Clinical Analysis of Inhaled Nitric Oxide Therapy in Preterm Infants at Different Gestational Ages: A National Retrospective Multicenter Study.

OBJECTIVE: This study aimed to investigate clinical features of inhaled nitric oxide (iNO) in preterm infants with a gestational age (GA) < 34 weeks in China. STUDY DESIGN: The clinical data of 434 preterm infants with GA < 34 weeks, treated with iNO in the neonatology departments of eight Class A tertiary hospitals in China over a 10-year period from January 2013 to December 2022, were included in this retrospective multicenter investigation. The infants were divided into three groups based on GA: 24 to 27 weeks (extremely preterm infants), 28 to 31 weeks (very preterm infants), and 32 to 33 weeks (moderate preterm infants). The use of iNO, perinatal data, incidence and mortality of indication for iNO treatment, therapeutic effects of iNO, incidence of short-term complications for iNO treatment, and mortality were compared among these three groups. RESULTS: Over the past 10 years, the proportion of iNO use was highest in extremely preterm infants each year. The lower the GA, the higher the iNO use rate: 4.20% for GA 24 to 27 weeks, 1.54% for GA 28 to 31 weeks, and 0.85% for GA 32 to 33 weeks. There was no significant difference in the therapeutic effect of iNO among the three groups. The incidence of neonatal pulmonary hemorrhage, neonatal shock, late-onset diseases, retinopathy of prematurity requiring intervention, intracranial hemorrhage (grade 3 or 4), periventricular leukomalacia, neonatal necrotizing enterocolitis (≥stage II), and moderate to severe bronchopulmonary dysplasia was highest in extremely preterm infants and increased with decreasing GA. Mortality was negatively correlated with GA and birth weight. The highest rate of iNO treatment in 24 to 27 weeks' preterm infants was due to hypoxic respiratory failure (HRF), whereas the highest rate of iNO treatment in 32 to 33 weeks' preterm infants was due to documented persistent pulmonary hypertension of the newborn (PPHN). The rates of iNO treatment due to HRF and documented PPHN were 54.3 and 60.6%, respectively, in extremely preterm infants, significantly higher than in very preterm and moderate preterm infants (all p < 0.05). Within the same GA group, the proportion of preterm infants treated with iNO for HRF was lower than that for documented PPHN (all p < 0.05), but there was no statistically significant difference in mortality between HRF and documented PPHN treated with iNO (all p > 0.05). CONCLUSION: Among preterm infants with GA < 34 weeks, the rate of iNO usage was highest in extremely preterm infants. However, iNO failed to improve the clinical outcome of extremely preterm infants with refractory hypoxemia, and there was no significant difference in the therapeutic effect of iNO among preterm infants with different GAs.

RIOK3 potentially regulates osteogenesis-related pathways in ankylosing spondylitis and the differentiation of bone marrow mesenchymal stem cells.

RNA-binding proteins (RBPs), which are key effectors of gene expression, play critical roles in inflammation and immune regulation. However, the potential biological function of RBPs in ankylosing spondylitis (AS) remains unclear. We identified differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of five patients with AS and three healthy persons by RNA-seq, obtained differentially expressed RBPs by overlapping DEGs and RBPs summary table. RIOK3 was selected as a target RBP and knocked down in mouse bone marrow mesenchymal stem cells (mBMSCs), and transcriptomic studies of siRIOK3 mBMSCs were performed again using RNA-seq. Results showed that RIOK3 knockdown inhibited the expression of genes related to osteogenic differentiation, ribosome function, and ß-interferon pathways in mBMSCs. In vitro experiments have shown that RIOK3 knockdown reduced the osteogenic differentiation ability of mBMSCs. Collectively, RIOK3 may affect the differentiation of mBMSCs and participate in the pathogenesis of AS, especially pathological bone formation.

Development and validation of a medication non-adherence scale for Malaysian hypertensive patients: a mixed-methods study.

