Diagnostic potential of differentially expressed Homer1, IL-1ß, and TNF-α in coronary artery disease.

Increasing evidences suggest that inflammation plays an important role in the pathogenesis of coronary artery disease (CAD). Numerous inflammatory cytokines and related genes mediate adverse cardiovascular events in patients with CAD, such as interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and Homer in the present study. The study was carried out on 163 CAD patients at different stages and 68 controls. The gene expression of Homer1, Homer2, Homer3, IL-1ß, and TNF-α in the peripheral blood leukocytes were measured by real-time polymerase chain reaction. The mRNA levels of Homer1, IL-1ß, and TNF-α in CAD patients were significantly higher than those in the control group, but not Homer2 and Homer3. However, there was no considerable difference in the mRNA levels of Homer1, IL-1ß, and TNF-α among AMI, UAP, and SAP three subgroups of CAD. The receiver operating characteristic (ROC) curves showed that Homer1 had a better diagnostic value for UAP patients compared with IL-1ß and TNF-α. Like IL-1ß and TNF-α, Homer1 may also be an important participant of atherosclerotic plaque development and eventually rupture. The results of the present study may provide an important basis for diagnosing CAD patients, and provide new therapeutic targets for CAD.

Efficacy of traditional Chinese medicine injections for treating idiopathic pulmonary fibrosis: A systematic review and network meta-analysis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF), acutely or slowly progressing into irreversible pulmonary disease, causes severe damage to patients' lung functions, as well as death. In China, Chinese medicine injections (CMIs) have been generally combined with Western medicine (WM) to treat IPF, which are safe and effective. This study aimed to systematically compare the efficacy of 14 CMIs combined with WM in the treatment of IPF based on a systematic review and network meta-analysis (NMA). MATERIAL AND METHODS: PubMed, Web of Science, Embase, Cochrane Library, MEDLINE, and Chinese databases, including the China National Knowledge Infrastructure, Wanfang Database, Scientific Journal Database, and China Biology Medicine Database were searched from inception to October 31, 2021. The inclusion criterion was randomized controlled trials (RCTs) on CMIs with WM for treating IPF. Reviewers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.4 software and Stata software (version 16.0) were used for the data analysis. NMA were carried out for calculating the odd ratios (ORs) with 95% confidence intervals (CI), the surface under cumulative ranking curve (SUCRA) and the probabilities of being the best. RESULTS: A total of 63 eligible RCTs involving 14 CMIs were included in this NMA. More CMIs can significantly improve the clinical effectiveness rate (CER); Shuxuening injection (SXN)+WM (OR 8.91, 95% CI 3.81-20.83), Shuxuetong injection (SXT)+WM (OR 7.36, 95% CI 3.30-16.00), Shenxiong injection (SX)+WM (OR 5.42, 95% CI 2.90-10.13), Danhong injection (DH)+WM (OR 4.06, 95% CI 2.62-6.29), and Huangqi injection (HQ)+WM (OR 3.47, 95% CI 1.55-7.77) were the top five treatment strategies. Furthermore, DH +WM ranked relatively high in the SUCRA value of the nine outcome indicators, oxygen partial pressure (PaO2) (OR -13.39; 95% CI -14.90,-11.89; SUCRA 83.7%), carbon dioxide partial pressure (PaCO2) (OR -4.77; 95% CI -5.55,-3.99; SUCRA 83.3), orced vital capacity (FVC) (OR -1.42; 95% CI -2.47,-0.36; SUCRA 73.5%), total lung capacity (TLC) (OR 0.93; 95% CI 0.51,1.36; SUCRA 89.0%), forced expiratory volume 1/ forced vital capacity (FEV1/FVC%) (OR -10.30; 95% CI -12.98,-7.62; SUCRA 72.7%), type III collagen (IIIC) (OR 13.08; 95% CI 5.11,21.05; SUCRA 54.9%), and transforming growth factor (TGF) (OR -4.22; 95% CI -6.06,-2.37; SUCRA 85.7%) respectively, which seems to indicate that DH+WM had the highest likelihood of being the best treatment. CONCLUSIONS: This review specified several CMIs combined with WM in the treatment of IPF in China. In contrast to glucocorticoids or antioxidants, CMIs combined with WM delayed the decline in lung function, maintained oxygenation and quality of life in patients with IPF. The combined use of DH, SXN, SX, and safflower yellow sodium chloride injection (HHS) with WM exerted a more positive effect in treating IPF than WM alone. However, there were limitations to the conclusions of this study due to quality control differences in the included trials.

