagnosis.Herein, we report a case of LEOPARD syndrome in a patient who only presented with pigmented skin spots and was initially diagnosed with multiple acquired melanocytic nevi. Subsequent pathological examination confirmed the diagnosis of multiple lentigines rather than melanocytic nevi. A genetic study showed a germline PTPN11 (Tyr279Cys) mutation and raised the suspicion of LEOPARD syndrome. A subsequent ECG examination detected potential cardiac defects and confirmed the diagnosis of LEOPARD. We considered that the potential damage of other systems underlying the skin multiple lentigines should not be ignored. The diagnosis of LEOPARD syndrome in an early stage before cardiac damage has reached a serious and irreversible stage can be meaningful for patients to fully understand the potential risks, complications and prognosis of the disease and to take appropriate precautions to prevent the potential risk of cardiac damage.

Ferroptosis, a newly discovered irondependent form of regulated cell death caused by excessive accumulation of lipid peroxides, is linked to the development and treatment response of various types of cancer, including gastric cancer (GC). Noncoding RNAs (ncRNAs), as key regulators in cancer, have both oncogenic and tumor suppressive roles. However, studies on ferroptosis-related ncRNA networks in GC are still lacking. Here, we first identified 61 differentially expressed genes associated with ferroptosis in GC by computing and analyzing gene expression profile of tumor and normal tissues for GC. Then, upstream lncRNAs and miRNAs interacting with them were found through miRNet and miRBase databases, and hub lncRNAs and miRNAs were obtained through topological analysis. Finally, the ceRNA regulatory network linked to ferroptosis in GC was established, which includes two ferroptosis marker genes (TXNIP and TSC22D3), one driver gene (GABARAPL1), and one suppressor gene (CAV1). Kaplan-Meier survival analysis showed that changes in the expression of these genes were associated with the survival of GC patients. Furthermore, our study revealed that this ceRNA network may influence the progression of GC by regulating ferroptosis process. These results will help experimental researchers to design an experiment study to further explore the roles of this regulatory network in GC ferroptosis.

Endometrial receptivity is essential for successful pregnancy, and its impairment is a major cause of embryo-implantation failure. MicroRNAs (miRNAs) that regulate epigenetic modifications have been associated with endometrial receptivity. However, the molecular mechanisms whereby miRNAs regulate endometrial receptivity remain unclear. Therefore, we investigated whether miR-182 and its potential targets influence trophoblast cell attachment. miR-182 was expressed at lower levels in the secretory phase than in the proliferative phase of endometrium tissues from fertile donors. However, miR-182 expression was upregulated during the secretory phase in infertile women. Transfecting a synthetic miR-182-5p mimic decreased spheroid attachment of human JAr choriocarcinoma cells and E-cadherin expression (which is important for endometrial receptivity). miR-182-5p also downregulated N-Myc downstream regulated 1 (NDRG1), which was studied further. NDRG1 was upregulated in the secretory phase of the endometrium tissues and induced E-cadherin expression through the nuclear factor-κΒ (NF-κΒ)/zinc finger E-box binding homeobox 1 (ZEB1) signaling pathway. NDRG1-overexpressing or -depleted cells showed altered attachment rates of JAr spheroids. Collectively, our findings indicate that miR-182-5p-mediated NDRG1 downregulation impaired embryo implantation by upregulating the NF-κΒ/ZEB1/E-cadherin pathway. Hence, miR-182-5p is a potential biomarker for negative selection in endometrial receptivity and a therapeutic target for successful embryo implantation.

Introduction: our previous pilot work suggests relational harm reduction strengthens relationships between people with HIV (PWH) who use drugs and their healthcare providers and improves HIV health outcomes. However, there is limited research examining ways that structural (eg, strategies like syringe service programmes) and/or relational (patient-provider relationship) harm reduction approaches in HIV clinical settings can mitigate experiences of stigma, affect patient-provider relationships and improve outcomes for PWH who use drugs. Our mixed methods, multisite, observational study aims to fill this knowledge gap and develop an intervention to operationalise harm reduction care for PWH who use drugs in HIV clinical settings. Methods and analysis: aim 1 will explore the relationship between healthcare providers' stigmatising attitudes towards working with PWH who use drugs and providers' acceptance and practice of structural and relational harm reduction through surveys (n=125) and interviews (n=20) with providers. Aim 2 will explore the interplay between patient-perceived harm reduction, intersectional stigma and clinical outcomes related to HIV, hepatitis C (if applicable) and substance use-related outcomes through surveys (n=500) and focus groups (k=6, total n=36) with PWH who use drugs. We will also psychometrically evaluate a 25-item scale we previously developed to assess relational harm reduction, the Patient: assessment of Provider Harm Reduction Scale. Aim 3: will use human-centred design approaches to develop and pretest an intervention to operationalise harm reduction care for PWH who use drugs in HIV clinical settings. Ethics and dissemination: this study was approved via expedited review by the University of Pittsburgh Institutional Review: board (STUDY21090002). Study: findings will be presented in peer-reviewed journals and public health conferences as well as shared with patient participants, community advisory boards and harm reduction organisations., Funding for this study was provided by the US National Institutes of Health, National Institute on Drug Abuse (1R01DA054832--01). The funder had no role in the design of the study, data collection, data analyses, interpretation of data, or preparation of this manuscript.

To establish a general performance evaluation index system for nursing managers in public hospitals of Wenzhou city.Head nurses' performance plays a critical role in the development and operation of hospitals. Owing to the lack of accuracy and defects in the current evaluation system in Mainland China, there is an urgent need to develop a systematic performance evaluation index system for nursing managers.A systematic review of literature, two rounds of expert consultation using the Delphi techniques, and empirical analyses were performed. In this study, a total of 20 experts in nursing-related fields were invited to provide reliable comments on the evaluation system. The index system was modified twice during the Delphi consultation, followed by a questionnaire (n = 113) to test the suitability of the system created for public hospitals in Wenzhou.Both rounds of the consultation showed high response rates of 20 experts. A consensus of over 70% was reached for most indicators in the first round, while a 100% consensus was achieved for the modified index system in the second round. The results of the questionnaire for the modified index system were 100%, 98.23%, 100%, 96.46%, and 93.80% in terms of scientificity, public welfare, importance, measurability, and feasibility, respectively.A suitable index system with 4 first-level indicators, 10 second-level indicators, and 37 third-level indicators was generated to assess head nurses' performance in public hospitals, thereby enhancing their cohesion and competitiveness.The modified performance evaluation index system serves as the cornerstone for the successful development of public hospitals and the provision of high-quality services for patients.

Background Congenital melanocytic naevi (CMN) are known to be associated with mosaic NRAS or BRAF variants. However, the exact correlations of the allele load of mosaic variants in CMN with phenotypic characteristics have not been determined. Aim To determine the correlation of variants allele load and different phenotypes of CMN. Methods A panel of genes in the Ras/Raf/MAPK signalling pathway was selected for sequencing in 110 patients with CMN. Correlations between variant allele load and clinical phenotypes, including anatomical localization, projected adult size of the lesion, satellites, subcutaneous nodules, surface rugosity, colour variation and hypertrichosis, were analysed. Results In addition to the predominant NRAS p.Q61R/K (61.8%) and BRAF p.V600E variants (10%) in patients, we also detected additional variants of NRAS (p.G13R and p.M72fs), BRAF (p.D22N) and MAP2K1 (p.I107fs, p.F209fs, p.Q354H and p.G91_L92insHDQARRLVGDLEHHKPSG). Furthermore, a higher allele load of NRAS p.Q61R/K was found in the trunk and limbs of CMN. It was also found in CMN with larger size, higher colour variation and more significant hypertrichosis, surface rugosity and asymmetry. Conclusion We discovered more genetic variants of NRAS, BRAF and MAP2K1 and established a correlation between the allele load of NRAS p.Q61R/K and various phenotypes in CMN. The findings of this study potentially facilitate a more accurate and comprehensive classification of CMN in addition to the phenotypic or pathological characteristics used in clinical practice.

