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The EGFR C797S mutation is the most common on-target resistance mechanism to osimertinib in patients with advanced non–small cell lung cancer (NSCLC). Currently there are no effective treatment options for patients with NSCLC harboring EGFR C797S triple mutants (Del19/T790M/C797S and L858R/T790M/C797S). Herein, we report an orally bioavailable EGFR PROTAC, HJM-561, which selectively degrades the EGFR C797S-containing triple mutants. HJM-561 potently inhibits the proliferation of Del19/T790M/C797S and L858R/T790M/C797S Ba/F3 cells while sparing cells expressing wild-type EGFR. Oral administration of HJM-561 shows robust antitumor activity in EGFR Del19/T790M/C797S-driven Ba/F3 CDX and PDX models that were resistant to osimertinib treatment. Taken together, our results suggest that HJM-561 is a promising therapeutic option for overcoming EGFR triple mutation-mediated drug resistance in NSCLC.

Ovarian cancer (OC) is the main type of cancer that affects the female reproductive system and has a high morbidity and mortality rate. This study aimed to explore the regulatory effect of the chromosomal region maintenance 1 (CRM1)-survivin axis on the progression of OC. Ovarian cancer cells were transfected with pcDNA3.1-survivin and short hairpin RNA (sh)-CRM1. Cell proliferation was analyzed by cell counting kit-8 (CCK8), 5-ethynyl-2´-deoxyuridine (EdU) staining, and colony formation assays. Apoptosis was detected using flow cytometry. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were performed to analyze the expression of RNA and protein, respectively. qRT-PCR and prognostic correlation analyses revealed that CRM1 is highly expressed in OC cells and related to survival. The results of qRT-PCR, CCK8, colony formation test, EdU staining, flow cytometry, and Western blotting showed that CRM1 silencing inhibited the proliferation and colony formation of OVCAR 3 and SKOV3 cells and promoted cell apoptosis by promoting Caspase-3 activation. Survivin was positively regulated by CRM1 and promoted the development of OC. The results of the rescue experiment showed that overexpression of survivin reversed the inhibitory effect of CRM1 knockdown on the proliferation of ovarian cancer cells and its inhibitory effect on apoptosis. Our findings confirm the role of the CRM1-survivin signal transduction axis in OC by regulating the proliferation and apoptosis of OC cells, and may thus serve as a potential therapeutic target for OC.

Purpose Vessel segmentation from volumetric medical images is becoming an essential pre-step in aiding the diagnosis, guiding the therapy, and patient management for vascular-related diseases. Deep learning-based methods have drawn many attentions, but most of them did not fully utilize the multi-scale spatial information of vessels. To address this shortcoming, we propose a multi-scale network similar to the well-known multi-scale DeepMedic. It also includes a double-pathway architecture and a class-balanced loss at the voxel level (MDNet-Vb) to achieve both the computation efficiency and segmentation accuracy. Methods The proposed network consists two parallel pathways to learn the multi-scale vessel morphology. Specifically, the pathway with a normal resolution uses three-dimensional (3D) U-Net fed with small inputs to learn the local details with relatively small storage and time consumption. The pathway with a low-resolution employs 3D fully convolutional network (FCN) fed with downsampled large inputs to learn the overall spatial relationships between vessels and adjacent tissues, and the morphological information of large vessels. To cope with the class-imbalanced issue in vessel segmentation, we propose a class-balanced loss at the voxel level with uniform sampling strategy. The class-balanced loss at the voxel level re-balances the loss function with a coefficient that is inversely proportional to the normalized effective number at the voxel level of each class. The uniform sampling strategy extracts training data by sampling uniformly from two classes in every epoch. Results Our MDNet-Vb outperforms several state-of-the-art methods including ResNet, DenseNet, 3D U-Net, V-Net, and DeepMedic with the highest dice coefficients of 72.91% and 69.32% on cardiac computed tomography angiography (CTA) dataset and cerebral magnetic resonance angiography (MRA) dataset, respectively. Among four different double-pathway networks, our network (3D U-Net+3D FCN) not only has the fewest training parameters and shortest training time, but also gets competitive dice coefficients on both the CTA and MRA datasets. Compared with classical losses, our class-balanced focal loss (FL-Vb) and dice coefficient loss at the voxel level (Dsc-Vb) alleviates class imbalanced issue by improving both the sensitivity and dice coefficient on the CTA and MRA datasets. Moreover, simultaneously training on two datasets shows that our method has the highest dice coefficient of 73.06% and 65.40% on CTA and MRA datasets, respectively, outperforming the commonly used methods, such as U-Net and DeepMedic, which demonstrates the generalization potential of our network for segmenting different blood vessels. Conclusions Our MDNet-Vb method demonstrates its superiority over other state-of-the-art methods, on both cardiac CTA and cerebral MRA datasets. For the network architecture, the MDNet-Vb combined the 3D U-Net and 3D FCN, which dramatically reduces the network parameters yet maintains the segmentation accuracy. The class-balanced loss at the voxel level further improves accuracy by properly alleviating the class-imbalanced issue between different classes. In summary, MDNet-Vb is promising for vessel segmentation from various volumetric medical images.

Selective induction of tumor thrombus infarction is a promising antitumor strategy. Non-persistent embolism due to non-compacted thrombus and activated fibrinolytic system within the tumor large blood vessels and tumor margin recurrence are the main therapeutic bottlenecks. Herein, an erythrocyte membrane-coated invisible acoustic-sensitive nanoparticle (TXA+DOX/PFH/RBCM@cRGD) is described, which can induce tumor thrombus infarction by precisely damaging tumor vascular endothelium. It is revealed that TXA+DOX/PFH/RBCM@cRGD can effectively accumulate on the endothelial surface of tumor vessels with the help of the red blood cell membrane (RBCM) stealth coating and RGD cyclic peptide (cRGD), which can be delivered in a targeted manner as nanoparticle missiles. As a kind of phase-change material, perfluorohexane (PFH) nanodroplets possess excellent acoustic responsiveness. Acoustic-sensitive missiles can undergo an acoustic phase transition and intense cavitation with response to low-intensity focused ultrasound (LIFU), damaging the tumor vascular endothelium, rapidly initiating the coagulation cascade, and forming thromboembolism in the tumor vessels. The drugs loaded in the inner water phase are released explosively. Tranexamic acid (TXA) inhibits the fibrinolytic system, and doxorubicin (DOX) eliminates the margin survival. In summary, a stealthy and acoustically responsive multifunctional nanoparticle delivery platform is successfully developed for inducing thrombus infarction by precisely damaging tumor vascular endothelium.