Mechanically Induced Switching between Two Discrete Conductance States: A Potential Single-Molecule Variable Resistor.

The fabrication of solid-state single-molecule switches with high on-off conductance ratios has been proposed to advance conventional technology in areas such as molecular electronics. Herein, we employed the scanning tunneling microscope break junction (STM-BJ) technique to modulate conductance in single-molecule junctions using mechanically induced stretching. Compound 1a possesses two dihydrobenzothiophene (DHBT) anchoring groups at the opposite ends linked with rigid alkyne side arms to form a gold-molecule-gold junction, while 1b contains 4-pyridine-anchoring groups. The incorporation of ferrocene into the backbone of each compound allows rotational freedom to the cyclopentadienyl (Cp) rings to give two distinct conductance states (high and low) for each. Various control experiments and suspended junction compression/retraction measurements indicate that these high- and low-conductance plateaus are the results of conformational changes within the junctions (extended and folded states) brought about by mechanically induced stretching. A high-low switching factor of 42 was achieved for 1a, whereas an exceptional conductance ratio in excess of 2 orders of magnitude (205) was observed for 1b. To the best of our knowledge, this is the highest experimental on-off conductance switching ratio for a single-molecule junction exploiting the mechanically induced STM-BJ method. Computational studies indicated that the two disparate conductance states observed for 1a and 1b result from mechanically induced conformational changes due to an interplay between conductance and the dihedral angles associated with the electrode-molecule interfaces. Our study reveals the structure-function relationship that determines conductance in such flexible and dynamic systems and promotes the development of a single-molecule variable resistor with high on-off switching factors.

Genomic monitoring of SARS-CoV-2 uncovers an Nsp1 deletion variant that modulates type I interferon response.

The SARS-CoV-2 virus, the causative agent of COVID-19, is undergoing constant mutation. Here, we utilized an integrative approach combining epidemiology, virus genome sequencing, clinical phenotyping, and experimental validation to locate mutations of clinical importance. We identified 35 recurrent variants, some of which are associated with clinical phenotypes related to severity. One variant, containing a deletion in the Nsp1-coding region (Δ500-532), was found in more than 20% of our sequenced samples and associates with higher RT-PCR cycle thresholds and lower serum IFN-ß levels of infected patients. Deletion variants in this locus were found in 37 countries worldwide, and viruses isolated from clinical samples or engineered by reverse genetics with related deletions in Nsp1 also induce lower IFN-ß responses in infected Calu-3 cells. Taken together, our virologic surveillance characterizes recurrent genetic diversity and identified mutations in Nsp1 of biological and clinical importance, which collectively may aid molecular diagnostics and drug design.

The Value of DNA Quantitative Cytology Test for the Screening of Endometrial Cancer.

OBJECTIVE: To evaluate the accuracy, sensitivity, and specificity of DNA quantitative cytology test for the diagnosis of endometrial cancer or precancerous lesions and then discuss the value of DNA quantitative cytology as a screening tool for endometrial cancer. METHODS: The study enrolled 575 patients from September 2013 to January 2017 in Shanghai Minhang Central Hospital. Endometrial hysteroscopy plus dilation and curettage and DNA quantitative cytology tests were conducted as a method for the diagnosis of endometrial cancer. The accuracy, sensitivity, and specificity of this method were calculated according to histopathologic diagnoses which were used as the gold standard for diagnosis confirmation. RESULTS: For the DNA quantitative cytology diagnosis of endometrial cancer, accuracy was estimated at 85.57%, sensitivity at 87.01%, specificity at 85.34%, positive predictive value (PPV) at 47.86%, and negative predictive value (NPV) at 97.07%. For the DNA quantitative cytology diagnosis of endometrial cancer in menopausal patients: accuracy was estimated at 89.95%, sensitivity at 97.73%, specificity at 87.59%, positive predictive value (PPV) at 70.49%, negative predictive value (NPV) at 99.22%. For the DNA quantitative cytology diagnosis of endometrial cancer in non-menopausal patients, accuracy was estimated at 83.42%, sensitivity at 72.73%, specificity at 84.42%, positive predictive value (PPV) at 30.38%, and negative predictive value (NPV) at 97.07%. CONCLUSION: DNA heteroploidy can be tested for the occurrence and the development of endometrial cancer. A small number of non-endometrial cancer cases may also appear DNA heteroploidy, but the number of >5c cells is less than 3. DNA quantitative analysis is a useful tool for the screening of endometrial cancer, worthy of being popularized and applied in endometrial cancer diagnosis.