Filgotinib has been approved for the treatment of rheumatoid arthritis (RA) in adults who respond inadequately to disease-modifying antirheumatic drugs (DMARDs) in Europe and Japan. Several randomized controlled trials (RCTs) have investigated its efficacy and safety in adult patients with RA. This meta-analysis aimed to study the efficacy and safety of filgotinib in patients with RA withan inadequate response to methotrexateor other DMARDs.A systematic literature search was conducted to identify articles in PubMed, MEDLINE, EMBASE, and Cochrane Library from inceptionto December 1, 2021. Outcomes of interest included ACR20/50/70 responses, DAS28-CRP ≤ 3.2, SF-36 PCS Score, FACIT-fatigue, SDAI,CDAI, and HAQ-DI, which were assessed after treatment. The safety outcomes included treatment-emergent adverse events (TEAEs) and serious TEAEs. Odds ratios (ORs) with 95% confidence intervals (CI) were pooled for categorical variables, and the mean difference with 95%CI were pooled for continuous variables. We used Review Manager 5.3 for the standard meta-analysis. This study followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).Four RCTs comparing filgotinib (200 and 100 mg once daily) with placebo were identified. Compared with placebo, 200 and 100 mg filgotinib was more effective in achieving ACR20/50/70 responses and other outcomes at weeks 12 and 24 (Plt; 0.05), with no significant difference in safety outcomes (Pgt; 0.05). Filgotinib 200 mg performed better than filgotinib 100 mg in terms of ACR20/50 responses, DAS28-CRP ≤ 3.2, SDAI, and CDAI at weeks 12 and 24, and caused fewer serious TEAEs than the 100 mg dose.Filgotinib is effective in the treatment of RA, and the 200 mg dose has a more beneficialprofile thanthe 100 mg dose.

Three new alkamides, achilleamide B-D (1-3) along with five known alkamides (4-8) were isolated from the aerial parts of Achillea alpina L. Structures were elucidated by spectroscopic analysis. Modified Mosher's method and electronic circular dichroism (ECD) calculations were introduced for the absolute configuration of 3. The neuroprotective effects of all the compounds were evaluated by 6-hydroxydopamine (6-OHDA)-induced cell death in human neuroblastoma SH-SY5Y cells, with concentration for 50 % of maximal effect (EC

As a type I viral fusion protein, SARS-CoV-2 spike undergoes a pH-dependent switch to mediate the endosomal positioning of the receptor-binding domain to facilitate viral entry into cells and immune evasion. Gaps in our knowledge concerning the conformational transitions and key intramolecular motivations have hampered the development of effective therapeutics against the virus. To clarify the pH-sensitive elements on spike-gating the receptor-binding domain (RBD) opening and understand the details of the RBD opening transition, we performed microsecond-time scale constant pH molecular dynamics simulations in this study. We identified the deeply buried D571 with a clear p

Renal cell carcinoma (RCC) is one of the most aggressive urological malignancies and has a poor prognosis, especially in patients with metastasis. Although RCC is traditionally considered to be radioresistant, radiotherapy (RT) is still a common treatment for palliative management of metastatic RCC. Novel approaches are urgently needed to overcome radioresistance of RCC. Black phosphorus quantum dots (BPQDs) have recently received great attention due to their unique physicochemical properties and good biocompatibility. In the present study, we found that BPQDs enhance ionizing radiation (IR)-induced apoptotic cell death of RCC cells. BPQDs treatment significantly increases IR-induced DNA double-strand breaks (DSBs), as indicated by the neutral comet assay and the DSBs biomarkers γH2AX and 53BP1. Mechanistically, BPQDs can interact with purified DNA–protein kinase catalytic subunit (DNA-PKcs) and promote its kinase activity in vitro. BPQDs impair the autophosphorylation of DNA-PKcs at S2056, and this site phosphorylation is essential for efficient DNA DSBs repair and the release of DNA-PKcs from the damage sites. Consistent with this, BPQDs suppress nonhomologous end-joining (NHEJ) repair and lead to sustained high levels of autophosphorylated DNA-PKcs on the damaged sites. Moreover, animal experiments indicate that the combined approach with both BPQDs and IR displays better efficacy than monotreatment. These findings demonstrate that BPQDs have potential applications in radiosensitizing RCC cells.

Tic disorders (TDs) are childhood onset neuropsychiatric disorders characterized by single or multiple sudden, rapid, recurrent, and motor tics and/or vocal tics. Several nuclear genes that are involved in mitochondrial functions suggest a potential role of mitochondria in TDs.To evaluate the association of mitochondrial DNA (mtDNA) variants with TDs, we screened the whole mitochondrial genomes in 493 TD patients and 109 age- and sex-matched healthy controls using next generation sequencing technology.A total of 1918 mtDNA variants including 1220 variants in patients only, 154 variants in controls only, and 544 variants shared by both cases and controls were identified. We found a higher number of overall mtDNA variants in TD patients (p = 0.00028). The variant density in MT-ATP6/8 and MT-CYB coding regions showed a significant difference between TD patients and controls (p = 0.0025 and p = 0.003, respectively). Furthermore, we observed a significant association of 15 common variants with TD based on an additive model, including m.14766C gt; T, m.14783 T gt; C, m.14905G gt; A, and m.15301G gt; A in MT-CYB; m.4769A gt; G, m.10398A gt; G, m.12705C gt; T, and m.12850A gt; G in MT-ND genes; m.7028C gt; T in MT-CO1; m.8701A gt; G in MT-ATP6; two variants with m.16223C gt; T, m.5580 T gt; C in noncoding regions; and three rRNA variants with m.1438A gt; G and m.750A gt; G in RNR1, and m.2352 T gt; C in RNR2.Our data provide evidence of mtDNA variants associated with TDs. The accumulation of the heteroplasmic levels may increase the risk of TDs. Replication studies with larger samples are necessary to understand the pathogenesis of TDs.

Clinical response to immunotherapy is closely associated with the immunosuppressive tumour microenvironment (TME), and influenced by the dynamic interaction between tumour cells and lymphatic endothelial cells (LECs). Here, we show that high levels of miR-142-5p positively correlate with indoleamine 2,3-dioxygenase (IDO) expression in tumour-associated lymphatic vessels in advanced cervical squamous cell carcinoma (CSCC). The miR-142-5p is transferred by CSCC-secreted exosomes into LECs to exhaust CD8+ T cells via the up-regulation of lymphatic IDO expression, which was abrogated by an IDO inhibitor. Mechanistically, miR-142-5p directly down-regulates lymphatic AT-rich interactive domain-containing protein 2 (ARID2) expression, inhibits DNA methyltransferase 1 (DNMT1) recruitment to interferon (IFN)-γ promoter, and enhances IFN-γ transcription by suppressing promoter methylation, thereby leading to elevated IDO activity. Furthermore, increased serum exosomal miR-142-5p levels and the consequent IDO activity positively correlate with CSCC progression. In conclusion, exosomes secreted by CSCC cells deliver miR-142-5p to LECs and induce IDO expression via ARID2–DNMT1–IFN-γ signalling to suppress and exhaust CD8+ T cells. Our study suggests that LECs act as an integral component of the immune checkpoint(s) in the TME and may serve as a potential new target for CSCC diagnosis and treatment.