Atrial fibrillation (AF) is a common atrial arrhythmia for which there is no specific therapeutic drug. Quercetin (Que) has been used to treat cardiovascular diseases such as arrhythmias. In this study, we explored the mechanism of action of Que in AF using network pharmacology and molecular docking. The chemical structure of Que was obtained from Pubchem. TCMSP, Swiss Target Prediction, Drugbank, STITCH, Pharmmapper, CTD, GeneCards, DISGENET and TTD were used to obtain drug component targets and AF-related genes, and extract AF and normal tissue by GEO database differentially expressed genes by GEO database. The top targets were IL6, VEGFA, JUN, MMP9 and EGFR, and Que for AF treatment might involve the role of AGE-RAGE signaling pathway in diabetic complications, MAPK signaling pathway and IL-17 signaling pathway. Molecular docking showed that Que binds strongly to key targets and is differentially expressed in AF. In vivo results showed that Que significantly reduced the duration of AF fibrillation and improved atrial remodeling, reduced p-MAPK protein expression, and inhibited the progression of AF. Combining network pharmacology and molecular docking approaches with in vivo studies advance our understanding of the intensive mechanisms of Quercetin, and provide the targeted basis for clinical Atrial fibrillation treatment.

BackgroundPsoriasis is an immune-related skin disease notable for its chronic inflammation of the entire system. Alzheimer’s disease (AD) is more prevalent in psoriasis than in the general population. Immune-mediated pathophysiologic processes may link these two diseases, but the mechanism is still unclear. This article aimed to explore potential molecular mechanisms in psoriasis and AD.MethodsGene expression profiling data of psoriasis and AD were acquired in the Gene Expression Omnibus (GEO) database. Gene Set Enrichment Analysis (GSEA) and single-sample GSEA (ssGSEA) were first applied in two datasets. Differentially expressed genes (DEGs) of two diseases were identified, and common DEGs were selected. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to explore common biological pathways. Signature transcription factors (STFs) were identified and their diagnostic values was calculated by receiver operating characteristic (ROC) curve analysis in the exploration cohort and verified in the validation cohort. The expression levels of STFs were further investigated in the validation cohort and the GTEx Portal Database. Additionally, four kinds of interaction analysis were performed: correlation analysis among STFs, gene-gene, chemical-protein, and protein-ligand interaction analyses. In the end, we predicted the transcription factor that potentially regulates STFs.ResultsBiosynthesis and metabolic pathways were enriched in GSEA analysis. In ssGSEA analysis, most immunoreaction gene lists exhibited differential enrichment in psoriasis cases, whereas three receptor-related gene lists did in AD. The KEGG analysis of common DEGs redetermined inflammatory and metabolic pathways essential in both diseases. 5 STFs (PPARG, ZFPM2, ZNF415, HLX, and ANHX) were screened from common DEGs. The ROC analysis indicated that all STFs have diagnostic values in two diseases, especially ZFPM2. The correlation analysis, gene-gene, chemical-protein, and protein-ligand interaction analyses suggested that STFs interplay and involve inflammation and aberrant metabolism. Eventually, ZNF384 was the predicted transcription factor regulating PPARG, ZNF415, HLX, and ANHX.ConclusionsThe STFs (PPARG, ZFPM2, ZNF415, HLX, and ANHX) may increase the morbidity rate of AD in psoriasis by initiating a positive feedback loop of excessive inflammation and metabolic disorders. ZNF384 is a potential therapeutic target for psoriasis and AD by regulating PPARG, ZNF415, HLX, and ANHX.

Background Lung carcinoma is a common geriatric disease. The development of genotype-targeted therapies greatly improved the management of lung carcinoma. However, the treatment for old patients can be more complex than that for young individuals. Results To investigate the benefits of genetic detection for older patients with lung carcinoma, we explored the genomic profiling of 258 patients with more than 55 years using a targeted next generation sequencing, and some of these patients were treated with targeted therapies based on the results of genomic detection. KRAS codon 61 mutations were found in 15.2% KRAS-mutated patients, which tend to be co-existing with other classical activating mutations other than codons 12/13. Acquired EGFR C797S mutations were identified in 2 cases and ERBB2 amplification was identified in 1 case. All these 3 cases developed resistance to EGFR tyrosine kinase inhibitors and showed expected results of their followed therapies. The median progression-free survival and median overall survival of patients treated with molecular targeted therapies were better than those of patients treated with chemoradiotherapy alone. Conclusions Our findings revealed the specific genomic profiles of patients older than 55 years with lung carcinoma and suggested that these old patients have been benefit from the genetic detection, which helped identify druggable mutations and distinguish resistance mechanisms.

Background Local recurrence is the main cause of death among patients with oral squamous cell carcinoma (OSCC). This study assessed near-infrared fluorescence (NIF) imaging and spectroscopy to monitor surgical margins intraoperatively for OSCC. Methods Cytological and animal experiments were first performed to confirm the feasibility of monitoring surgical margins with NIF imaging and spectroscopy. Then, 20 patients with OSCC were included in the clinical trials. At 6–8 h after 0.75 mg/kg indocyanine green (ICG) injection, all patients underwent surgery with NIF imaging. During the surgery, both NIF images and quantified fluorescence intensity were acquired to monitor the surgical margins. Results In cytological and animal experiments, the results showed it was feasible to monitor surgical margins with NIF imaging and spectroscopy. Fluorescence was detected in primary tumors in all patients. The fluorescence intensities of the tumor, peritumoral, and normal tissues were 398.863 ± 151.47, 278.52 ± 84.89, and 274.5 ± 100.93 arbitrary units (AUs), respectively (P < 0.05). The SBR of tumor to peritumoral tissue and normal tissues was computed to be 1.45 ± 0.36 and 1.56 ± 0.41, respectively. After primary tumor excision, the wounds showed abnormal fluorescence in four patients (4/20), and residual cancer cells were confirmed by pathological examination in two patients (2/20). Conclusion These findings confirmed the complementary value of NIF imaging during radical tumor resection of OSCC. Before tumor resection, we could utilize the fluorescence margin produced by ICG NIF imaging to determine the surgical margin. Moreover, after tumor blocks were removed, the status of surgical margin could also be evaluated rapidly by ICG NIF imaging of tumor bed and in vitro specimens.

BackgroundAcrodermatitis enteropathica (AE) is a rare autosomal recessive hereditary skin disease caused by mutations in the SLC39A4 gene and is characterized by periorificial dermatitis, alopecia and diarrhoea due to insufficient zinc absorption. Only one of the three known sets of twins with AE has genetic information. This case reports the discovery of new mutation sites in rare twin patients and draws some interesting conclusions by analysing the relationship between genetic information and clinical manifestations.Case presentationHere, we report a pair of 16-month-old twin boys with AE exhibiting periorificial and acral erythema, scales and blisters, while subsequent laboratory examination showed normal plasma zinc and alkaline phosphatase levels. Further Sanger sequencing demonstrated that the patients were compound heterozygous for two unreportedSLC39A4mutations: a missense mutation in exon 5 (c.926G > T), which led to a substitution of the 309th amino acid residue cysteine with phenylalanine, a splice site mutation occurring in the consensus donor site of intron 5 (c.976 + 2 T > A). A family study revealed that the boys’ parents were heterozygous carriers of these two mutations.ConclusionWe identified a new compound heterozygous mutation in Chinese twins with AE, which consisted of two previous unreported variants in exon 5 and intron 5 of SLC39A4. We propose an up-to-date review that different mutations in SLC39A4 may exhibit different AE manifestations. In conjunction with future research, our work may shed light on genotype-phenotype correlations in AE patients and provide knowledge for genetic counselling and treatment for AE patients.