BACKGROUND: Non-adherence to anti-hypertensive medications can lead to hypertension-related complications. One of the most effective preventive measures to mitigate these complications is to understand the underlying determinants of medication non-adherence using various scales. Unfortunately, existing scales for measuring non-adherence to anti-hypertensive medications have certain limitations, such as insufficient consideration of validity, dimensionality, and cultural adaptation. In response, the current study aimed to develop and validate a measure of non-adherence to anti-hypertensive medications-known as the Malaysian Anti-hypertensive Agent Non-Adherence Scale (MAANS)-for use in local hypertensive patients. METHODS: A two-phase mixed-methods approach was used. Phase 1 involved qualitative interviews with hypertensive patients from two health clinics in Kuala Lumpur, Malaysia. The themes extracted from these interviews were used to generate items for the MAANS. In Phase 2, data from 213 participants were analysed using exploratory factor analysis (EFA) to establish the scale's factor structure, thereby created the modified version of the MAANS. Confirmatory factor analysis (CFA) was then conducted on a separate dataset of 205 participants to confirm the factor structure, resulted in the final version of the MAANS. The reliability of the final MAANS version was assessed using Cronbach's alpha coefficient. The MAANS scores were used to predict subscales of the Malay version of the WHO Quality-of-Life (QOL) BREF, demonstrating the scale's predictive validity. RESULTS: Ten qualitative interviews yielded 73 items. The EFA produced a modified MAANS with 21 items grouped into five factors. However, the CFA retained three factors in the final scale: Perceived Non-Susceptibility, Poor Doctor-Patient Relationship, and Unhealthy Lifestyle. The final 14-item, 3-factor MAANS demonstrated moderate reliability (Cronbach's alpha coefficient = 0.64) and exhibited partial predictive validity, with the Poor Doctor-Patient Relationship and Unhealthy Lifestyle subscales significantly predicting Social QOL and Environmental QOL. CONCLUSION: The MAANS is a reliable, valid, and multidimensional scale specifically developed to evaluate non-adherence to anti-hypertensive medications in local clinical settings with the potential to further the advancement of research and practice in sociomedical and preventive medicine.

Effect of nitrite on hydrolysis-acidification, biogas production and microbial community in semi-continuous two-phase anaerobic digestion of sewage sludge.

Previous study found that the pre-treatment of sewage sludge with nitrite improves the biogas production during the mono/two-phase anaerobic digestion (AD) using batch biochemical methane potential tests. In this study, the effects of nitrite on hydrolysis-acidification, biogas production, volatile solids destruction and microbial composition in semi-continuous two-phase AD of sewage sludge were investigated. The addition of nitrite promotes sludge organic matter solubilization (+484%) and VFAs production (+98.9%), and causes an increase in the VS degradation rate during the AD process (+8.7%). The comparison of biogas production from the acidogenic and methanogenic reactors with or without the addition of nitrite implies that the nitrite has no significant effect on the overall biogas production of two-phase sludge AD process. High-throughput sequencing analysis shows that the microbial communities of bacteria and archaea in two-phase AD reactors significantly changes after the addition of nitrite. Vulcanibacillus (bacteria) and Candidatus Methanofastidiosum (archaea) become the dominant genera in the acidogenic and methanogenic reactors with the nitrite respectively. These findings provide new insights about using nitrite to promote the organic matter degradation of sewage sludge in a semi-continuous two-phase AD system.