Background Carbapenem-resistant hypervirulent Klebsiella pneumoniae strains have recently come into existence worldwide; however, researchers in northeast China are not aware of their clinical features and molecular characteristics. Methods Here, the molecular and virulent characteristics of 44 carbapenem-resistant K. pneumoniae (CRKP) isolates collected from January 2015 to December 2017 were studied. Multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were carried out to define the clonal relatedness among the isolates. PCR and capsular serotyping of the virulence-associated genes, as well as biofilm formation and serum complement-mediated killing assays, were employed to determine the virulent potential. The genomic features and associated mobile genetic elements of JmsCRE57 were detected by whole genome sequencing. Results The only positive isolate was JmsCRE57, which belonged to the ST375 serotype K2 that expressed uge, mrkD, fimH, kpn, aerobactin and rmpA virulence-associated genes and showed strong biofilm formation and serum sensitivity. Sequencing results showed that the JmsCRE57 genome mainly consisted of a circular chromosome, three antibiotic resistance plasmids and a virulent plasmid. The antibiotic resistance plasmid expressing blaKPC-2, blaCTX-M-15, aph(3'')-Ib, aph(6)-Id, qnrB1, aac(3)-IIa, aac(6')-Ib-cr, blaOXA-1, blaTEM-1B, catB4, sul2, dfrA14 and blaSHV-99. The virulent plasmid belonged to the IncHI1B group, which is mainly composed of capsular polysaccharide genes and siderophore-associated genes. The remaining CRKP strains that expressed uge, fimH, mrkD and kpn virulence-associated genes were not successfully typed. We also identified an isolate that expressed the alls gene. Conclusion Our results provide new insights on the epidemiology of carbapenem-resistant K2 hypervirulent K. pneumoniae ST375 and CRKP ST76 strains in northeast China, which may help control their future outbreaks.

Signal transducer and activator of transcription (STAT) proteins are latent cytoplasmic transcription factors essential for cytokine signaling. Our previous study showed that interleukin-3 (IL-3) induced STAT5 translocation to mitochondria and binding to mitochondrial DNA (mtDNA) in vitro. In this report, we further demonstrated in vivo binding of endogenous STAT5a to mtDNA transcriptional control region and reduced gene expression from all three mtDNA promoters after IL-3 stimulation. To specifically define the function of mitochondrial STAT5a, we generated mitochondrial-targeting wild-type and mutant STAT5a proteins. Compared with non-targeting STAT5a, mitochondrial-targeting wild-type STAT5a significantly reduced mitochondrial gene expression in transfected HEK293 cells. The level of attenuation was amplified in cells expressing constitutively active STAT5a, but abrogated in cells expressing DNA-binding-defective STAT5a. STAT5a-mediated repression of mtDNA expression also positively correlated with STAT5a binding to the E2 subunit of pyruvate dehydrogenase complex (PDC-E2), both a gate-keeping metabolic enzyme and a component of mtDNA nucleoid in mitochondrial matrix. Metabolic shift away from mitochondrial respiration is known in many cytokine-stimulated cells and cancer cells. STAT5a-mediated repression of mitochondrial gene expression and its interaction with PDC-E2 may provide important insights into its underlying mechanisms.

Oxidative stress is one of the principal causes of hypoxia-induced kidney injury. The ceria nanoparticle (CNP) is known to exhibit free radical scavenger and catalytic activities. When zirconia is attached to CNPs (CZNPs), the ceria atom tends to remain in a Ce3+ form and its efficacy as a free radical scavenger thus increases. We determined the effectiveness of CNP and CZNP antioxidant activities against hypoxia-induced acute kidney injury (AKI) and observed that these nanoparticles suppress the apoptosis of hypoxic HK-2 cells by restoring autophagy flux and alleviating mitochondrial damage. In vivo experiments revealed that CZNPs effectively attenuate hypoxia-induced AKI by preserving renal structures and glomerulus function. These nanoparticles can successfully diffuse into HK-2 cells and effectively counteract reactive oxygen species (ROS) to block hypoxia-induced AKI. This suggests that these particles represent a novel approach to controlling this condition.

BACKGROUND: The Patient-Reported Outcomes Measurement Information System (PROMIS) includes two instruments to quantify sleep symptoms (sleep disturbance [SDA] and sleep-related impairment [SRI]) in diverse populations across a wide symptom spectrum. However, the responsiveness of PROMIS measures to treatment of sleep disorders is unknown. We examined the responsiveness of the PROMIS sleep scales to the treatment of OSA. METHODS: We collected SDA, SRI, and Epworth Sleepiness Scale (ESS) before and after initiation of positive airway pressure (PAP) in patients with type 2 diabetes newly diagnosed with OSA. To compare responsiveness, we compared effect sizes and classifications of symptom improvement using both the reliable change method and thresholds of minimum important difference (MID). RESULTS: A total of 103 patients completed assessments pre- and post-PAP. SDA, SRI, and ESS scores all declined significantly with PAP therapy. We observed the largest effect size for SDA (−0.64; 95% CI, −0.86 to −0.42), followed by SRI (−0.43; 95% CI, −0.63 to −0.23), and ESS (−0.28; 95% CI, −0.42 to −0.15). More patients experienced the reliable change category of symptom remission categorized by the PROMIS measures (SDA: 23.3%; SRI: 31.1%) relative to the ESS (5.8%) (P < .001 for both). Using the MID, SDA and SRI also classified more patients as improved (SDA: 54.4%; SRI: 49.5%) relative to the ESS (35.0%) (P < .001 for both pairwise comparisons). CONCLUSIONS: PROMIS sleep measures were more likely than the ESS to detect an improvement with PAP therapy. Incorporating PROMIS measures into research and clinical care may provide a more sensitive assessment of symptomatic response to OSA treatment.

OBJECTIVE: The Emotion Dysregulation Inventory (EDI) is an informant questionnaire developed based on the Patient-Reported Outcomes Measurement Information System (PROMIS(®)) Scientific Standards and refined through factor analyses and item response theory (IRT) analyses. Although it was developed to improve measurement of emotion dysregulation in youth with autism spectrum disorder, emotion dysregulation has transdiagnostic significance. Therefore, the aim of this study was to evaluate the EDI’s psychometric properties and to establish IRT-based scores for a general population of youth. METHODS: Data were collected from a sample of 1000 caregivers of 6- to 17-year old youth matched to the US census on age, gender, race/ethnicity, years of education, and region. Confirmatory factor analyses and IRT analyses using the two-parameter graded response model were performed to evaluate the EDI’s structure and psychometric properties. RESULTS: Analyses supported the original two-factor structure of the EDI, reflecting factors for Reactivity and Dysphoria. Simulations of computerized adaptive testing supported use of the same items for a Reactivity short form as those that emerged as most informative in the original autism psychometric analyses. IRT co-calibration with commonly used measures of emotion regulation and irritability in child clinical or community samples indicated the EDI scales provide more information across a wider range of emotion dysregulation. Validity was supported by moderate correlations with measures of related constructs and expected known-group differences. CONCLUSIONS: The EDI is an efficient and precise measure of emotion dysregulation for use in general community and clinical samples as well as samples of youth with ASD.