The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide, and the WHO declared it a pandemic on March 11, 2020. Clinical characteristics and epidemiology features of patients infected with SARS-CoV-2 have been explored in the previous study. However, little is known about the combinative association of liver dysfunction and abnormal interleukins (ILs) in severe patients with COVID-19. This study was designed to estimate whether liver dysfunction and abnormal ILs could predict the severity of COVID-19. This study integrated liver function data and ILs data in patients with COVID-19 and found that liver injury and two ILs, interleukin-2 receptor (IL-2R) and interleukin-6 (IL-6), were closely related to the prognosis of patients with COVID-19. This study may give more exact information to clinicians about the prognosis of patients with COVID-19. In addition, this correlational study between liver disorder and ILs may provide a new vision to diagnosis and treatment in patients.

To explore whether medication non-adherence experience, readiness for hospital discharge, financial toxicity and symptoms predicted oral chemotherapy adherence at home for Chinese cancer patients.Oral chemotherapy adherence is critical to determine the treatment efficacy among cancer patients. Identifying predictors before discharge from hospital based on transition theory could assist healthcare providers to improve oral chemotherapy adherence at home.An observational prospective study.Between October 2018 and December 2019, self-reported questionnaires were used to collect data among 151 cancer patients with oral chemotherapy at home. At discharge, baseline data of patient-perceived readiness for hospital discharge, financial toxicity and non-adherence experience were collected, while symptoms and adherence of oral chemotherapy at home were collected after finishing one cycle of oral chemotherapy at home (21 days, the first 14 days received oral chemotherapy). Regression analyses were performed for the predictors' explorations. The STROBE guidelines were followed.Among 151 participants with oral chemotherapy at home, 30.46% of patients reported medication non-adherence experience at discharge and 82.12% of patients reported adherence to oral chemotherapy at home. Patients with non-adherence experience at discharge were 5.4 times more likely to being non-adhered to oral chemotherapy at home. Numbness were the most frequent and severe symptoms during at home, patients with numbness were 6.6 times more likely to being non-adhered to oral chemotherapy. Although patients reported high level of readiness for discharge and financial toxicity at discharge, which did not predicted oral chemotherapy adherence at home.Patients with medication non-adherence experience at discharge and symptom of numbness from oral chemotherapy suggested a higher risk of oral chemotherapy non-adherence at home.Preventive interventions should focus on patients with previous medication non-adherence experience at discharge and experiencing numbness to promote oral chemotherapy adherence.

BACKGROUND Both healthcare provider-patient communication and self-care efficacy affect psychological distress, which is prevalent among patients with gastrointestinal (GI) cancers. It is essential to explore the underlying mechanism among them to relieve psychological distress. OBJECTIVE The aim of this study was to examine whether self-care efficacy mediated the association between healthcare provider-patient communication and psychological distress among patients with GI cancers. METHODS A cross-sectional study was conducted between March 2018 and May 2019 in China. In total, 219 patients with GI cancers were recruited before discharge from chemotherapy. Healthcare provider-patient communication was assessed by the revised Physician-Patient Communication Scale; patient self-care efficacy was assessed by the Strategies Used by People to Promote Health; and psychological distress was assessed by the Distress Thermometer and the Hospital Anxiety and Depression Scale. Mediation analyses were conducted to examine the mediating effect of self-care efficacy on the association between healthcare provider-patient communication and psychological distress. RESULTS A total of 54.34% of patients experienced psychological distress. Patients reported a mean score of 89.93 (SD, 13.81) for healthcare provider-patient communication and 93.91 (SD, 23.39) for self-care efficacy. Self-care efficacy completely mediated the association between healthcare provider-patient communication and psychological distress, and communication outcome was the only domain that significantly influenced self-care efficacy. CONCLUSION Psychological distress is prevalent among patients with GI cancers. Healthcare provider-patient communication, especially communication outcome, promoted patients' self-care efficacy to reduce psychological distress. IMPLICATIONS FOR PRACTICE Healthcare providers should design interventions to improve communication outcomes and eventually increase self-care efficacy to relieve psychological distress among patients with GI cancers.

Real-life data on guselkumab in psoriasis are limited and not available in China hitherto. This study aimed to evaluate the short-term effectiveness and safety of guselkumab in patients with psoriasis under Chinese real-life conditions and to explore the effect of guselkumab on CD4+ CD25+ Foxp3+ regulatory T cells (Tregs). A Chinese prospective and real-life study involving patients with psoriasis in Dermatology Hospital of Southern Medical University, Guangzhou, China from April to September 2020 was conducted. A total of 45 patients with psoriasis were finally enrolled in the study. Psoriasis Area Severity Index (PASI) 90 and 100 responses at week 16 were achieved by 88.6% and 45.5% of patients, respectively. The analysis of PASI response in different subgroups showed no statistically significant difference. Univariate logistic regression analysis revealed that at week 16, none of the variables were associated with decreasing PASI 90 response, whereas age at onset of disease was a predictor of PASI 100 response. Dynamic detection of CD4+ CD25+ Foxp3+ Tregs frequency from peripheral blood suggested a stable maintained trend in terms of guselkumab treatment duration. No severe adverse events occurred during the follow-up period. This study confirmed the short-term effectiveness and safety of guselkumab, as well as its good tolerance against psoriasis, in the Chinese population. Guselkumab treatment maintains levels of Tregs in patients with psoriasis.

At present, there is limited research on pregnancy body image and no valid tool to measure body image in pregnant Chinese women. The purpose of this study was to translate the Body Understanding Measure Pregnancy Scale into Chinese to determine its reliability and validity in measuring body image in pregnant women.The translation of the Body Understanding Measure Pregnancy Scale (BUMPs) was carried out with a standardized procedure. This study was conducted from July to December 2020 in the outpatient department of three tertiary hospitals in China. There were 1069 pregnant women completed the questionnaire and 1057 of those women were included in the analysis. Internal consistency, test-retest reliability, content validity, and construct validity of the translation version were examined.The final Chinese version of the BUMPs (BUMPs-C) had four dimensions with 16 items. Exploratory factor analysis obtained a three-factor solution, which explained 50.26% of the total variances. Confirmatory factor analysis showed that the model fit of the four-factor model was better than the three-factor model, and the four-factor model also reached a satisfactory model fit after modifying: Minimum Discrepancy was 2.82; Comparative Fit Index was 0.939, and Tucker-Lewis Index was 0.92; Root Mean Square Error of Approximation was 0.059. The content validity index of the scale was 1.0; the Cronbach's alpha (α) coefficient was 0.82 for the total scale, the McDonald's omega (ω) coefficient was 0.829; the test-retest reliability was 0.796.The BUMPs-C showed good reliability and validity among pregnant Chinese women, which can be used as a simple and valid measurement tool to assess the feelings of pregnant Chinese women on body changes during pregnancy.