Coexpression network analysis identified that plakophilin 1 is associated with the metastasis in human melanoma.

BACKGROUND AND AIMS: Malignant melanoma is a fatal cancer with high metastatic characteristics. Approximately 80% of skin cancer deaths are caused by metastatic melanoma. It has been established that the metastatic ability of melanoma is regulated by an intricate gene interconnection network. Thus, the aim of this study was to identify and validate hub genes associated with metastatic melanoma and to further illustrate its potential mechanisms. METHODS: The method of weighted gene coexpression network analysis (WGCNA) was applied to explore potential regulatory targets and investigate the relationship between the key module and hub genes associated with the metastasis ability of melanoma. RESULTS: In the turquoise module, 26 hub genes were initially selected, and 6 of them were identified as "real" hub genes with high connectivity in the protein-protein interaction network. In terms of validation, PKP1 had the highest correlation with metastasis among all the "real" hub genes. Data obtained from the GEPIA database and the Gene Expression Omnibus database showed a lower expression of PKP1 in melanoma tissues compared to normal skin tissues. The results also showed that PKP1 was downregulated in metastatic melanomas (n = 367) compared with primary melanomas (n = 103) in The Cancer Genome Atlas (TCGA) database (n = 470). Furthermore, an ROC curve showed that PKP1 expression had good power in the diagnostics of both primary melanoma (p = 5.30e-06, AUC = 0.8) and metastatic melanoma (p = 1.13e-10, AUC = 0.925). We also found that PKP1 could distinguish low- and high-grade of metastatic melanomas and was associated with inflammatory melanoma. Moreover, in a tumor-bearing mouse model, melanoma tissues also showed lower mRNA expression of PKP1 than the adjacent normal skin. Finally, Gene Set Enrichment Analysis indicated that the calcium signaling was significantly enriched in metastatic melanoma with highly expressed PKP1. CONCLUSIONS: PKP1 was identified as a new potential tumor suppressor in human melanoma, likely through regulating calcium signaling pathways.

Interactions between Cytosolic Phospholipase A2 Activation and Mitochondrial Reactive Oxygen Species Production in the Development of Ventilator-Induced Diaphragm Dysfunction.

Cytosolic phospholipase A2 (cPLA2) has been reported to be critical for infection-induced mitochondrial reactive oxygen species (ROS) production and diaphragm dysfunction (DD). In the present study, we aim to investigate whether cPLA2 was involved in ventilator-induced diaphragm dysfunction (VIDD). Our results showed that mechanical ventilation (MV) induced cPLA2 activation in the diaphragm with excessive mitochondrial ROS generation and muscle weakness. Specific inhibition of cPLA2 with CDIBA resulted in decreased mitochondrial ROS levels and improved diaphragm forces. In addition, mitochondria-targeted antioxidant MitoTEMPO attenuated ventilator-induced mitochondrial oxidative stress and downregulated cPLA2 activation in vivo. Both CDIBA and MitoTEMPO were able to attenuate protein degradation, muscle atrophy, and weakness following prolonged MV. Furthermore, laser Doppler imaging showed that MV decreased diaphragm tissue perfusion and induced subsequent hypoxia. An in vitro study also demonstrated a positive association between cPLA2 activation and mitochondrial ROS generation in C2C12 cells cultured under hypoxic condition. Collectively, our study showed that cPLA2 activation positively interacts with mitochondrial ROS generation in the development of VIDD, and ventilator-induced diaphragm hypoxia serves as a possible contributor to this positive feedback loop.

Gd-DTPA-coupled Ag2Se quantum dots for dual-modality magnetic resonance imaging and fluorescence imaging in the second near-infrared window.