Background Enterobacter cloacae complex (ECC) is one of the most common extended-spectrum β-lactamase and carbapenemase-producing pathogen that threatens millions of the elderly and vulnerable sick persons. The objective of this study was to perform the molecular characteristics of the carbapenem-resistant E. cloacae complex (CREC) emerged in Heilongjiang Province of China. Methods Six CREC strains were isolated from the patients with infectious diseases. The identities of ECC isolates were confirmed by sequencing the polymerase chain reaction (PCR) products of 16S rRNA gene. The characterization of the CREC isolates were analyzed by sequencing PCR products of the carbapenemase, ampC and fluoroquinolone resistance genes and performing multilocus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and whole genome sequencing. Results All 6 isolates harbored multiple resistance genes. Of them, 5 carried metallo-β-lactamases and one was blaKPC-2-positive. The levofloxacin and ciprofloxacin-resistant strains had substitutions of gyrA83, gyrA87, and parC80 in the quinolone-resistance determining regions. The MLST analyses revealed that 6 isolates belonged to five sequence types (ST520, ST528, ST1119, ST1120, and ST93) while the PFGE patterns of the isolates fallen into four clusters. The strain ST1120 was found to carry two separated plasmids that encode blaNDM-1 and blaIMP-4. Conclusions Our study, for the first time, identified a CREC strain that co-produces blaNDM-1 and blaIMP-4 in the Northeast China. Our finding emphasizes an urgent need for more intensive surveillance and precaution measures to prevent the CERC spread.

OBJECTIVE. The aim of the present study was to compare the diagnostic accuracy of liver stiffness measurements (LSMs) obtained using MR elastography (MRE), transient elastography (TE), and 2D shear wave elastography (SWE) in patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD). SUBJECTS AND METHODS. We prospectively enrolled 62 adult subjects (mean age [± SD], 50 ± 13 years; 58% women; body mass index [weight in kilograms divided by the square of height in meters], 35 ± 7). Two-dimensional SWE, MRE, and TE were performed at a mean of 105 ± 86 days after liver biopsy. The area under the ROC curve (AUROC) values and 95% CIs for the corresponding LSMs (expressed in kilopascals) were calculated, with significant fibrosis (Metavir liver fibrosis score, F2-F4) and advanced fibrosis (F3-F4) used as outcome measures. Pairwise comparisons of AUROC values were conducted using the DeLong test. Statistical significance was set at p < 0.05. RESULTS. For the 62 subjects, valid LSMs were obtained for 57 subjects with the use of 2D SWE, for 59 subjects with TE, for 59 subjects with MRE, and for 54 subjects with all three modalities combined. The AUROC values (95% CIs) of 2D SWE, TE, and MRE for the diagnosis of significant fibrosis were 0.80 (0.67-0.92), 0.77 (0.64-0.89), and 0.85 (0.74-0.95), respectively. The AUROC values (95% CIs) of 2D SWE, TE, and MRE for the diagnosis of advanced fibrosis were 0.89 (0.80-0.98), 0.86 (0.77-0.95), and 0.95 (0.89-1.00), respectively. Pairwise comparisons revealed similar diagnostic accuracy for significant fibrosis (2D SWE vs MRE, p = 0.431; 2D SWE vs TE, p = 0.317; and MRE vs TE, p = 0.052) and advanced fibrosis (2D SWE vs MRE, p = 0.348; 2D SWE vs TE, p = 0.293; and MRE vs TE, p = 0.059). CONCLUSION. For patients with biopsy-proven NAFLD, 2D SWE, MRE and TE exhibited comparable and very good to excellent diagnostic accuracy for advanced fibrosis and comparable but lower accuracy for significant fibrosis.

Penthorum chinense Pursh. is a traditional herbal medicine of Miao, and its extracts (PCPE) have been used for treatment of liver diseases in the clinic including nonalcoholic fatty liver disease (NAFLD). However, the active components and pharmacological mechanisms of PCPE for treating NAFLD remain unclear. This study aimed to explore potential mechanisms of action through network pharmacology, molecular docking combined with experimental in vitro. A total of five dihydroflavonoids (1-5) with the same parent nucleus of pinocembrin (PCB) from PCPE, were selected as bioactive ingredients and 109 potential targets related to NAFLD were obtained from public databases and literature mining. The core targets related to the bile secretion signaling were selected based on PPI network and KEGG enrichment analysis for exploring the mechanism of PCPE against NAFLD. Molecular docking results showed good interaction between the core targets in bile secretion signaling pathway and the five compounds predicted to be bioactive. With the strong binding activity to retinoid X receptor-alpha (RXRA) and farnesoid X receptor (FXR) protein, pinocembrin-7-O-β-D-glucoside (PCBG, the highest content in PCPE) and its metabolite PCB, could significantly increase the expression of RXRA, FXR and bile salt export pump (BSEP) in L02 cells, and significantly decrease the expression of cholesterol 7α-hydroxylase (CYP7A1) at mRNA and protein levels. This study provided favorable evidence for mechanism of the main dihydroflavonoids of PCPE against NAFLD, and presented a paradigm for the study of ethnomedicine.

Diminished ovarian reserve (DOR) is associated with compromised fertility that affects approximately 10% of couples. Gene mutations are implicated in the pathogenesis of DOR. Here, we aimed to assess the clinical and genetic characteristics of two sisters with impaired fertility history. The two sisters showed DOR and suffered from recurrent pregnancy loss (RPL) in natural pregnancy and in vitro fertilization-embryo transfer (IVF-ET).Whole exome sequencing (WES) was performed for the proband and pathogenic variants detected were validated by Sanger sequencing in all available family members. Minigene assay was performed to evaluate the impact of sequence variants on splicing effect.Two novel heterozygous variants on the HFM1 gene, c.1978-2A C and c.2680 + 3_2680 + 4delAT, were observed in the two patients. The genotype of their parents was all heterozygous, while the unaffected sister and brother did not carry the variants. Both variants could produce alternative transcripts compared to wild-type counterparts, which might result in protein dysfunction.Our results demonstrated that the pathogenic splicing variants in HFM1 are associated with DOR in these two sisters. Mutations in HFM1 may contribute to RPL and poor IVF-ET outcomes because of descending quality and quantity of oocytes. The study enriched the genetic defect spectrum of DOR and understanding of the roles of HFM1 in female reproduction.

Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that ginkgolic acid (GA), as a SUMO-1 inhibitor, exerted an inhibitory effect on cardiac fibrosis induced by myocardial infarction. Regarding the pathogenesis of PF, previous studies have concluded that small ubiquitin-like modifier (SUMO) polypeptides bind multiple target proteins and participate in fibrosis of multiple organs, including PF. In this study, we found altered expression of SUMO family members in lung tissues from IPF patients. GA mediated the reduced expression of SUMO1/2/3 and the overexpression of SENP1 in a PF mouse model, which improved PF phenotypes. At the same time, the protective effect of GA on PF was also confirmed in the SENP1-KO transgenic mice model. Subsequent experiments showed that SUMOylation of SMAD4 was involved in PF. It was inhibited by TGF-β1, but GA could reverse the effects of TGF-β1. SENP1 also inhibited the SUMOylation of SMAD4 and then participated in epithelial-mesenchymal transition (EMT) downstream of TGF-β1. We also found that SENP1 regulation of SMAD4 SUMOylation affected reactive oxygen species (ROS) production during TGF-β1-induced EMT and that GA prevented this oxidative stress through SENP1. Therefore, GA may inhibit the SUMOylation of SMAD4 through SENP1 and participate in TGF-β1-mediated pulmonary EMT, all of which reduce the degree of PF. This study provided potential novel targets and a new alternative for the future clinical testing in PF.

BackgroundIt was reported that tumor heterogeneity and the surrounding tumor microenvironment (TME) in ovarian cancer affects immunotherapy efficacy and patient outcomes. And the TME of ovarian cancer is intrinsically heterogeneous. CD47 plays vital roles in cell functional behavior and immune homeostasis relating to cancer prognosis. But how it affects TME and its contribution to heterogeneity in ovarian cancer has not been fully illustrated. Therefore, we aimed to identify a prognostic biomarker which may help explain tumor immune microenvironment heterogeneity of ovarian cancer.MethodsCancer single-cell state atlas (CancerSEA) was used to evaluate functional role of CD47. Several bioinformatics database including Oncomine, Gene Expression Profiling Interaction Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), The Human Protein Atlas (HPA), Ualcan and Kaplan-Meier plotter (KM plotter) were applied to illustrate correlation of CD47 with ovarian cancer prognosis and immune infiltration. Tumor Immune Single-cell Hub (TISCH) single cell database was employed to evaluate correlation of CD47 with tumor microenvironment. GeneMANIA was implemented to identify regulation networks of CD47. Differentially expressed genes (DEGs) between CD47 high and low expression groups were analyzed with R package DESeq2. Kyoto encyclopedia of genes and genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) were utilized to explore how CD47 affect the immune related cell signaling pathway.ResultsCD47 expression was upregulated and connected to worse OS and PFS in ovarian cancer. Close relation was found between CD47 expression level and immune infiltration in ovarian cancer, especially with Treg cells, Monocytes, Macrophages and T cell exhaustion (PConclusionOur results indicated that CD47 is closely correlated to ovarian cancer immune microenvironment and might induce ovarian cancer heterogeneity. Therefore, CD47 may be used as a candidate prognostic biomarker and provide us with new insights into potential immunotherapy in ovarian cancer patients.

Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer-related deaths. We have previously connected a non-sulfated glycosaminoglycan, hyaluronic acid (HA), with a common hydrogen sulfide (H

Protective autophagy can be activated by external stimuli such as chemotherapy (CT) and photothermal therapy (PTT), leading to tumour resistance. As a key subcellular for autophagy, lysosomal dysfunction is crucial for autophagy suppression. Furthermore, lysosomal drug sequestration enhances basic drug resistance such as doxorubicin (DOX), which is trapped away from its target site, namely, the nucleus. Moreover, most of nanodrug delivery systems are internalised to lysosome for degradation, which further leads to DOX resistance. Lysosome serves as an essential organelle in drug resistance mechanisms, whose acidification arrest provides a potential strategy to inhibit autophagy and lysosomal drug sequestration simultaneously. The chloride channel-3 (ClC-3) protein is known as an important Cl

ObjectivesThe primary aim of this study was to establish the normal reference ranges of the fetal left ventricular (LV) Modified Myocardial Performance Index (Mod-MPI). A secondary aim was to evaluate the agreement between manual and automatic measurements for fetal Mod-MPI.DesignA prospective, multicentre, cross-sectional study.ParticipantsNormal singleton pregnancies.MethodsThe LV functions of normal singleton pregnancies were assessed in nine centres covering eight provinces in China using unified ultrasound protocols and settings and standardised measurements by pulsed Doppler at 20–24, 28–32 and 34–38 weeks of gestation. The isovolumetric relaxation time (IRT), isovolumetric contraction time, ejection time (ET) and Mod-MPI were measured both automatically and manually.ResultsThis cross-sectional study included 2081 fetuses, and there was a linear correlation between gestational age (GA) and Mod-MPI (0.416+0.001×GA (weeks), p2=0.013), IRT (36.201+0.162× GA (weeks), p2=0.021) and ET (171.418–0.078*GA (weeks), p2=0.002). This finding was verified using longitudinal data in a subgroup of 610 women. The agreement between the manual and automated measurements for Mod-MPI was good.ConclusionsWe constructed normal reference values of fetal LV Mod-MPI. Automatic measurement can be considered for ease of measurement in view of the good agreement between the automatic and manual values.

Immune checkpoint inhibitor associated pneumonia (CIP) is a serious side effect of immune checkpoint inhibitors. There is a consensus on the treatment of acute phase of CIP, but the treatment of pulmonary interstitial fibrosis after the acute phase is still a clinical problem to be solved.The diagnosis and treatment of a non-small cell lung cancer (NSCLC) patient with immune checkpoint inhibitor associated pneumonia in the Stereotactic Radiotherapy Department of Qingdao Central Hospital were retrospectively analyzed, and literatures were reviewed.A 70-year-old male patient was diagnosed with Poorly differentiated squamous cell carcinoma of left lung with mediastinal lymph node metastasis T3N3M0 stage IIIc, EGFR/ALK/ROS1/RAF negative, PD-L1 (22c3) immunohistochemistry negative. After the progression of first-line chemotherapy, the patient was diagnosed as immune checkpoint inhibitor associated pneumonia grade 3 during second-line monotherapy with Nivolumab. After initial high-dose glucocorticoid pulse therapy, the lung computed tomography (CT) imaging and clinical symptoms of the patients were partially relieved, and then pirfenidone (300 mg tid) was given orally for more than 11 months. During the treatment of pirfenidone, the CT imaging and clinical symptoms of the patients were significantly improved, and there were no other adverse reactions except grade 1 nausea. During this period, chemotherapy and Anlotinib was given concurrently with pirfenidone and showed good safety profile.This case report is the first report of pirfenidone in the treatment of CIP, which provides a new idea for the clinical practice and research of CIP treatment.【中文题目：PD-1单抗导致免疫检查点抑制剂相关肺炎 1例——吡非尼酮治疗的安全性和有效性】 【中文摘要：背景与目的 免疫检查点抑制剂相关肺炎（checkpoint inhibitor pneumonitis, CIP）是严重的免疫检查点抑制剂副反应，急性期治疗手段已有共识，但急性期之后的肺间质纤维化治疗手段仍是临床需要解决的问题。方法 回顾性分析了青岛市中心医院立体定向放疗科收治的1例细胞程序性死亡受体1（programmed cell death1, PD-1）单抗导致免疫检查点抑制剂相关肺炎的非小细胞肺癌（non-small cell lung cancer, NSCLC）患者的诊断、治疗过程，并文献复习。结果 患者男性，70岁，初始诊断：左肺低分化鳞癌T3N3M0 IIIc期纵隔淋巴结转移表皮生长因子受体（epidermal growth factor receptor, EGFR）/间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）/原癌基因1酪氨酸激酶（C-ros oncogene 1 receptor tyrosine kinase, ROS1）/RAF阴性PD-L1（22C3）阴性。一线化疗进展后纳武利尤单抗单药二线治疗过程中确诊为免疫检查点抑制剂相关肺炎3级。初始大剂量糖皮质激素冲击治疗后患者肺部计算机断层扫描（computed tomography, CT）影像学和临床症状部分缓解，随后给予吡非尼酮口服（300 mg tid）11个月余，治疗过程中患者CT影像学和临床症状明显好转，除1级恶心外无其他不良反应。期间吡非尼酮与化疗、安罗替尼联合应用安全性好。结论 本病例报道为目前吡非尼酮治疗CIP的第1例报道，为CIP治疗的临床实践和临床研究提出了新的思路。】 【中文关键词：免疫检查点抑制剂；肺炎；PD-1单抗；吡非尼酮；肺肿瘤】.