WWP2 overexpression inhibits the antitumor effects of doxorubicin in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common liver cancer that accounts for 90% of cases. Doxorubicin exhibits a broad spectrum of antitumor activity and is one of the most active agents in HCC. WW domain-containing protein 2 (WWP2) is highly expressed in HCC tissues and activates protein kinase B (AKT) signaling pathway to enhance tumor metastasis. However, the role of WWP2 in the glycolysis and antitumor effects of doxorubicin and the epigenetic alterations of WWP2 in HCC remain to be elucidated. The levels of WWP2 and N6-methyladenosine methyltransferase-like 3 (METTL3) in clinical samples and cells were investigated. WWP2 were silenced or overexpressed to study the role of WWP2 in regulating cell proliferation, colony formation, and glycolysis. RNA immunoprecipitation was performed to test m6 A levels. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) and Western blot were used to measure mRNA and protein, respectively. WWP2 silencing inhibits cell proliferation, colony formation, and glycolysis, while WWP2 overexpression has the inverse effects via the AKT signaling pathway. Silencing WWP2 enhances doxorubicin's antitumor effect, while WWP2 overexpression suppresses doxorubicin's antitumor effect. Data also support that METTL3 mediates WWP2 m6A modification, and m6A reader, IGF2BP2, binds to the methylated WWP2 to promote the stability of WWP2, leading to upregulation of WWP2. METTL3 mediates WWP2 m6A modification, which can be recognized and bound by IGF2BP2 to increase the stability of WWP2, leading to WWP2 overexpression which inhibits the antitumor effects of doxorubicin through METTL3/WWP2/AKT/glycolysis axis.

Investigation on forced vibration characteristics of Nitinol tracheal stent.

BACKGROUND: Tracheal stents can be placed in a narrow position in the human trachea to ensure smooth breathing. And the stent will deform during service by the influence of the physiological environment or random excitations, such as coughing. METHODS: This paper divides the vibration into periodic and random vibrations according to the different pressures. And a coupling vibration model was established by analyzing the contact relationship between the stent and the trachea tissue. And this study discusses the influence of tracheal diameter, respiratory pressure, and frequency on the stent vibration characteristics through Ansys simulation. In addition, the nonlinear equations were solved by the Matlab numerical analysis method, which could help analyze the influence of cough intensity on the stability of the tracheal stent system. RESULTS: The results showed that when tracheal stenosis occurred in the trachea's more significant grade, the trachea stent was more likely to fall off when treated with a tracheal stent. With the increase in respiratory frequency and pressure, the deformation of the tracheal stent is more considerable. Moreover, the frequency of normal cough hardly affects the stability of the stent system, while the excitation force and damping coefficient value greatly influence the system. When the excitation force of the cough exceeds the critical importance of 20 N, the tracheal stent is prone to fall off. This study comprehensively obtained the forced vibration characteristics of the stent under service conditions, which could make up for the shortage of the vibration theory of the stent. CONCLUSION: The results can provide a theoretical basis for predicting the possibility of stent loss in clinical treatment.

Optical phasing method based on scanning white-light interferometry for multi-aperture optical telescopes.

A novel, to the best of our knowledge, sensing approach based on scanning white-light interferometry (SWLI) is proposed to detect piston errors of the multi-aperture optical telescope. The scanning white-light interferometer is composed of a Mach-Zehnder interferometer (MZI) and an optical path modulator (OPM). A lenslet array is used to image the interferometric wavefront between the reference and the other individual apertures. The piston errors can be estimated from these SWLI signals focused by the lenslet array. The measurement range of the proposed method depends on the modulation range of the OPM and can reach millimeter order, and its accuracy is better than a 1/20 wavelength. In addition, the proposed method's amplitude-splitting interferometry of the MZI makes it fit for a multi-aperture optical telescope. We demonstrate a proof of concept and validate the feasibility of our proposed phasing method.

BAFF, involved in B cell activation through the NF-κB pathway, is related to disease activity and bone destruction in rheumatoid arthritis.