Long non‐coding RNAs (lncRNAs) play critical roles in regulating immune‐associated diseases and chronic inflammatory disorders. Here, we found that lncRNAs involve in the pathogenesis of psoriasis through integrative analysis of RNA‐seq data sets from a psoriasis cohort. Then, lncRNA‐protein‐coding genes (PCGs) co‐expression network analysis demonstrated that lncRNAs extensively interact with IFN‐γ signalling pathway‐associated genes. Further, we validated 3 lncRNAs associate with IFN‐γ signalling pathway activation upon IFN‐γ stimulated in HaCaT cells, and loss of function experiments indicate their functional roles in the activation of inflammatory cytokine genes. Additionally, microRNA target screening analysis showed that lncRNAs may regulate JAK/STAT pathway activity through complete endogenous RNA (ceRNA) mechanism. Further experimental validation of PRKCQ‐AS1/STAT1/miR‐545‐5p regulatory circuitry showed that lncRNAs regulate the expression of JAK/STAT signalling pathway genes through competing for miR‐545‐5p. In summary, our results demonstrated that dysregulation of lncRNA‐JAK/STAT pathway axis promotes the inflammation level in psoriasis and thus provide potential therapeutic targets for psoriasis treatments.

Psoriasis is a chronic inflammatory skin disease. Although miRNAs are reported to be associated with the pathogenesis of psoriasis, the contribution of individual microRNAs toward psoriasis remains unclear. The miR-17-92 cluster regulates cell growth and immune functions that are associated with psoriasis. miR-17-3p is a member of miR-17-92 cluster; however, its role in dermatological diseases remains unclear. Our study aims at investigating the effects of miR-17-3p and its potential target gene on keratinocytes proliferation and secretion of pro-inflammatory cytokine and their involvement in psoriasis. Initially, we found that miR-17-3p was upregulated in psoriatic skin lesions, and bioinformatic analyses suggested that CTR9 is likely to be a target gene of miR-17-3p. Quantitative reverse-transcriptase PCR and immunohistochemical analysis revealed that CTR9 expression was downregulated in psoriatic lesions. Using dual-luciferase reporter assays, we identified CTR9 as a direct target of miR-17-3p. Further functional experiments demonstrated that miR-17-3p promoted the proliferation and pro-inflammatory cytokine secretion of keratinocytes, whereas CTR9 exerted the opposite effects. Gain-of-function studies confirmed that CTR9 suppression partially accounted for the effects of miR-17-3p in keratinocytes. Furthermore, Western blot revealed that miR-17-3p activates the downstream STAT3 signaling pathway while CTR9 inactivates the STAT3 signaling pathway. Together, these findings indicate that miR-17-3p regulates keratinocyte proliferation and pro-inflammatory cytokine secretion partially by targeting the CTR9, which inactivates the downstream STAT3 protein, implying that miR-17-3p might be a novel therapeutic target for psoriasis.

An 80-year-old women complained of painful erythema, papules, nodules on her right wrist for 9 months. Granuloma and inflammatory infiltrates with septate fungal hyphae were observed in pathological sections. Growth of demaciatious fungus on SDA was confirmed to be Exophiala spinifera by microscopic appearance and ITS rDNA sequencing. The diagnosis of phaeohyphomycosis due to E. spinifera was established. The patient had a poor response to oral itraconazole (200 mg/d) combining with terbinafine (250 mg/d) for 6 weeks. Then, following three courses of ALA-PDT, used as adjuvant therapy, skin lesions greatly improved and remained stable after 3 months follow-up. The case suggests that ALA-PDT is an effective adjuvant treatment option for patients with recalcitrant local subcutaneous fungal infection.

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain. It cannot be cured currently, and those suffering from AD place a great burden on their caregivers and society. AD is characterized by high levels of iron ions in the brain, which catalyze radicals that damage the neurons. Knowing that the Aβ42 peptide precipitates iron by binding iron ions at amino acid residues D1, E3, H11, H13, and H14, we synthesized a 5-repeat (HAYED) sequence peptide. By treating iron-stressed SH-SY5Y cells with it and injecting it into the cerebrospinal fluid (CSF) of naturally senescence Kunming mouse, which displaying AD-similar symptoms such as learning and memory dysfunction, neuron degeneration and high level of iron in brain, we found that HAYED (5) decreased the iron and radical levels in the cell culture medium and in the CSF. Specially, the synthesized peptide prevented cell and brain damage. Furthermore, functional magnetic resonance imaging (fMRI), Morris water maze and passive avoidance tests demonstrated that the peptide ameliorated brain blood-oxygen metabolism and slowed cognitive loss in the experimental senescence mice, and clinical and blood tests showed that HAYED (5) was innoxious to the kidney, the liver and blood and offset the AD-associated inflammation and anemia.

Wnt signaling is one of the key cascades regulating normal tissue development and has been tightly associated with cancer. The Wnt signaling can be subdivided into two categories: canonical & noncanonical. Noncanonical Wnt signaling pathways mainly include Wnt/PCP (planar cell polarity) signaling and Wnt-cGMP (cyclic guanosine monophosphate) /Ca2+ signaling. It has been well studied by previous researches that noncanonical Wnt signaling regulates multiple cell functions including proliferation, differentiation, adhesion, polarity, motility, and migration. The aberrant activation or inhibition of noncanonical Wnt signaling is crucial in cancer progression, exerting both oncogenic and tumor-suppressive effects. Recent studies show the involvement of noncanonical Wnt in regulating cancer cell invasion, metastasis, metabolism, and inflammation. Here, we review current insights into novel components of non-canonical signalings and describe their involvement in various cancer types. We also summarize recent biological and clinical discoveries that outline non-canonical Wnt signaling in tumorigenesis. Finally, we provide an overview of current strategies to target non-canonical Wnt signaling in cancer and challenges that are associated with such approaches.