Objective This study aims to investigate the association of filamin A with the function and morphology of prostate cancer (PCa) cells, and explore the role of filamin A in the development of PCa, in order to analyze its significance in the evolvement of PCa. Materials and Methods A stably transfected cell line, in which filamin A expression was suppressed by RNA interference, was first established. Then, the effects of the suppression of filamin A gene expression on the biological characteristics of human PCa LNCaP cells were observed through cell morphology, in vitro cell growth curve, soft agar cloning assay, and scratch test. Results A cell line model with a low expression of filamin A was successfully constructed on the basis of LNCaP cells. The morphology of cells transfected with plasmid pSilencer-filamin A was the following: Cells were loosely arranged, had less connection with each other, had fewer tentacles, and presented a fibrous look. The growth rate of LNCap cells was faster than cells transfected with plasmid pSilencer-filamin A (P

Wearable sensors have garnered considerable interest because of their great promise in terms of personalized health and disease management. Tears are a superior target for wireless, non-invasive wearable devices, and tear-based platforms have developed rapidly over the past decade. Although an increasing number of tear analytes have been found to be associated with multiple diseases, glucose still serves as a main target for tear-based wearable devices. There has been much investment and efforts to develop tear-based wearable biosensors, with contact lens-based and spring-like sensors flourishing commercially. Current efforts have moved past ocular and systematic disease markers to nutrients and chemicals. Moreover, tear-based wearable devices also have the potential to treat some ocular diseases. This review discusses aspects of tear-based wearable devices and it emphasizes that strict clinical validation is needed before such platforms enter the market. Multifunctional and theranostic strategies would further broaden their clinical use in the future.

Supplemental Digital Content is available in the text, Objective: To investigate the association of serum bilirubin level with hearing outcomes in bilateral sudden sensorineural hearing loss (BSSHL) patients. Participants: One hundred thirteen in-patient BSSHL patients were consecutively enrolled between July 2008 and December 2015 in a tertiary center. Main Outcome Measures: Multivariable linear regression, generalized estimating equations (GEE), and stratified analyses were applied to examine the association between serum bilirubin level and hearing outcome measures such as final hearing threshold and absolute and relative hearing gains in BSSHL. Results: After full adjustment for potential confounders, total bilirubin levels (TBIL) were observed to be positively and independently associated with hearing outcomes as measured by final hearing (β [95% confidence interval {CI}]: −1.5 [−2.7, −0.2] dB HL per 1 μmol/L increase in TBIL) and absolute and relative hearing gains (β [95% CI]: 1.4 [0.2, 2.7] dB and 1.6 [0.2, 3.1] dB, respectively) in the severe to profound hearing loss subpopulation. Conclusions: Higher TBIL levels, within the normal or mildly elevated ranges, were independently and significantly associated with better hearing outcome in BSSHL patients with severe to profound hearing loss. Given bilirubin elevation treatments exist, our finding suggests a novel pharmacological strategy for this specific subpopulation.

Previously, it has been reported that homeobox A9 (HOXA9) protein expression is downregulated in lung cancer cells, and that its expression is inversely correlated with the metastatic potential of lung cancer cells both in vitro and in vivo. As such, HOXA9 shows therapeutic potential. The development of therapeutic strategies based on this protein is, however, limited due to its poor membrane permeability. To overcome this problem, we developed a system to deliver HOXA9 protein into non-small cell lung cancer (NSCLC) cells. First, we constructed a delivery vector expressing polyarginine, a cell-penetrating peptide, as well as HOXA9. The resulting recombinant R10-HOXA9 protein was effectively introduced into A549 and NCI-H1299 NSCLC cells. Next, we examined the roles and molecular mechanisms of recombinant R10-HOXA9 in processes involved in tumor progression. To investigate the therapeutic efficacy of the delivery system, we performed cell motility assays using both in vitro and in vivo experimental models. We found that recombinant R10-HOXA9 protein reduced the invasion and migration rate, but not the proliferation rate, of the NSCLC cells tested, both in vitro and in vivo. Treatment of NSCLC cells with recombinant R10-HOXA9 protein led to a significant increase in E-cadherin expression. Conversely, we found that the expression of snail family zinc finger 2 (SLUG), a transcriptional repressor of E-cadherin, was markedly decreased. In an experimental metastatic mouse model, recombinant R10-HOXA9 protein was found to effectively reduce the rate of lung cancer cell motility. Our data suggest that the developed cell-permeable R10-HOXA9 system may serve as a useful tool to prevent NSCLC cell migration and invasion.

Objective To analyze the clinical characteristics of patients with unilateral auditory neuropathy (UAN), and to provide guidance for future clinical diagnosis and research. Methods Patients who were clinically diagnosed with UAN from 2004 to 2019 were included. Clinical characteristics, audiological features, imaging findings, genetic test results and management effect were summarized and followed. Results A total of 44 patients [mean age, 4.35 ± 4.39 years; 22 (50.00%) males and 22 (50.00%) females] were enrolled for analyses. Among the 38 patients who were tested by pure-tone or behavioral audiometry, the degree of hearing loss of the affected ear was characterized as mild in 2 ears (5.26%), moderate in 5 (13.16%), severe in 9 (23.68%) and profound in 22 (57.89%). For the 44 contralateral ears, 33 (75.00%) showed normal hearing and 11 (25.00%) presented with sensorineural hearing loss. Auditory brainstem responses were absent or abnormal in all 44 affected ears, while otoacoustic emissions and/or cochlear microphonics were present. Among the 18 patients who underwent magnetic resonance imaging (MRI), 7 (38.89%) presented cochlear nerve deficiency (CND). Nineteen candidate variants were found in 12 patients among the 15 UAN patients who were conducted targeted gene capture and next generation sequencing. Thirty patients were followed up by telephone to investigate their management effect. Conclusions Our study demonstrates comprehensive audiological features of patients with UAN to improve the clinical understanding and diagnosis. Some patients with UAN could show ipsilateral CND and MRI is essential to evaluate if the nerve is deficient. No pathogenic variants that directly related to the pathogenesis of UAN have been found in this study currently.

