Clinical characteristics and the severity of coronary atherosclerosis of different subtypes of bundle-branch block.

BACKGROUND: Right bundle-branch block (RBBB) and left bundle-branch block (LBBB) play a role in the pathogenesis and progression of coronary artery disease (CAD). However, the clinical features and the severity of coronary artery disease associated with different subtypes of bundle-branch block, according to time of new appearance, is not well characterized in patients with no known CAD. METHODS: We retrospectively analyzed data pertaining to consecutive patients with RBBB or LBBB who underwent coronary angiography. The severity of coronary lesions was evaluated using the SYNTAX score. The differential effect of new-onset RBBB, old RBBB, new-onset LBBB, and old LBBB on the severity of CAD and its association with clinical characteristics was quantified. Multivariate logistic regression analysis was performed to evaluate the effect of RBBB and LBBB on the degree of coronary atherosclerosis in patients without known CAD. RESULTS: Out of the 243 patients, 72 patients had old LBBB, 37 had new-onset LBBB, 93 patients had old RBBB, and 41 patients had new-onset RBBB. On univariate analysis, age, systolic blood pressure, diastolic blood pressure, creatinine, serum glucose, and glycosylated hemoglobin level were associated with high SYNTAX score (p < .05 for all). Patients in the new-onset RBBB, old RBBB, new-onset LBBB, and old LBBB groups showed significant differences in baseline characteristics and coronary atherosclerosis (p < .05 for all). However, there were no significant between-group differences with respect to the degree of coronary atherosclerosis as assessed by SYNTAX score. CONCLUSIONS: New-onset RBBB, old RBBB, new-onset LBBB, and old LBBB were not associated with the severity of coronary lesions as assessed by SYNTAX score in patients without known CAD.

Kinesin family member 11 is a potential therapeutic target and is suppressed by microRNA-30a in breast cancer.

Kinesin family member 11 (KIF11) is a plus end-directed kinesin indispensable for the formation of the bipolar spindle in metaphase, where it objects to the action of minus end-directed molecular motors. Here, we hypothesize that KIF11 might be a therapeutic target of breast cancer and regulated by miR-30a. Cell Counting Kit 8 assays were used to investigate cell proliferation. Invasion assays were used to survey the motility of cells. Kaplan-Meier and Cox proportional analyses were employed for this outcome study. The prognostic significance and performance of KIF11 were validated on 17 worldwide independent microarray datasets and two The Cancer Genome Atlas-Breast Invasive Carcinoma sets. microRNA was predicted targeting KIF11 through sequence alignment in microRNA.org and confirmed by coexpression analysis in human breast cancer samples. Dual-luciferase reporter assays were employed to validate the interaction between miR-30a and KIF11 further. Higher KIF11 mRNA levels and lower miR-30a were significantly associated with poor survival of breast cancer patients. Inhibition of KIF11 by small-hairpin RNA significantly reduced the proliferation and invasion capabilities of the breast cancer cells. Meanwhile, downregulation of KIF11 could enhance the cytotoxicity of adriamycin in breast cancer cell lines MCF-7 and MDA-MB-231. A population study also validated that chemotherapy and radiotherapy significantly improved survival in early-stage breast cancer patients with low KIF11 expression levels. Further bioinformatics analysis demonstrated that miR-30a could interact with KIF11 and validated by dual-luciferase reporter assays. Therefore, KIF11 is a potential therapeutic target of breast cancer. miR-30a could specifically interact with KIF11 and suppress its expression in breast cancer.

MXRA7 is involved in monocyte-to-macrophage differentiation.