B cell activating factor of TNF family (BAFF) is a member of TNF ligand superfamily and plays a key role in B cell homeostasis, proliferation, maturation, and survival. In this study, we detected BAFF level, the expressions of BAFF receptors and important molecules in NF-κB pathway in rheumatoid arthritis (RA) patients and analyzed the correlation between BAFF level and clinical variables, laboratory parameters or X-ray scores in order to elucidate the roles of BAFF in RA. A total of 50 RA patients and 50 healthy controls (HCs) were enrolled. We showed that the serum BAFF level in RA patients was significantly higher than that of HCs, and the percentages of B cell subsets (CD19+ B cells, CD19+CD27+ B cells, CD19+CD20+CD27+ B cells, and CD19+CD20-CD27+ B cells) in the serum of RA patients were significantly increased compared with those of HCs. The percentages of CD19+BAFFR+ B cells, CD19+ BCMA+ B cells, and CD19+ TACI+ B cells in RA patients were significantly increased compared with those in HCs. The expression of important molecules in the NF-κB pathway (MKK3, MKK6, p-P38, p-P65, TRAF2, and p52) was significantly higher in RA patients than in HCs, but p100 level in RA patients was lower than that in HCs. The serum BAFF level was positively correlated with C-reactive protein, rheumatoid factor, disease activity score (in 28 joints), swollen joint counts, tender joint counts, and X-ray scores. When normal B cells were treated with BAFF in vitro, the percentages of the B cell subset and the expression of BAFF receptors were significantly upregulated. BAFF also promoted the expression of MKK3, MKK6, p-P38, p-P65, TRAF2, and p52. In conclusion, this study demonstrates that BAFF level is correlated with the disease activity and bone destruction of RA. BAFF is involved in the differentiation, proliferation, and activation of B cells in RA through NF-κB signaling pathway, suggesting that BAFF might be an ideal therapeutic target for RA.

Bioinformatics Analyses of Potential miRNA-mRNA Regulatory Axis in HBV-related Hepatocellular Carcinoma.

Aims: We aimed to explore the crucial miRNA-mRNA axis through bioinformatics analysis and provide evidences for the development of pathophysiological mechanisms and new therapies for HBV-related HCC. Methods: MiRNA (GSE76903) and mRNA (GSE77509) dataset were used to screen differentially expressed miRNAs (DE-miRNAs) and differentially expressed mRNAs (DE-mRNAs) using R software. Overlapping genes between DE-mRNAs and target genes of DE-miRNAs were identified as candidate genes. Hub genes were obtained via cytohubba analysis. The expression at protein and mRNA levels and prognostic value of hub genes were evaluated based on The Cancer Genome Atlas (TCGA) data. Key miRNA-mRNA axes were constructed according to predicted miRNA-mRNA pairs. MiRNA expression and prognostic role were respectively identified using starBase v3.0 and Kaplan-Meier plotter database. Real-time PCR was performed to verify the expression of crucial miRNAs and mRNAs. Coexpression of crucial miRNA and mRNA were analyzed using starBase v3.0. Results: CDK1, CCNB1, CKS2 and CCNE1 were screened as hub genes, which were significantly upregulated at protein and mRNA levels. These up-regulated hub genes were also significantly associated with poor prognosis. Hsa-mir-195-5p/CDK1, hsa-mir-5589-3p/CCNB1 and hsa-let-7c-3p/CKS2 were screened as critical miRNA-mRNA axes. Critical miRNAs were decreased in HCC, which indicates unfavourable prognosis. QPCR results showed that crucial miRNAs were decreased, whereas critical mRNAs were increased in HBV-related HCC. A reverse relationship between miRNA and mRNA in crucial axis was further verified. Conclusion: This study identified several miRNA-mRNA axes in HBV-related HCC. Hsa-mir-195-5p/CDK1, hsa-mir-5589-3p/CCNB1 and hsa-let-7c-3p/CKS2 might serve as potential prognostic biomarkers and therapeutic targets for HBV-related HCC.

α-Galactosylceramide and its analog OCH differentially affect the pathogenesis of ISO-induced cardiac injury in mice.