Objective To investigate the expression and clinical significance of phosphatase and tension homolog deleted on chromosome ten (PTEN) and stimulator of interferon genes (STING) in human tongue squamous cell carcinoma (TSCC). Methods The expression of PTEN and STING protein in 65 pairs of TSCC and paracancerous tissues was detected by immunohistochemical EnVision method, and the relationships between PTEN, STING and clinicopathological parameters, overall survival (OS) and prognosis were analyzed by statistical methods. Results Compared with the adjacent tissues, the expression of PTEN in TSCC significantly decreased, and the expression of STING significantly increased. PTEN was negatively correlated with STING. In TSCC, the expression of PTEN and STING were correlated with pathological grade, TNM stage and lymph node metastasis. There were no significant correlations between the expression intensity of PTEN, STING and the gender and age of patients. The low expression of PTEN and the high expression of STING in TSCC tissues were significantly associated with poor prognosis and significantly shortened overall survival of patients. Conclusion TSCC patients with low expression of PTEN and high expression of STING have poor prognosis and short survival time. Combined detection of PTEN and STING expression is helpful to evaluate the degree of tumor progression and patient prognosis.

ObjectiveTo investigate the blood coagulation function in COVID-19 patients, and the correlation between coagulopathy and disease severity.MethodsWe retrospectively collected 147 clinically diagnosed COVID-19 patients at Wuhan Leishenshan Hospital of Hubei, China. We analyzed the coagulation function in COVID-19 patients through the data including thrombin-antithrombin complex (TAT), α2-plasmininhibitor-plasmin Complex (PIC), thrombomodulin (TM), t-PA/PAI-1 Complex (t-PAIC), prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT), D-Dimer (DD), and platelet (PLT).ResultThe levels of TAT, PIC, TM, t-PAIC, PT, INR, FIB, and DD in COVID-19 patients were higher than health controls (pConclusionThe coagulation systems in COVID-19 patients are inordinate, and dynamic monitoring of them, might be a key in the control of COVID-19 death.

Leukemic stem cells (LSCs) and hematopoietic stem cells (HSCs) are both dependent on the hypoxic bone marrow (BM) microenvironment (also known as the BM niche). There is always fierce competition between the two types of cells, and the former exhibits a greater competitive advantage than the latter via multiple mechanisms. Under hypoxia, the dynamic balance between the generation and clearing of intracellular reactive oxygen species (ROS) is conducive to maintaining a quiescent state of cells. Quiescent LSCs can reside well in the BM niche, avoiding attack by chemotherapeutic agents, which is the cause of chemotherapeutic resistance and relapse in leukemia. HSCs acquire energy mainly through anaerobic glycolysis, whereas LSCs achieve energy metabolism largely through mitochondrial oxidative respiration. Mitochondria are the primary site of ROS generation. Thus, in theory, mitochondria-mediated respiration will cause an increase in ROS generation in LSCs and a higher intracellular oxidative stress level. The sensitivity of the cells to pro-oxidant drugs increases as well, which allows for the selective clearing of LSCs by pro-oxidative therapy. However, HSCs are also highly sensitive to changes in ROS levels, and the toxic effects of pro-oxidant drugs on HSCs poses a major challenge to pro-oxidative therapy in leukemia. Given the above facts, we reviewed studies on the oxidative resistance of LSCs and the oxidative damage to HSCs under pro-oxidative therapy. An in-depth investigation into the oxidative stress status and regulatory mechanisms of LSCs and HSCs in hypoxic environments will promote our understanding of the survival strategy employed by LSCs and the mechanism of the oxidative damage to HSCs in the BM niche, thus facilitating individualized treatment of leukemia patients and helping eliminate LSCs without disturbing normal hematopoietic cells.

The superficial inferior epigastric artery (SIEA) flap is widely used in the repair of large soft tissue defects of the extremities and in breast reconstruction. Because of the high fat content of the abdomen, it has been less used for glossectomy reconstruction. Here we present a series of seven patients who each underwent reconstruction with a thin SIEA flap after resection of the tongue. There were six men and one woman (mean age 48, range 24-66 years). All patients underwent preoperative computed tomographic (CT) angiography, and colour Doppler ultrasound (US) was used to select and map the most suitable SIEA. The flap was raised above the Scarpa's layer while adjusted the plane of dissection according to the specific needs for bulk in each case. All the flaps survived; one flap required a secondary anastomosis because of a venous anastomotic embolus. The size of flap used was 5.0cm×6.0cm - 7.0cm×9.0cm, and the flap was 0.8cm-1.4cm thick. The functional outcome was evaluated at 6 - 18 months follow up, when speech and swallowing were both good in all cases. The dissection above the pubic symphysis is an important refinement of the SIEA flap, and we conclude that the thin SIEA flap is a good choice for reconstruction after excision of cancer of the tongue.

Acute lymphoblastic leukemia (ALL) is a hematological malignancy originating from B- or T-lymphoid progenitor cells. Recent studies have shown that redox dysregulation caused by overproduction of reactive oxygen species (ROS) has an important role in the development and progression of leukemia. The application of pro-oxidant therapy, which targets redox dysregulation, has achieved satisfactory results in alleviating the conditions of and improving the survival rate for patients with ALL. However, drug resistance and side effects are two major challenges that must be addressed in pro-oxidant therapy. Oxidative stress can activate a variety of antioxidant mechanisms to help leukemia cells escape the damage caused by pro-oxidant drugs and develop drug resistance. Hematopoietic stem cells (HSCs) are extremely sensitive to oxidative stress due to their low levels of differentiation, and the use of pro-oxidant drugs inevitably causes damage to HSCs and may even cause severe bone marrow suppression. In this article, we reviewed research progress regarding the generation and regulation of ROS in normal HSCs and ALL cells as well as the impact of ROS on the biological behavior and fate of cells. An in-depth understanding of the regulatory mechanisms of redox homeostasis in normal and malignant HSCs is conducive to the formulation of rational targeted treatment plans to effectively reduce oxidative damage to normal HSCs while eradicating ALL cells.

As a clonal disease of hematopoietic stem cells (HSCs), the etiology and pathogenesis of leukemia is not fully understood. Recent studies suggest that cellular homeostasis plays an essential role in maintaining the function of HSCs because dysregulation of cellular homeostasis is one of the major factors underlying the malignant transformation of HSCs. Reactive oxygen species (ROS) and autophagy, key factors regulating cellular homeostasis, are commonly observed in the human body. Autophagy can be induced by ROS through a variety of signaling pathways, and conversely inhibits ROS-induced damage to cells and tissues. ROS and autophagy coordinate to maintain cellular homeostasis. Previous studies have demonstrated that both of ROS and autophagy play important roles in the development of leukemia and are closely involved in drug resistance in leukemia. Interference with cellular homeostasis by promoting programmed leukemia cell death via ROS and autophagy has been verified to be an efficient technique in the treatment of leukemia. However, the critical roles of ROS and autophagy in the development of leukemia are largely unknown. In this review, we summarize the roles of ROS and autophagy in the pathogenesis of leukemia, which may allow the identification of novel targets and drugs for the treatment of leukemia based on the regulation of HSCs homeostasis through ROS and autophagy.