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly that is often accompanied by other anomalies. Although the role of genetics in the pathogenesis of CDH has been established, only a small number of disease-associated genes have been identified. To further investigate the genetics of CDH, we analyzed de novo coding variants in 827 proband-parent trios and confirmed an overall significant enrichment of damaging de novo variants, especially in constrained genes. We identified LONP1 (lon peptidase 1, mitochondrial) and ALYREF (Aly/REF export factor) as candidate CDH-associated genes on the basis of de novo variants at a false discovery rate below 0.05. We also performed ultra-rare variant association analyses in 748 affected individuals and 11,220 ancestry-matched population control individuals and identified LONP1 as a risk gene contributing to CDH through both de novo and ultra-rare inherited largely heterozygous variants clustered in the core of the domains and segregating with CDH in affected familial individuals. Approximately 3% of our CDH cohort who are heterozygous with ultra-rare predicted damaging variants in LONP1 have a range of clinical phenotypes, including other anomalies in some individuals and higher mortality and requirement for extracorporeal membrane oxygenation. Mice with lung epithelium-specific deletion of Lonp1 die immediately after birth, most likely because of the observed severe reduction of lung growth, a known contributor to the high mortality in humans. Our findings of both de novo and inherited rare variants in the same gene may have implications in the design and analysis for other genetic studies of congenital anomalies.

Background. Endometriosis (EMs) is a benign chronic condition that tends to recur in women of childbearing age, with an incidence of approximately 10%. It is a multifactorial disease for which the pathogenesis is currently unclear. This study is aimed at investigating the expression and clinical significance of tRNA-derived small RNA (tsRNA), a novel noncoding small RNA with potential regulatory functions, in endometriosis. Methods. The tRF/tiRNA expression profiles in endometrial tissues from three pairs of endometriosis patients and controls were detected by tRF&tiRNA PCR microarray technology and then verified by quantitative real-time polymerase chain reaction (qPCR). The target genes and target sites of TRF396, tiRNA-5030-GlnTTG-3, TRF308, and TRF320 were predicted by miRanda, and the network diagram of their interaction with miRNA was drawn. The impact of tRNA-derived fragments on the pathogenesis of endometriosis was analyzed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Results. Two upregulated and 19 downregulated tRNA-derived fragments were identified. The qRT-PCR results of 2 upregulated and 2 downregulated RNA-derived fragments were consistent with the RNA Seq data. The OR2B4 gene related to TRF396, the DGAT1 gene related to tiRNA-5030-GlnTTG-3, the KLF16 gene of TRF308, and the RNF213 gene of TRF320 had significant correlations. Gene Ontology and pathway analysis showed that the target genes of TRF396 and tiRNA-5030-GlnTTG-3 were mainly involved in the intrinsic components of the membrane and the overall composition of the membrane in cell components; molecular functions mainly involve olfactory conduction and G protein-coupled receptor activity. In the biological process, it was mainly involved in the detection of sensory stimuli. The target genes of TRF308 and TRF320 were mainly involved in the intracellular part; molecular functions are mainly related to DNA binding transcription factor activity and protein binding and mainly related to biological regulation of biological processes. Pathway analysis showed that the RAP1 signaling pathway and the AXON GUIDANCE signaling pathway may participate in the progression of endometriosis. Conclusion. The differential expression of tRF/tiRNA in endometriosis may be related to the pathogenesis of endometriosis. Furthermore, tRF/tiRNA may be a biomarker for the diagnosis and treatment of EMs in the future.

Primary breast angiosarcoma (PBA) is a rare malignant tumor. PBA usually undergoes hematogenous metastasis; lymph node metastasis is very rare in such patients, and metastasis of PBA to the supraclavicular lymph nodes has not previously been reported. Here, we describe a rare case of PBA manifested by a diffuse enlargement of the left breast, with metastasis to the left axillary and bilateral supraclavicular lymph nodes. Contrast-enhanced ultrasound and positron emission tomography findings indicated a malignant lesion, whereas magnetic resonance imaging suggested a benign lesion. Core needle biopsy identified the lesion as a lymphangioma, and the histological characteristics suggested a high-grade angiosarcoma. Multimodal imaging and perfusion patterns obtained using various contrast agents can thus help to diagnose PBA.

Background lncRNAs have important roles in regulating cancer biology. Accumulating evidence has established a link between the dysregulation of lncRNAs and microRNA in cancer progression. In previous studies, miR-7-5p has been found to be significantly down-regulated in mesenchymal-like lung cancer cell lines and directly regulated EGFR. In this work, we investigated the lncRNA partner of miR-7-5p in the progression of lung cancer. Methods We investigated the expression of miR-7-5p and the lncRNA after transfection with an miR-7-5p mimics using a microarray. The microarray results were validated using quantitative real time-polymerase Chain Reaction (qRT-PCR). The regulatory effects of lncRNA on miR-7-5p and its target were evaluated by changes in the expression of miR-7-5p after transfection with siRNAs for lncRNA and the synthesis of full-length lncRNA. The effect of miR-7-5p on lncRNA and the miRNA target was evaluated after transfection with miRNA mimic and inhibitor. The role of lncRNA in cancer progression was determined using invasion and migration assays. The level of lncRNA and EGFR in lung cancer and normal lung tissue was analyzed using TCGA data. Results We found that LINC00240 was downregulated in lung cancer cell line after miR-7-5p transfection with an miR-7-5p mimic. Further investigations revealed that the knockdown of LINC00240 induced the overexpression of miR-7-5p. The overexpression of miR-7-5p diminished cancer invasion and migration. The EGFR expression was down regulated after siRNA treatment for LINC00240. Silencing LINC00240 suppressed the invasion and migration of lung cancer cells, whereas LINC00240 overexpression exerted the opposite effect. The lower expression of LINC00240 in squamous lung cancer was analyzed using TCGA data. Conclusions Taken together, LINC00240 acted as a sponge for miR-7-5p and induced the overexpression of EGFR. LINC00240 may represent a potential target for the treatment of lung cancer.

Background: This study aimed to access the efficacy and safety of integrated Traditional Chinese and Western medicine treatment for patients with ulcerative colitis (UC) combined diabetes. Methods: This protocol adheres to the preferred reporting items for systematic reviews and meta-analysis protocol statement. We plan to search 8 electronic databases to identify qualifying studies published from database inception until December 1, 2020. The software of EndNote reference manager (X9) will be used to study selection. A pre-developed standardized data collection form will be used to extract from all eligible studies. For included studies, the quality will be assessed by Cochrane Risk of bias tool. The RevMan 5.3 software (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014) developed by the Cochrane Collaboration will be used for all statistical analysis. If possible, meta-analysis will be undertaken for each of the outcomes. For continuous variable data, we will used mean differences with 95% confidence intervals (CIs) as summary statistics. For dichotomous variable data, we will calculate Mantel-Haenszel odds ratio with 95% CIs as summary statistics from the numbers of events in control and intervention groups. We will consider a result to be statistically significant if P