Immunotherapies for cancers may cause severe and life-threatening cardiotoxicities. The underlying mechanisms are complex and largely elusive. Currently, there are several ongoing clinical trials based on the use of activated invariant natural killer T (iNKT) cells. The potential cardiotoxicity commonly associated with this particular immunotherapy has yet been carefully evaluated. The present study aims to determine the effect of activated iNKT cells on normal and ß-adrenergic agonist (isoproterenol, ISO)-stimulated hearts. Mice were treated with iNKT stimulants, α-galactosylceramide (αGC) or its analog OCH, respectively, to determine their effect on ISO-induced cardiac injury. We showed that administration of αGC (activating both T helper type 1 (Th1)- and T helper type 2 (Th2)-liked iNKT cells) significantly accelerated the progressive cardiac injury, leading to enhanced cardiac hypertrophy and cardiac fibrosis with prominent increases in collagen deposition and TGF-ß1, IL-6, and alpha smooth muscle actin expression. In contrast to αGC, OCH (mainly activating Th2-liked iNKT cells) significantly attenuated the progression of cardiac injury and cardiac inflammation induced by repeated infusion of ISO. Flow cytometry analysis revealed that αGC promoted inflammatory macrophage infiltration in the heart, while OCH was able to restrain the infiltration. In vitro coculture of αGC- or OCH-pretreated primary peritoneal macrophages with primary cardiac fibroblasts confirmed the profibrotic effect of αGC and the antifibrotic effect of OCH. Our results demonstrate that activating both Th1- and Th2-liked iNKT cells is cardiotoxic, while activating Th2-liked iNKT cells is likely cardiac protective, which has implied key differences among subpopulations of iNKT cells in their response to cardiac pathological stimulation.

Hsp70 Gene Polymorphisms Are Associated With Disease Susceptibility and HRQOL Improvement in Chinese Han Population With Systemic Lupus Erythematosus.

OBJECTIVES: The aim of this study is to investigate whether heat shock protein 70 (Hsp70) gene polymorphisms are implicated in systemic lupus erythematous (SLE) susceptibility, the efficacy of glucocorticoids (GCs) treatment, and improvement of health-related quality of life. METHODS: A total of 499 SLE patients and 499 controls were included in a case-control study, and 468 SLE patients treated with GCs for 12 weeks were involved in a follow-up study. Patients who completed the 12-week follow-up were divided into GCs-sensitive and GCs-insensitive group by using the SLE disease activity index. The SF-36 was used to evaluate the health-related quality of life of SLE patients, and genotyping was performed by improved multiplex ligation detection reaction. RESULTS: rs2075800 was associated with SLE susceptibility (adjusted odds ratio [ORadj], 1.437; 95% confidence interval [CI], 1.113-1.855; Padj = 0.005; PBH = 0.020 by dominant model; ORadj, 1.602; 95% CI, 1.072-2.395; Padj = 0.022; PBH = 0.029 by TT vs CC model; ORadj = 1.396; 95% CI = 1.067-1.826; Padj = 0.015; PBH = 0.029 by TC vs CC model). In the follow-up study, rs2075799 was associated with the improvement in mental health (p = 0.004, PBH = 0.044), but we failed to find any association between the efficacy of GCs and Hsp70 gene polymorphisms. CONCLUSIONS: Hsp70 gene polymorphisms may be associated with susceptibility to SLE and improvement of mental health in Chinese Han population.

Correlation between systemic osteoporosis and local bone erosion with rheumatoid arthritis patients in Chinese population.

OBJECTIVE: RA is a systemic auto-immune inflammatory disease that can lead to local bone erosions and generalized osteoporosis (OP). The aim of this study was to investigate the relationship between systemic osteoporosis and local bone erosion with RA patients in the Chinese population. METHODS: In total, 1235 patients with RA and 158 normal subjects were enrolled in this study. Clinical and laboratory features were recorded in detail. Information about functional class and physical activity was collected using specific questionnaires. Dual-energy X-ray absorptiometry was used to measure BMD. The MECALL castor-50-hf model X-ray scanner was used for two-hand (including wrist) photographs. RESULTS: The median Sharp scores differed significantly between the normal bone mass group, osteopenia group and OP group (P < 0.001). There was a modest negative linear correlation between Sharp and HAQ scores and longer disease duration (P < 0.001). There was a clear increasing trend in Sharp score, incidence of OP and HAQ score in the different DAS in 28 joints (DAS28) activity groups (P < 0.001). Spearman's correlation test showed that Sharp and HAQ scores were negatively correlated with BMD at all measured sites (femoral neck, total hip and L1-4) (P < 0.001). Logistic regression indicated that age, female gender, and Sharp and HAQ scores were independent risk factors in the occurrence of OP in RA patients. The use of DMARDs and BMI were protective factors for OP. CONCLUSION: These results suggest that BMD is associated with local bone erosion among Chinese patients with RA. Local bone erosion is closely related to clinical symptoms and BMD in patients with RA.