Introduction: More than 42 million people are estimated to suffer from valvular heart disease (VHD) worldwide with a prevalence of 5.3% to 7.7% in the Chinese adult population. The purpose of this study was to examine the associations between symptoms, hope, self-management behaviors, and quality of life (QOL) for preoperative patients with symptomatic VHD in a rural area of China. Method: This was a descriptive comparative study that took place in Nanning, China, between January 2015 and March 2016. The sample was 128 preoperative patients with symptomatic VHD. Data were collected using the Symptom Distress Questionnaire, Herth Hope Index, Self-Management Scale, and Minnesota Living with Heart Failure Questionnaire. Results: Data from 122 patients were included in the final analysis. Mean scores of hope, self-management, and QOL were 36.71, 55.27, and 55.56. Worse total scores of symptom severity ( r = 0.57 to 0.69, p < .001) and self-management behaviors ( r = −0.22 to −0.25, p < .05) were associated with poorer QOL. Fatigue, loss of appetite, and self-management behaviors explained 49.90% variance of QOL ( p < .001). Discussion: Fatigue, loss of appetite, and self-management influenced QOL of patients with symptomatic VHD. Interventions aimed at strengthening self-management and relieving symptoms should be tailored for patients with symptomatic VHD base on their traditional animist belief and food culture in rural areas of China such as the Zhuang Autonomous Region.

Background The purpose of this study was to analyze the association between the genetic polymorphism of genes (PAX6, SOSTDC1and FAM20B) and the susceptibility to mesiodens. Methods This study was carried out on 50 patients with mesiodens and 50 controls. The family history of each patient with mesiodens were recorded. Genomic DNA was extracted from saliva samples, and single nucleotide polymorphisms were detected in all exons and exon/intron boundaries of PAX6, SOSTDC1 and FAM20B using Sanger sequencing. The data were analyzed using pearson chi-square test with theoretical frequency ≥ 5. For theoretical frequency less than 5 but at least 1 (≤20% cell), the data were analyzed by continuity correction. For the rest, Fisher’s Exact test was used. A P-value

Morphea profunda (MP) is a variant of morphea that presents clinically as localized fibrotic plaques. Based on previous reports, there was no unified standard treatment for MP. Here we report a rare case of MP, which is the first report about treatment by hydroxychloroquine in combination with superficial X-ray. Compared with other regular therapeutic methods, this method not only produced a positive clinical effect in a short amount of time, but also caused fewer side effects.

Introduction: Acquired resistance to reversible EGFR tyrosine kinase inhibitors remains a significant obstacle, and acquired ERBB2 amplification is the most common “bypass” mechanism. For patients with sensitizing EGFR mutation who experience resistance via ERBB2 amplification, no targeted drug has been demonstrated to be effective. Patient concerns: A 56-year-old female nonsmoker suffered from left leg paralysis and low back pain. Imaging examination revealed a mass in the anterior segment of the right upper lobe lung and possible multiple metastases in the right hilar, mediastinal lymph nodes, bone metastases, and soft tissue invasion. Diagnosis: Transbronchial lung biopsy revealed a moderately differentiated adenocarcinoma (cT4N2M1c, stage IV). An EGFR exon 19 deletion was identified using amplification refractory mutation system. Interventions: After the patient was treated with gefitinib initiation (250 mg/d) for 15 months, the tumor progressed with ERBB2 amplification revealed by next-generation sequencing test. Then, the patient was started on afatinib (40 mg/d) plus bevacizumab (7.5 mg/kg every 3 weeks). Outcomes: The combination therapy of afatinib and bevacizumab in this patient was effective with some slight side effects. Computed tomography scans showed the tumor shrinkage and the pleural effusion disappeared in the right lung. The overall survival was 23.5 months. Conclusion: To date, there is no targeted therapy approved and demonstrated to be effective for non-small cell lung cancer patients with EGFR sensitizing mutations, and ERBB2 amplification. The effectiveness of combination therapy with afatinib and bevacizumab may provide a new therapeutic option for these patients.

This meta-analysis was conducted to evaluate the value of indocyanine green (ICG) in guiding sentinel lymph node biopsy (SLNB) for patients with oral cavity cancer. An electronic database search (PubMed, MEDLINE, Cochrane Library, Embase, and Web of Science) was performed from their inception to June 2020 to retrieve clinical studies of ICG applied to SLNB for oral cavity cancer. Data were extracted from 14 relevant articles (226 patients), and 9 studies (134 patients) were finally included in the meta-analysis according to the inclusion and exclusion criteria. The pooled sentinel lymph node (SLN) sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 88.0% (95% confidence interval [CI], 74.0-96.0), 64.0% (95% CI, 61.0-66.0), 2.45 (95% CI, 1.31-4.60), 0.40 (95% CI, 0.17-0.90), and 7.30 (95% CI, 1.74-30.68), respectively. The area under the summary receiver operating characteristic curve was 0.8805. In conclusion, ICG applied to SLNB can effectively predict the status of regional lymph nodes in oral cavity cancer.

Cell proliferation was inhibited following forced over-expression of miR-30a in the ovary cancer cell line A2780DX5 and the gastric cancer cell line SGC7901R. Interestingly, miR-30a targets the DNA replication protein RPA1, hinders the replication of DNA and induces DNA fragmentation. Furthermore, ataxia telangiectasia mutated (ATM) and checkpoint kinase 2 (CHK2) were phosphorylated after DNA damage, which induced p53 expression, thus triggering the S-phase checkpoint, arresting cell cycle progression and ultimately initiating cancer cell apoptosis. Therefore, forced miR-30a over-expression in cancer cells can be a potential way to inhibit tumour development.

Human fibroblast-like synoviocytes play a vital role in joint synovial inflammation in rheumatoid arthritis (RA). Proinflammatory cytokines induce fibroblast-like synoviocyte activation and dysfunction. The inflammatory mediator Krüppel-like factor 4 is upregulated during inflammation and plays an important role in endothelial and macrophage activation during inflammation. However, the role of Krüppel-like factor 4 in fibroblast-like synoviocyte activation and RA inflammation remains to be defined. In this study, we identify the notion that Krüppel-like factor 4 is higher expressed in synovial tissues and fibroblast-like synoviocytes from RA patients than those from osteoarthritis patients.In vitro, the expression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes is induced by proinflammatory cytokine tumor necrosis factor-α. Overexpression of Krüppel-like factor 4 in RA fibroblast-like synoviocytes robustly induced interleukin-6 production in the presence or absence of tumor necrosis factor-α. Conversely, knockdown of Krüppel-like factor 4 markedly attenuated interleukin-6 production in the presence or absence of tumor necrosis factor-α. Krüppel-like factor 4 not only can bind to and activate the interleukin-6 promoter, but also may interact directly with nuclear factor-kappa B. These results suggest that Krüppel-like factor 4 may act as a transcription factor mediating the activation of fibroblast-like synoviocytes in RA by inducing interleukin-6 expression in response to tumor necrosis factor-α.