Near-infrared (NIR) fluorescent quantum dots (QDs) are ideal platforms to fabricate multifunctional contrast agents for multimodal imaging. Herein, second near-infrared window fluorescent (NIR-II) Ag2Se QDs were coupled with gadopentetate dimeglumine injection (Gd-DTPA) for dual-modality T1-weighted magnetic resonance (MR) imaging and fluorescence imaging. In vitro experiments suggested that the prepared Ag2Se-Gd QDs exhibit low cytotoxicity, remarkable T1-weighted MR imaging, and fluorescence imaging contrast properties. In vivo experiment results showed that Ag2Se-Gd QDs were the preferred contrast agents for dual-modality T1-weighted MR imaging and fluorescence imaging with high spatial resolution. Moreover, excellent temporal resolution and high tissue penetration depth were also achieved by fluorescence imaging. These results indicate the potential of Ag2Se-Gd QDs as multifunctional contrast agents for multimodal imaging in clinical diagnosis and research.

Prognosis of 591 fetuses with ultrasonic soft markers during mid-term pregnancy.

The present study aimed to examine the value of ultrasonic soft markers in prenatal screening by analyzing the clinical outcome of fetuses with ultrasonic soft markers during the second trimester of pregnancy. A retrospective analysis was performed to evaluate the outcome of 591 fetuses with ultrasonic soft markers from January 2015 to August 2016 in Zhongnan Hospital of Wuhan University, China. It was found that 591 fetuses showed ultrasonic soft markers in 4927 cases with the occurrence rate being 12.0%. Among them, 564 fetuses (95.4%) were delivered and the remaining 27 cases (4.6%) were aborted. Five hundred and sixty-seven cases had single ultrasonic soft marker, including echogenic intracardiac focus (n=343), mild renal pelvis dilatation (n=116), short long bones (n=72), single umbilical artery (n=31), mild lateral ventriculomegaly (n=21), choroid plexus cysts (n=19), and echogenic bowel (n=13), with the disappearing rates in pregnancy being 97.1% (333/343), 77.6% (90/116), 0% (0/72), 0% (0/31), 57.1% (12/21), 89.5% (17/19) and 61.5% (8/13) respectively. The rate of pregnancy termination due to single ultrasonic soft marker was 3.4% (19/567), and that was 33.3% (8/24) due to two ultrasonic soft markers with the difference being statistically significant (P<0.05). The reasons of pregnancy termination included malformations (polycystic kidney, cleft lip and palate, congenital heart diseases, pcromphalus, hypospadias, hydrocephalus), chromosome abnormality, and stillbirth. It was concluded that single ultrasonic soft marker is usually transient manifestation in pregnancy. Without the other structural defects, single ultrasonic soft marker usually disappears spontaneously with favorable prognosis in a low-risk population. It is suggested that ultrasonic soft markers should be appropriately interpreted to avoid unnecessary invasive examination.

Decreased expression of LncRNA SRA1 in hepatocellular carcinoma and its clinical significance.

BACKGROUND: Hepatocellular carcinoma (HCC), is an extremely aggressive malignancy with poor prognosis and high fatality rates worldwide. Accumulating evidence indicated that novel biomarkers are required to get a better understanding of the biological mechanisms of HCC. SRA1, a long non-coding RNA (lncRNA), serves as a critical regulator in several cancers. However, the association between SRA1 expression and tumorigenesis in HCC tissues remains unclear. OBJECTIVE: In the present study, we evaluated the expression of SRA1 in HCC and its clinical association. METHODS: The expression levels of SRA1 in 67 pairs of cancer tissues and adjacent normal tissues from HCC patients were detected using quantitative real-time PCR. Expression of SRA1 in HCC cell lines compared with normal human hepatocyte cell lines was also measured. Finally, the potential associations between its level in HCC tissues and the clinicopathological parameters were analyzed as well. RESULTS: The results indicated that the expression levels of SRA1 in HCC were remarkably decreased, compared with matched normal tissues (P< 0.001). Levels of SRA1 in HCC cell lines were also significantly decreased than that in normal human hepatocyte cell line L-02. Additionally, the levels of SRA1 were significantly associated with tumor size (P= 0.020) and serum GLU level (P= 0.046). CONCLUSIONS: This study highlighted that SRA1 was downregulated in HCC and might serve as a tumor suppressor in HCC, which laid a solid foundation for future research.