Combining targeted therapeutic agents is an attractive cancer treatment strategy associated with high efficacy and low toxicity. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is an essential factor in DNA damage repair. Studies from us and others have revealed that DNA-PKcs also plays an important role in normal mitosis progression. Histone deacetylase (HDACs) inhibitors commonly lead to mitotic aberration and have been approved for treating various cancers in the clinic. We showed that DNA-PKcs depletion or kinase activity inhibition increases cancer cells’ sensitivity to HDACs inhibitors in vitro and in vivo. DNA-PKcs deficiency significantly enhances HDACs inhibitors (HDACi)-induced mitotic arrest and is followed by apoptotic cell death. Mechanistically, we found that DNA-PKcs binds to HDAC6 and facilitates its acetylase activity. HDACi is more likely to impair HDAC6-induced deacetylation of HSP90 and abrogate HSP90’s chaperone function on Aurora A, a critical mitotic kinase that regulates centrosome separation and mitotic spindle assembly in DNA-PKcs-deficient cells. Our current work indicates crosstalk between DNA-PKcs and HDACs signaling pathways, and highlights that the combined targeting of DNA-PKcs and HDACs can be used in cancer therapy. Abbreviations: DNA-PKcs, DNA-dependent protein kinase catalytic subunit, HDACs, Histone deacetylases, DSBs, DNA double-strand breaks, ATM, ataxia telangiectasia mutated, ATR, ATM-Rad3-related

COVID-19 has spread globally with over 90,000,000 incidences and 1,930,000 deaths by Jan 11, 2021, which poses a big threat to public health. It is urgent to distinguish COVID-19 from common pneumonia. In this study, we reported multiple clinical feature analyses on COVID-19 in Inner Mongolia for the first time. We dynamically monitored multiple clinical features of all 75 confirmed COVID-19 patients, 219 pneumonia patients, and 68 matched healthy people in Inner Mongolia. Then, we studied the association between COVID-19 and clinical characteristics, based on which to construct a novel logistic regression model for predicting COVID-19. As a result, among the tested clinical characteristics, WBC, hemoglobin, C-reactive protein (CRP), ALT, and Cr were significantly different between COVID-19 patients and patients in other groups. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve was 0.869 for the logistic regression model using multiple factors associated with COVID-19. Furthermore, the CRP reaction showed five different time-series patterns with one-peak and double-peak modes. In conclusion, our study identified a few clinical characteristics significantly different between COVID-19 patients and others in Inner Mongolia. The features can be used to establish a reliable logistic regression model for predicting COVID-19.

Purpose. To investigate whether the radiomics analysis of MR imaging in the hepatobiliary phase (HBP) can be used to predict microvascular invasion (MVI) in patients with hepatocellular carcinoma (HCC). Method. A total of 130 patients with HCC, including 80 MVI-positive patients and 50 MVI-negative patients, who underwent MR imaging with Gd-EOB-DTPA were enrolled. Least absolute shrinkage and selection operator (LASSO) regression was applied to select radiomics parameters derived from MR images obtained in the HBP 5 min, 10 min, and 15 min images. The selected features at each phase were adopted into support vector machine (SVM) classifiers to establish models. Multiple comparisons of the AUCs at each phase were performed by the Delong test. The decision curve analysis (DCA) was used to analyze the classification of MVI-positive and MVI-negative patients. Results. The most predictive features between MVI-positive and MVI-negative patients included 9, 8, and 14 radiomics parameters on HBP 5 min, 10 min, and 15 min images, respectively. A model incorporating the selected features produced an AUC of 0.685, 0.718, and 0.795 on HBP 5 min, 10 min, and 15 min images, respectively. The predictive model for HBP 5 min, 10 min and 15 min showed no significant difference by the Delong test. DCA indicated that the predictive model for HBP 15 min outperformed the models for HBP 5 min and 10 min. Conclusions. Radiomics parameters in the HBP can be used to predict MVI, with the HBP 15 min model having the best differential diagnosis ability.

Background Online hospitals are part of an innovative model that allows China to explore telemedicine services based on national conditions with large populations, uneven distribution of medical resources, and lack of quality medical resources, especially among residents needing to be protected from COVID-19 infection. Objective In this study, we built a hypothesis model based on the Unified Theory of Acceptance and Use of Technology (UTAUT) in order to analyze the factors that may influence patients’ willingness to use mobile medical services. This research was designed to assist in the development of mobile medical services. Residents who do not live in urban areas and cannot access medical assistance would greatly benefit from this research, as they could immediately go to the online hospital when needed. Methods A cross-sectional study based at the West China Hospital, Sichuan University, was conducted in July 2020. A total of 407 respondents, 18 to 59 years old, in Western China were recruited by convenience sampling. We also conducted an empirical test for the hypothesis model and applied structural equation modeling to estimate the significance of path coefficients so that we could better understand the influencing factors. Results Out of 407 respondents, 95 (23.3%) were aware of online hospitals, while 312 (76.7%) indicated that they have never heard of online hospitals before. Gender (P=.048) and education level (P=.04) affected people’s willingness to use online hospitals, and both of these factors promoted the use of online hospitals (odds ratio [OR] 2.844, 95% CI 1.010-8.003, and OR 2.187, 95% CI 1.031-4.636, respectively). According to structural equation modeling, the results of the path coefficient analysis indicated that performance expectancy, effort expectancy, and facilitating conditions have positive effects on patients’ willingness to use online hospitals. Conclusions The goal of our research was to determine the factors that influence patients’ awareness and willingness to use online hospitals. Currently, the public’s awareness and usage of online hospitals is low. In fact, effort expectancy was the most important factor that influenced the use of online hospitals; being female and having a high education also played positive roles toward the use of mobile medical services.

OBJECTIVES Auditory neuropathy (AN) is the term used to describe a group of hearing disorders, in which the hearing impairment occurs as a result of abnormal auditory nerve function. While our understanding of this condition has advanced significantly over recent years, the ability to determine the site of lesion and the extent of dysfunction in affected individuals remains a challenge. To this end, we investigated potential axonal degeneration in the white matter tracts of the brainstem in individuals with X-linked AN. We hypothesized that individuals with X-linked AN would show focal degeneration within the VIII nerve and/or auditory brainstem tracts, and the degree of degeneration would correlate with the extent of auditory perceptual impairment. DESIGN This was achieved using a higher-order diffusion magnetic resonance imaging (dMRI)-based quantitative measure called apparent fiber density as obtained from a technique called single-shell 3-tissue constrained spherical deconvolution and analyzed with the fixel-based analysis framework. Eleven subjects with genetically confirmed X-linked AN and 11 controls with normal hearing were assessed using behavioral and objective auditory measures. dMRI data were also collected for each participant. RESULTS Fixel-based analysis of the brainstem region showed that subjects with X-linked AN had significantly lower apparent fiber density in the VIII nerve compared with controls, consistent with axonal degeneration in this region. Subsequent analysis of the auditory brainstem tracts specifically showed that degeneration was also significant in these structures overall. The apparent fiber density findings were supported by objective measures of auditory function, such as auditory brainstem responses, electrocochleography, and otoacoustic emissions, which showed VIII nerve activity was severely disrupted in X-linked AN subjects while cochlear sensory hair cell function was relatively unaffected. Moreover, apparent fiber density results were significantly correlated with temporal processing ability (gap detection task) in affected subjects, suggesting that the degree of VIII nerve degeneration may impact the ability to resolve temporal aspects of an acoustic signal. Auditory assessments of sound detection, speech perception, and the processing of binaural cues were also significantly poorer in the X-linked AN group compared with the controls with normal hearing. CONCLUSIONS The results of this study suggest that the dMRI-based measure of apparent fiber density may provide a useful adjunct to existing auditory assessments in the characterization of the site of lesion and extent of dysfunction in individuals with AN. Additionally, the ability to determine the degree of degeneration has the potential to guide rehabilitation strategies in the future.