Background In late December 2019, an outbreak of acute respiratory illness, coronavirus disease 2019 (COVID-19), emerged in Wuhan, China. We aimed to study the epidemiology, clinical features and short-term outcomes of patients with COVID-19 in Wuhan, China. Methods We performed a single center, retrospective case series study in 221 patients with laboratory confirmed SARS-CoV-2 pneumonia at a university hospital, including 55 severe patients and 166 non-severe patients, from January 2, 2020 to February 10, 2020. Results Of the 221 patients with COVID-19, the median age was 55.0 years and 48.9% were male and only 8 (3.6%) patients had a history of exposure to the Huanan Seafood Market. Compared to the non-severe pneumonia patients, the median age of the severe patients was significantly older, and they were more likely to have chronic comorbidities. Most common symptoms in severe patients were high fever, anorexia and dyspnea. On admission, 33.0% patients showed leukopenia and 73.8% showed lymphopenia. In addition, the severe patients suffered a higher rate of co-infections with bacteria or fungus and they were more likely to developing complications. As of February 15, 2020, 19.0% patients had been discharged and 5.4% patients died. 80% of severe cases received ICU (intensive care unit) care, and 52.3% of them transferred to the general wards due to relieved symptoms, and the mortality rate of severe patients in ICU was 20.5%. Conclusions Patients with elder age, chronic comorbidities, blood leukocyte/lymphocyte count, procalcitonin level, co-infection and severe complications might increase the risk of poor clinical outcomes.

Alzheimer's disease (AD) is currently incurable and places a large burden on the caregivers of AD patients. In the AD brain, iron is abundant, catalyzing free radicals and impairing neurons. The blood-brain barrier hampers antidementia drug delivery via circulation to the brain, which limits the therapeutic effects of drugs. Here, according to the method described by Gobinda, we synthesized a 16 lysine (K) residue-linked low-density lipoprotein receptor-related protein (LRP)-binding amino acid segment of apolipoprotein E (K16APoE). By mixing this protein with our designed therapeutic peptide HAYED, we successfully transported HAYED into an AD model mouse brain, and the peptide scavenged excess iron and radicals and decreased the necrosis of neurons, thus easing AD.

Background Agents promoting oligodendrocyte precursor cell differentiation have the potential to restore halted and/or delayed remyelination in patients with multiple sclerosis. However, few therapeutic targets have been identified. The objective of this study was to identify novel targets for promotion of remyelination and characterize their activity in vitro and in vivo. Methods A high-content screening assay with differentiation of primary rat oligodendrocyte precursor cells was used to screen GSK-proprietary annotated libraries for remyelination-promoting compounds. Compounds were further validated in vitro and in vivo models; clinical relevance of target was confirmed in human post-mortem brain sections from patients with MS. Results Of ~1000 compounds screened, 36 promoted oligodendrocyte precursor cell differentiation in a concentration-dependent manner; seven were histamine receptor-3 (H3R) antagonists. Inverse agonists of H3R but not neutral antagonists promoted oligodendrocyte precursor cell (OPC) differentiation. H3R was expressed throughout OPC differentiation; H3R expression was transiently upregulated on Days 3–5 and subsequently downregulated. H3R gene knockdown in OPCs increased the expression of differentiation markers and the number of mature oligodendrocytes. Overexpression of full-length H3R reduced differentiation marker expression and the number of mature cells. H3R inverse agonist GSK247246 reduced intracellular cyclic AMP (cAMP) and downstream cAMP response element-binding protein (CREB) phosphorylation in a dose-dependent manner. Histone deacetylase (HDAC-1) and Hes-5 were identified as key downstream targets of H3R during OPC differentiation. In the mouse cuprizone/rapamycin model of demyelination, systemic administration of brain-penetrable GSK247246 enhanced remyelination and subsequently protected axons. Finally, we detected high H3R expression in oligodendroglial cells from demyelination lesions in human samples of patients with MS, and validated a genetic association between an exonic single nucleotide polymorphism in HRH3 and susceptibility to multiple sclerosis. Conclusions From phenotypic screening to human genetics, we provide evidence for H3R as a novel therapeutic target to promote remyelination in patients with multiple sclerosis.

Background A lot of time and money was needed during the diagnosis and treatment process of leprosy, the delayed leprosy would also impair the labor capability of patients as well, and these put a heavy burden for the leprosy patients. The migrant leprosy patient is a special group and need more concern. Our goal was to assess the economic burden of leprosy on migrant and resident patient populations in Guangdong province, China. Methods We conducted a population-based cross-sectional survey from February to July of 2016. A self-designed questionnaire was administered to leprosy patients who: (1) had registered in Leprosy Management Information System in China (LEPMIS) by the end of February 2016, (2) had received multiple drug treatment (MDT) drugs at a local leprosy control institution for three consecutive months or had had at least one physical check in the past half year, and (3) were willing to take part in the investigation and give informed written consent. Demographic characteristics, Financial and disease information, and costs before and after leprosy diagnosis were collected and compared using t-test and χ2 test. Results A total of 254 participants completed the questionnaires, including 168 males and 86 females. Migrants and residents accounted for 33.9% and 66.1% of patients, respectively. Among migrant patients, the median cost before diagnosis was $131.6 (39.2–450.9), the median yearly cost of leprosy treatment after diagnosis was $300.6 (158.4–868.5), and the median yearly cost of leprosy complications was $69.5 (11–178.4). In comparison, among residents the median yearly costs were $152.4 (30.7–770.9) pre-diagnosis, $309.7 (103.2–1016.7) after diagnosis, and $91.9 (32.6–303.1) for leprosy complications. Base on this, we determined that the median yearly total expense after diagnosis amounted to 15% of migrant and 38% of resident patients’ annual income. Conclusion Leprosy places a heavy economic burden on both migrant and resident leprosy patients and governmental policies and programs could substantially alleviate this. Measures to implement more active surveillance and early diagnosis would benefit both populations, while labor protection and medical insurance are urgently needed for migrant patients and easier access to medical services and social aids could substantially decrease the burden of leprosy for resident patients.

The aim of the present study was to review the effectiveness of psychological and/or educational interventions for reducing psoriasis severity and improving psychological and quality of life (QOL) outcomes in psoriasis. Sixteen papers met the inclusion criteria. Overall, the effectiveness of the existing interventions from this narrative synthesis is positive, especially in psychological and QOL outcomes. Of the 16 included studies, only five were randomized controlled trials (RCTs). The strength of the evidence to support the effectiveness of the existing interventions was limited due to methodological weakness in the included studies. The review concludes that further research is needed to examine the effectiveness of psychological and/or educational interventions for individuals with psoriasis, including a greater number of RCTs in order to increase the methodological validity of intervention studies. Also, future research needs to be conducted to establish which interventions are most effective for specific sub-populations who may best profit from psycho-educational interventions.