Prognostic value of abnormally expressed lncRNAs in ovarian carcinoma: a systematic review and meta-analysis.

Ovarian cancer (OC) is the most deadly gynecological cancer and it is urgently needed to find a new marker for the progress of OC. Many long noncoding RNAs (lncRNAs) have been reported to be aberrantly expressed in ovarian carcinoma, and may serve as prognostic markers. Therefore, we conducted this meta-analysis to gain a better understanding of the prognostic value of lncRNAs in patients with varian carcinoma. We systematically searched PubMed, EMBASE, and Web of Science. A total of 13 eligible studies, including 10 on clinicopathological features, 13 on prognosis were identified. Pooled hazard ratios (HRs) or odds ratios (OR) and 95% confidence intervals (95% CIs) were calculated using random- or fixed-effects models. Our results revealed that the increased expressions of 8 lncRNAs were associated with poor prognosis and the decreased expressions of 5 lncRNAs were related to poor prognosis in ovarian carcinoma. High HOTAIR expression was associated with shorter overall survival in ovarian cancer (pooled HR: 2.05, 95% CI: 1.51-2.77, P < 0.001). In conclusion, our meta-analysis suggested that LncRNAs could function as potential prognostic markers for ovarian cancer patients and high expression HOTAIR was associated with shorter overall survival in ovarian cancer.

The clinical significance of PR, ER, NF- κ B, and TNF- α in breast cancer.

OBJECTIVES: To investigate the expression of estrogen (ER), progesterone receptors (PR), nuclear factor- κ B (NF- κ B), and tumor necrosis factor- α (TNF- α ) in human breast cancer (BC), and the correlation of these four parameters with clinicopathological features of BC. METHODS AND RESULTS: We performed an immunohistochemical SABC method for the identification of ER, PR, NF- κ B, and TNF- α expression in 112 patients with primary BC. The total positive expression rate of ER, PR, NF- κ B, and TNF- α was 67%, 76%, 84%, and 94%, respectively. The expressions of ER and PR were correlated with tumor grade, TNM stage, and lymph node metastasis (P < 0.01, resp.), but not with age, tumor size, histological subtype, age at menarche, menopause status, number of pregnancies, number of deliveries, and family history of cancer. Expressions of ER and PR were both correlated with NF- κ B and TNF- α expression (P < 0.05, resp.). Moreover, there was significant correlation between ER and PR (P < 0.0001) as well as between NF- κ B and TNF- α expression (P < 0.05). CONCLUSION: PR and ER are highly expressed, with significant correlation with NF- κ B and TNF- α expression in breast cancer. The important roles of ER and PR in invasion and metastasis of breast cancer are probably associated with NF- κ B and TNF- α expression.

Risk of breast cancer and total malignancies in rheumatoid arthritis patients undergoing TNF-α antagonist therapy: a meta-analysis of randomized control trials.

CONTEXT: Interest exits in whether TNF-alpha antagonists increase the risk of breast cancer and total malignancies in patients with rheumatoid arthritis (RA). OBJECTIVES: To analyze the risk of malignancies, especially breast cancer, in patients with RA enrolled in randomized control trials (RCTs). METHODS: A systematic literature search for RCTs from 1 January 1998 to 1 July 2013 from online databases, such as PubMed, WILEY, EMBASE, ISI web of knowledge and Cochrane Library was conducted. Studies included RCTs that compared the safety of at least one dose of the five TNF-α antagonists with placebo or methotrexate (MTX) (or TNF-α antagonists plus MTX vs placebo plus MTX) in RA patients for more than 24 weeks and imported all the references into document management software EndNotex6. Two independent reviewers selected studies and extracted the data about study design, patients' characteristics and the type, number of all malignancies. RESULTS: 28 RCTs from 34 records with 11,741 patients were analyzed. Of the total, 97 developed at least one malignancy during the double-blind trials, and breast cancer was observed in 17 patients (17.5% of total malignancies). However, there was no statistically significant increased risk observed in either the per protocol (PP) model (OR 0.65, 95%CI [0.22, 1.93]) or the modified intention to treat (mITT) model (OR 0.75, 95%CI [0.25, 2.21]). There were also no significant trend for increased risk of total malignancies on anti-TNF-α therapy administered at approved doses in either model (OR, 1.06, 95%CI [0.64, 1.75], and OR, 1.30, 95%CI [0.80, 2.14], respectively). As to the two models, modified intention to treat model analysis led to higher estimation than per protocol model analysis. CONCLUSIONS: This study did not find a significantly increased risk of breast cancer and total malignancies in adults RA patients treated with TNF-α antagonists at approved doses. However, it cannot be ignored that more patients developed malignancies with TNF-α antagonists therapy compared with patients with placebo or MTX, in spite of the lack of statistical significance, so that more strict clinical trials and long-term follow-up are needed, and both mITT and PP analyses should be used in such safety analyses.