Osteoporosis Self-Assessment Tool As a Screening Tool for Predicting Osteoporosis in Elderly Chinese Patients With Established Rheumatoid Arthritis.

Osteoporosis Self-Assessment Tool for Asians (OSTA) is an indicator for assessing osteoporosis in postmenopausal women. The aim of this study was to investigate the value of OSTA index on predicting osteoporosis in elderly Chinese patients with established rheumatoid arthritis (RA). A total of 320 patients with RA and 158 normal individuals were recruited from January 2015 to October 2017. Bone mineral density (BMD) at the femur and lumbar spine was measured by dual-energy X-ray absorptiometry. RA group and control group were divided into low risk (values≥-1), medium risk (values between -4 and -1), and high risk (values ≤-4) group according to the value of OSTA index. One-way analysis of variance showed that BMD at all detected regions among the 3 groups were obviously different (p < 0.0001). Incidences of osteoporosis among different OSTA groups were 21.76% (47/216), 56.41% (44/78), and 80.77% (21/26), separately (x2 = 67.389, p < 0.0001). In RA group including premenspausal or postmenspausal female subgroup, prevalences of osteoporosis among different OSTA groups were different (p < 0.05-0.0001). We also found a positive linear correlation between OSTA index and BMD (p < 0.0001) both in RA and in control groups. Logistic regression revealed OSTA index (odds ratio = 0.734, p < 0.0001, 95% confidence interval: 0.657-0.819) was a protective factor for occurrence of RA-induced osteoporosis. OSTA had the highest discriminatory power, with an estimated Area Under Curve (AUC) of 0.750 (95% confidence interval 0.694-0.807, p < 0.0001), sensitivity of 76.9% and specificity of 66.5%. Our findings indicated that OSTA index was closely associated with BMD in RA patients, the degree of correlation was much stronger than age or BMI. OSTA index was a predictor for osteoporosis in RA, but it might have little relationship with disease status in RA.

Effect of anti-tumor necrosis factor α treatment on radiographic progression in patient with ankylosing spondylitis: A systematic review and meta-analysis.

BACKGROUND: Efficacy of anti-tumor necrosis factor (anti-TNF)α treatment in patient with active ankylosing spondylitis (AS) had been proved by many clinical studies. Inflammation and new bone formation in spine were two pivotal aspects in AS. TNF α inhibitor could eliminate inflammation including clinical and laboratory inflammatory manifestation. Paradoxical results whether TNF α antagonist could delay radiographic progression in AS were often been reported simultaneously. OBJECTIVES: To review the literature about the effect of TNF α inhibitor on radiographic progression and disease activity in patient with AS. METHODS: We conducted a comprehensive search including Medline, EMBASE and the Cochrane Library from 1 January 2000 to 15 August 2017. Two reviewers independently supplemented with hand searching for the reference lists of inclusion. All trials focusing on radiographic progression or disease activity in patients with AS treated with anti-TNF α agents. Primary outcomes were modified Stokes AS Spinal Score (mSASSS), as well as Bath AS disease activity index (BASDAI) and Bath AS functional index (BASFI). Two reviewers independently selected studies and analyzed data. Methodological quality was assessed using the Newcastle-Ottawa scale (NOS). We pooled effects recorded on different scales as Standardized mean differences (SMDs) with 95% confidence intervals (CIs) using random-effects models. RESULTS: We included 14 studies of low to moderate risk of bias with 3,186 patients, compared with control group, there was no effect of mSASSS changes (SMD = -0.12, 95% CI: -1.17-0.93, p value = .82, I2 = 95%) and follow-up (SMD = 0.03, 95% CI: 0.21-0.26, p value = .82, I2 = 36%) estimation in anti-TNF α group. However anti-TNF α agent treatment led to remarkable improvements on both Bath AS disease activity index (BASDAI) (SMD = 1.06, 95% CI: 0.22-1.89, p value = .01, I2 = 96%) and Bath AS functional index (BASFI) (SMD = 0.93, 95% CI: 0.24-1.92, p value = .01, I2 = 97%) scores at 12 weeks. CONCLUSION: Our meta-analysis found no significant effect on delaying radiographic progression in AS treated with TNF α inhibitor, although TNF α inhibitor could do improve significantly disease activity and physical function in AS.