Cigarette smoking is an important risk factor for chronic obstructive pulmonary disease (COPD), yet its pathogenic mechanisms are not yet fully understood. Endothelial dysfunction is known to be involved in the pathogenesis of COPD. A detailed understanding of the mechanism involved in its progression would have a substantial impact on the optimization and development of treatment strategies. Here, we report that the expression of SIRT4, a mitochondrial sirtuin, is markedly down-regulated in cigarette smoke extract (CSE)-treated human pulmonary microvascular endothelial cells (HPMECs). Overexpression of SIRT4 significantly inhibits CSE-induced mononuclear cell adhesion to HPMECs. Consistently, we found that overexpression of SIRT4 attenuates the induction of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. Importantly, SIRT4 was found to negatively regulate CSE-induced NF-κB activation via inhibiting the degradation of IκBα. Moreover, we also found that proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6, the downstream target genes of NF-κB, are also inhibited by overexpression of SIRT4. These results suggest that SIRT4 protects HPMECs exposed to CSE stress via a mechanism that may involve the NF-κB pathway. Strategies based on the enhancement of SIRT4 may prove to be beneficial in the treatment of cigarette smoking caused COPD.

During early embryonic development, bone morphogenetic protein (BMP) signaling is essential for neural/non-neural cell fate decisions. BMP signaling inhibits precocious neural differentiation and allows for proper differentiation of mesoderm, endoderm, and epidermis. However, the mechanisms underlying the BMP pathway-mediated cell fate decision remain largely unknown. Here, we show that the expression of Ovol2, which encodes an evolutionarily conserved zinc finger transcription factor, is down-regulated during neural differentiation of mouse embryonic stem cells. Knockdown of Ovol2 in embryonic stem cells facilitates neural conversion and inhibits mesendodermal differentiation, whereas Ovol2 overexpression gives rise to the opposite phenotype. Moreover, Ovol2 knockdown partially rescues the neural inhibition and mesendodermal induction by BMP4. Mechanistic studies further show that BMP4 directly regulates Ovol2 expression through the binding of Smad1/5/8 to the second intron of the Ovol2 gene. In the chick embryo, cOvol2 expression is specifically excluded from neural territory and is up-regulated by BMP4. In addition, ectopic expression of cOvol2 in the prospective neural plate represses the expression of the definitive neural plate marker cSox2. Taken together, these results indicate that Ovol2 acts downstream of the BMP pathway in the cell fate decision between neuroectoderm and mesendoderm to ensure proper germ layer development.

Nestin is a molecular marker for neural progenitor cells. Rat and human nestin genes possess a central nervous system-specific enhancer within their second introns. However, the transcription factors that bind to the nestin enhancer have not been fully elucidated. Here, we show that the second intron of the mouse nestin gene is sufficient to drive reporter gene expression in the developing nervous system. The core sequence of this central nervous system-specific enhancer localizes to the 3′ 320-bp region. The cis-elements for Sox and POU family transcription factors and the hormone-responsive element are essential for nestin expression during embryonic carcinoma P19 cell neural differentiation and in the developing chick neural tube. Interestingly, different transcription factors bind to the nestin enhancer at different stages of P19 cell neural differentiation and central nervous system development. Sox2 and SF1 may mediate basal nestin expression in undifferentiated P19EC cells, whereas Sox2, Brn1, and Brn2 bind to the enhancer in P19 neural progenitor cells. Similarly, in vivo, Oct1 binds to the nestin enhancer in embryonic day 8.5 (E8.5) mouse embryos, and Oct1, Brn1, and Brn2 bind to this enhancer in E10.5 and E12.5 mouse embryos. Our studies therefore suggest a temporal coordination of transcription factors in determining nestin gene expression.

Accumulation of senile plaques composed of amyloid beta-peptide (Abeta) is a pathological hallmark of Alzheimer disease (AD), and Abeta is generated through the sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase. Although oxidative stress has been implicated in the AD pathogenesis by inducing Abeta production, the underlying mechanism remains elusive. Here we show that the pro-oxidant H(2)O(2) promotes Abeta production through c-Jun N-terminal kinase (JNK)-dependent activation of gamma-secretase. Treatment with H(2)O(2) induced significant increase in the levels of intracellular and secreted Abeta in human neuroblastoma SH-SY5Y cells. Although gamma-secretase-mediated cleavage of APP or C99 was enhanced upon H(2)O(2) treatment, expression of APP or its alpha/beta-secretase-mediated cleavage was not affected. Silencing of the stress-activated JNK by small interfering RNA or the specific JNK inhibitor SP600125 reduced H(2)O(2)-induced gamma-secretase-mediated cleavage of APP. JNK activity was augmented in human brain tissues from AD patients and active JNK located surrounding the senile plaques in the brain of AD model mouse. Our data suggest that oxidative stress-activated JNK may contribute to senile plaque expansion through the promotion of gamma-secretase-mediated APP cleavage and Abeta production.

Aim To examine the effect of an educational intervention on parental readiness for premature infant discharge from neonatal intensive care units. Background Low readiness for discharge can result in negative healthcare outcomes for infants and their parents. However, few studies have examined the effect of discharge education programmes on parental readiness for premature infant discharge in Chinese critical care settings. Design A quasi-experimental study. Methods Between October 2011–March 2012, 154 parents of premature infants were recruited from neonatal intensive care units of two tertiary hospitals in Central China. These parents were assigned to either the intervention or control group based on their entry order. Parents in the intervention group received two sessions of 60-minute discharge education along with hospital routine care; parents in the control group only received hospital routine care. Parental readiness for discharge and quality of discharge education were assessed on the day of infant discharge from neonatal intensive care units. Independent samples t-test and linear regression were used to analyse the data. Results Parental readiness for premature infant discharge was in the moderate level. Independent samples t-test showed that both mean scores of parental discharge readiness and discharge teaching quality from the intervention group were significantly higher than those in the control group. Linear regression analysis showed that discharge teaching quality explained 39·7% of the variance in parental readiness for premature infant discharge. Conclusion Discharge education can improve parental readiness for premature infant discharge. Quality of discharge teaching can significantly predict parental readiness for premature infant discharge.

The mechanism of acquired aplastic anemia (AA), a bone marrow hematopoiesis failure disease, has not been fully understood. TNF-α is a pleiotropic cytokine involved in cell proliferation, differentiation and death, and inflammation through binding to specific receptors on cell membranes. Aberrant secretion of TNF-α contributes to a number of human diseases, including tumor development and inflammation. TNF-α is also an important negative regulator of hematopoiesis. Over-expression of TNF-α not only directly inhibits the proliferation and differentiation of hematopoietic cells, but also initiates the intracellular death pathway to induce hematopoietic cell death, leading to bone marrow hematopoiesis failure. In this review, we summarize the mechanisms underlying extrinsic apoptosis and necroptosis of hematopoietic cells induced by TNF-α, and discuss the role of TNF-α-induced programmed cell death in the pathogenesis of acquired AA.