Macrophages are critical in mediating immune and inflammatory responses, while monocyte-to-macrophage differentiation is one of the main macrophage resources that involves various matrix proteins. Matrix remodeling associated 7 (MXRA7) was recently discovered to affect a variety of physiological and pathological processes related to matrix biology. In the present study, we investigated the role of MXRA7 in monocyte-to-macrophage differentiation in vitro. We found that knockdown of MXRA7 inhibited the proliferation of THP-1 human monocytic cells. Knockdown of MXRA7 increased the adhesion ability of THP-1 cells through upregulation the expression of adhesion molecules VCAM-1 and ICAM1. Knockdown of MXRA7 alone could promoted the differentiation of THP-1 cells to macrophages. Furthermore, the MXRA7-knockdown THP-1 cells produced a more significant upregulation pattern with M1-type cytokines (TNF-α, IL-1ß and IL-6) than with those M2-type molecules (TGF-ß1 and IL-1RA) upon PMA stimulation, indicating that knockdown of MXRA7 facilitated THP-1 cells differentiation toward M1 macrophages. RNA sequencing analysis revealed the potential biological roles of MXRA7 in cell adhesion, macrophage and monocyte differentiation. Moreover, MXRA7 knockdown promoted the expression of NF-κB p52/p100, while PMA stimulation could increase the expression of NF-κB p52/p100 and activating MAPK signaling pathways in MXRA7 knockdown cells. In conclusion, MXRA7 affected the differentiation of THP-1 cells toward macrophages possibly through NF-κB signaling pathways.

MXRA7 is involved in megakaryocyte differentiation and platelet production.

Matrix remodeling is a critical process in hematopoiesis. The biology of MXRA7, as a matrix remodeling associated gene, has still not been reported in hematopoietic process. Public databases showed that MXRA7 expressed in hematopoietic stem cells, suggesting that it may be involved in hematopoiesis. We found that the amounts of megakaryocytes were lower in bone marrow and spleen from Mxra7-/- mice compared with that from wild-type mice. Knock-out of MXRA7 also reduced the amount of platelet in peripheral blood and affected the function of platelets. Knock-out of MXRA7 inhibited hematopoietic stem/progenitor cells differentiate to megakaryocytes possibly through down-regulating the expression of GATA-1 and FOG-1. Moreover, knockdown of MXRA7 in MEG-01 cells could inhibit the cell proliferation and cell apoptosis. Knockdown of MXRA7 inhibited the differentiation of MEG-01 cells and proplatelet formation through suppressing the ERK/MAPK signaling pathway and the expression of ß-tubulin. In conclusion, the current study demonstrated the potential significance of MXRA7 in megakaryocyte differentiation and platelet production. The novel findings proposed a new target for the treatment of platelet-related diseases, and much more investigations are guaranteed to dissect the mechanisms of MXRA7 in megakaryocyte differentiation and platelet production.

Critical role of MXRA7 in differentiation blockade in human acute promyelocytic leukemia cells.

The biology of the matrix remodeling-associated 7 (MXRA7) gene has been ill defined. Bioinformatic analysis of public data sets revealed that MXRA7 messenger RNA (mRNA) was highly expressed in acute myeloid leukemia (AML), especially acute promyelocytic leukemia (APL). High expression of MXRA7 was associated with poor overall survival of patients with AML. We confirmed that MXRA7 expression was upregulated in patients with APL and cell lines. Knockdown or overexpression of MXRA7 did not affect the proliferation of NB4 cells directly. Knockdown of MXRA7 in NB4 cells promoted drug-induced cell apoptosis, whereas overexpression of MXRA7 had no obvious influence on drug-induced cell apoptosis. Lowering MXRA7 protein levels in NB4 cells promoted all-trans retinoic acid (ATRA)-induced cell differentiation possibly through decreasing the PML-RARα level and increasing PML and RARα levels. Correspondingly, overexpression of MXRA7 showed consistent results. We also demonstrated that MXRA7 altered the expression of genes involved in leukemic cell differentiation and growth. Knockdown of MXRA7 upregulated the expression levels of C/EBPB, C/EBPD, and UBE2L6, and downregulated the expression levels of KDM5A, CCND2, and SPARC. Moreover, knockdown of MXRA7 inhibited the malignancy of NB4 cells in a non-obese diabetic-severe combined immune-deficient mice model. In conclusion, this study demonstrated that MXRA7 influences the pathogenesis of APL via regulation of cell differentiation. The novel findings about the role of MXRA7 in leukemia not only shed light on the biology of this gene but also proposed this gene as a new target for APL treatment.

Novel Insights into the Predictors of Obstructive Sleep Apnea Syndrome in Patients with Chronic Coronary Syndrome: Development of a Predicting Model.