Actinomycin D synergistically enhances the cytotoxicity of CDDP on KB cells by activating P53 via decreasing P53-MDM2 complex.

The aim of this study is to investigate the synergism of low dose of actinomycin D (LDActD) to the cytotoxicity of cisplatin (CDDP) on KB cells. The role of P53 reactivation by LDActD in the synergism and its mechanism were further studied. Cell viability was determined by MTT assay. Apoptosis was determined by AnnexinV-FITC/PI staining. Mitochondrial membrane potential (MMP) was detected by JC-1 staining. Expression of proteins was detected by Western blotting (WB) and/or immunofluorescence (IF). Molecular docking of actinomycin D (ACTD) to Mouse double minute 2 homolog (MDM2) and Mouse double minute 2 homolog X (MDMX). MDMX was analyzed by Discovery Studio. The content of P53-MDM2 complex was detected by ELISA assay. The cytotoxicity of CDDP was increased by the combination of LDActD in kinds of cancer cells. Molecular docking showed strong interaction between ACTD and MDM2/MDMX. Meanwhile, LDActD significantly decreased P53-MDM2 complex. Significant increase of the apoptotic activity by the combination therapy in KB cells is P53 upregulated modulator of apoptosis (PUMA) dependent. In addition to the decrease in MMP, LDActD increased P53 regulated protein and decreased BCL-XL in KB cells. LDActD efficiently enhanced the cytotoxicity of CDDP in cancer cells and induced P53-PUMA-dependent and mitochondria-mediated apoptosis in KB cells. The reactivation of P53 was probably achieved by disturbing the interaction of P53 and MDM2/MDMX.

Silencing of WWP2 inhibits adhesion, invasion, and migration in liver cancer cells.

The role and clinical implication of the WWP2 E3 ubiquitin ligase in liver cancer are poorly understood. In the current study, we investigated the expression level of WWP2 and its functions in cell adhesion, invasion, and migration in liver cancer. We used real-time PCR to detect the expression of WWP2 in liver cancer and adjacent samples from the People's Hospital of Lishui and also analyzed The Cancer Genome Atlas (TCGA) RNA-seq data by bioinformatics. Migration and invasion were detected by transwell analysis. We detected a strong WWP2 expression in tumor tissues of the People's Hospital of Lishui, and the survival rate was significantly higher in patients with lower WWP2-expressing tumors. WWP2 small hairpin RNA (shRNA) lentivirus stably infected cells (shWWP2), Huh7, showed slower growth speed compared with scramble control-infected cells in a xenograft mouse model. Knockdown of WWP2 Huh7 and BEL-7404 cells demonstrated a reduction in adhesion, invasion, and migration. Gene set enrichment analysis (GSEA) showed that WWP2 is positively correlated to cancer-related pathways including the chemokine signaling pathway. WWP2 also regulated MMP-9, caspase-9, CXCR3, and CCR5 expression in liver cancer cells. In addition, knockdown of CXCR3 and CCR5 significantly inhibited cell proliferation, adhesion, invasion, and migration in Huh7 and BEL-7404 cells. Our data suggest that targeting of WWP2 may be a therapeutic strategy for liver cancer treatment.

Atomic layer deposition modified track-etched conical nanochannels for protein sensing.