Identification of Homer1 as a potential prognostic marker for intrahepatic cholangiocarcinoma.

BACKGROUND: The aim of the present study was to analyze whether Homer1 is a potential prognostic marker for intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: The expression of Homer1 in ICC tissue was detected with immunohistochemistry and levels of protein in ICC and paratumor tissues were evaluated by Western blotting. Survival analysis by the Kaplan-Meier method was performed to assess prognostic significance. RESULTS: Homer1 expression was high in 67.4% (58/86) of ICC samples, and there was significant difference between ICC and adjacent noncancerous tissues (p<0.001); high expression was associated with poor histologic differentiation (p=0.019), TNM stage (p=0.014), lymph node metastasis (p=0.040), and lymphatic invasion (p=0.025). On Kaplan-Meier analysis, a comparison of survival curves of low versus high expressors of Homer1 revealed a highly significant difference in OS (p=0.001) and DFS (p=0.006), indicating that high expression of Homer1 was linked with a worse prognosis. Multivariate analyses showed that Homer1 expression was an independent risk factor predicting overall survival[Hazard ratio(HR), 7.52; 95% confidence interval (CI), 2.63- 21.47; p=0.002] and disease-free survival (HR, 11.56; 95%CI, 5.17-25.96; p<0.001) in ICC. CONCLUSIONS: Homer1 promotes lymphatic invasion and associates with lymph node metastasis and poor prognosis of ICC. The current study shows that Homer1 may be an independent prognostic factor for ICC patients after curative resection, and it provides an important basis for screening/treating high-risk patients.

[Biological characteristics and effect of TNF-alpha binding peptide and TNFR blocking peptide in vitro].

AIM: To investigate the biological characteristics and effect of TNF-alpha binding peptide (TBP) and TNFR blocking peptide (TRBP) in vitro. METHODS: The binding specificity of TBP or TRBP was tested by competition experiment using GFP-TNF fusion protein and detected by FCM and fluorescent microscope. The interaction between TBP and TRBP was determined by non-denatured PAGE and the inhibitory effect of TBP and TRBP on TNF-alpha cytotoxicity against U937 was carried out by MTT colorimetry. The effects of TBP and TRBP on the functions of human monocytes activated by TNF-alpha and IFN-gamma in vitro were detected by nitrotetrazolium blue chloride (NBT) reduction assay for evaluating respiratory burst and by RT-PCR for evaluating IL-1beta and IL-8 mRNA transcription. RESULTS: It was showed that TBP and TRBP was able to block the GFP-TNF binding to the TNFR on the surface of cells and no binding interaction took place between TBP and TRBP. Both TBP and TRBP were able to inhibit the TNF-alpha cytotoxicity against U937 and this inhibitory effect was dose-dependent and the combination of TBP and TRBP (pep.38+X4) was able to inhibit the TNF-alpha cytotoxicity more efficiently than the individual peptide at all tested concentrations. The combination of TBP and TRBP was able to obviously inhibit both respiratory burst of monocytes induced by TNF-alpha and IFN-gamma and transcription level of IL-1beta and IL-8 mRNA induced by TNF-alpha. CONCLUSION: TBP or TRBP can bind with their ligands specifically and don't interact with each other. They can also block the biological activity of the TNF-alpha in vitro, and the combination of TBP and TRBP is able to inhibit the biological activity of the TNF-alpha more efficiently. This research will provide an experimental basis for the clinical treatment of the inflammatory disease.