Nanopore-based devices have recently become popular tools to detect biomolecules at the single-molecule level. Unlike the long-chain nucleic acids, protein molecules are still quite challenging to detect, since the protein molecules are much smaller in size and usually travel too fast through the nanopore with poor signal-to-noise ratio of the induced transport signals. In this work, we demonstrate a new type of nanopore device based on atomic layer deposition (ALD) Al2O3 modified track-etched conical nanochannels for protein sensing. These devices show very promising properties of high protein (bovine serum albumin) capture rate with well time-resolved transport signals and excellent signal-to-noise ratio for the transport events. Also, a special mechanism involving transient process of ion redistribution inside the nanochannel is proposed to explain the unusual biphasic waveshapes of the current change induced by the protein transport.

Dual-colored graphene quantum dots-labeled nanoprobes/graphene oxide: functional carbon materials for respective and simultaneous detection of DNA and thrombin.

Convenient and simultaneous detection of multiple biomarkers such as DNA and proteins with biocompatible materials and good analytical performance still remains a challenge. Herein, we report the respective and simultaneous detection of DNA and bovine α-thrombin (thrombin) entirely based on biocompatible carbon materials through a specially designed fluorescence on-off-on process. Colorful fluorescence, high emission efficiency, good photostability and excellent compatibility enables graphene quantum dots (GQDs) as the best choice for fluorophores in bioprobes, and thus two-colored GQDs as labeling fluorophores were chemically bonded with specific oligonucleotide sequence and aptamer to prepare two probes targeting the DNA and thrombin, respectively. Each probe can be assembled on the graphene oxide (GO) platform spontaneously by π-π stacking and electrostatic attraction; as a result, fast electron transfer in the assembly efficiently quenches the fluorescence of probe. The presence of DNA or thrombin can trigger the self-recognition between capturing a nucleotide sequence and its target DNA or between thrombin and its aptamer due to their specific hybridization and duplex DNA structures or the formation of apatamer-substrate complex, which is taken advantage of in order to achieve a separate quantitative analysis of DNA and thrombin. A dual-functional biosensor for simultaneous detection of DNA and thrombin was also constructed by self-assembly of two probes with distinct colors and GO platform, and was further evaluated with the presence of various concentrations of DNA and thrombin. Both biosensors serving as a general detection model for multiple species exhibit outstanding analytical performance, and are expected to be applied in vivo because of the excellent biocompatibility of their used materials.

Morphology and novel classification of proximal humeral fractures.

Background: The morphology of proximal humeral fractures (PHFs) is complex, and the fixation and selection of implants need to be guided by the fracture type and classification, which requires an accurate understanding of the fracture line. This study had three purposes. 1) Define and analyze the fracture lines and morphological features of all types PHFs by three-dimensional (3D) mapping technology. 2) Determine the osteotomy position of the biomechanical model of the PHFs according to the fracture heat map. 3) Based on the analysis of the pathological morphology and distribution of a large number of consecutive cases of PHFs, propose a novel classification of PHFs. Methods: We retrospectively collected 220 cases of PHFs and generated a 3D fracture map and heat map based on computed tomography (CT) imaging. Through analysis of the fracture morphology of the 220 PHFs, a novel classification was proposed. The primary criterion for staging was the continuity between the humeral head and the greater tuberosity and lesser tuberosity, and the secondary criterion was the relationship between the humeral head segment and the humeral shaft. Results: The fracture line was primarily found around the metaphyseal zone of region of the surgical neck, with the most extensive distribution being below the larger tuberosity and on the posterior medial side of the epiphysis. We suggest that the osteotomy gap should be immediately (approximately 5-10 mm) below the lower edge of the articular surface. The most common type of fracture was type I3 (33 cases, 15.0%), followed by type IV3 fracture (23 cases, 10.4%), and type III2 fracture (22 cases, 10.0%). Interobserver and intraobserver reliability analysis for the fracture classification revealed a k value (95% confidence interval) of 0.639 (0.57-0.71) and 0.841, P < 0.01, respectively. Conclusion: In this study, the fracture line and morphological characteristics of PHFs were clarified in detail by 3D mapping technique. In addition, a new classification method was proposed by analysis of the morphological characteristics of 220 PHFs, A two-part fracture model for PHFs is also proposed.