Background: Obstructive sleep apnea syndrome (OSAS) is common in patients with chronic coronary syndrome (CCS); however, a predictive model of OSAS in patients with CCS remains rarely reported. The study aimed to construct a novel nomogram scoring system to predict OSAS comorbidity in patients with CCS. Methods: Consecutive CCS patients scheduled for sleep monitoring at our hospital from January 2019 to September 2020 were enrolled in the current study. Coronary CT angiography or coronary angiography was used for the diagnosis of CCS, and clinical characteristics of the patients were collected. Significant predictors for OSAS in patients with moderate/severe CCS were estimated via logistic regression analysis, and a clinical nomogram was constructed. A calibration plot, examining discrimination (Harrell's concordance index) and decision curve analysis (DCA), was applied to validate the nomogram's predictive performance. Internal validity of the predictive model was assessed using bootstrapping (1000 replications). Results: The nomograms were constructed based on available clinical variables from 527 patients which were significantly associated with moderate/severe OSAS in patients with CCS, including body mass index, impaired glucose tolerance, hypertension, diabetes mellitus, nonalcoholic fatty liver disease, and routine laboratory indices such as neutrophil to lymphocyte ratio, platelet-to-lymphocyte ratio, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The C-index (0.793) and AUC (0.771, 95% CI: 0.731-0.811) demonstrated a favorable discriminative ability of the nomogram. Moreover, calibration plots revealed consistency between moderate/severe OSAS predicted by the nomogram and validated by the results of sleep monitoring. Clinically, DCA showed that the nomogram had good discriminative ability to predict moderate/severe OSAS in patients with CCS. Conclusions: The risk nomogram constructed via the routinely available clinical variables in patients with CCS showed satisfying discriminative ability to predict comorbid moderate/severe OSAS, which may be useful for identification of high-risk patients with OSAS in patients with CCS.

Corrigendum to "Novel Insights into the Predictors of Obstructive Sleep Apnea Syndrome in Patients with Chronic Coronary Syndrome: Development of a Predicting Model".

[This corrects the article DOI: 10.1155/2022/5497134.].

New permanent bundle-branch block and long-term prognosis of patients with new onset ST-elevation myocardial infarction who underwent percutaneous coronary intervention.

Aim: The aim of the study was to evaluate the potential predictive value of permanent RBBB and LBBB for longer-term prognosis in patients with new-onset STEMI who underwent percutaneous coronary intervention (PCI). Methods: Patients with new-onset STEMI that underwent emergency PCI at our department from June 2012 to September 2020 were included in the study. Gensini score (GS) was employed to evaluate the severity of coronary lesions. The primary endpoint of the study was the occurrence of major adverse cardiac and cerebrovascular events (MACCEs), the composite of cardiac mortality, recurrence of myocardial infarction, cardiac shock, stroke, stent thrombosis, or revascularization. We also set all-cause mortality as a secondary endpoint. Results: Out of the 547 patients, 29 patients had new-onset permanent LBBB, 51 patients had new-onset permanent RBBB, and 467 patients had no bundle-branch block (BBB). The occurrence of no BBB, new permanent LBBB, or RBBB was not associated with the severity of coronary artery lesions as evaluated by the GS. After follow-up at an average of 43.93 months, MACCEs occurred in 52 patients. Kaplan-Meier analysis showed that patients with new-onset RBBB were at greater risk for MACCEs compared to those with new onset LBBB (χ2 = 5.107, p = 0.021). Also, an independent correlation was found between new permanent RBBB and LBBB and MACCEs risk. The adjusted hazard ratios (HRs) were 6.862 [95% confidence interval (CI) of 3.764-12.510] for the new-onset permanent RBBB and 3.395 (95% CI of 1.280-9.005) for LBBB, compared to those with no BBB, respectively (both p < 0.05). Conclusion: New onset permanent RBBB in patients with new onset STEMI who underwent PCI may be correlated independently with increased risk of poor long-term prognosis.

Identification of megakaryocytes as a target of advanced glycation end products in diabetic complications in bone marrow.

AIMS: To define the possible effect of diabetic conditions on megakaryocytes, the long-know precursors of platelets and lately characterized modulator of hematopoietic stem quiescence-activation transition. METHODS: Megakaryoblastic MEG-01 cell culture and TPO/SCF/IL-3-induced differentiation of human umbilical blood mononuclear cells toward megakaryocytes were used to test effects of glycated bovine serum albumin (BSA-AGEs). The ob/ob mice and streptozotocin-treated mice were used as models of hyperglycemia. MTT was used to measure cell proliferation, FACS for surface marker and cell cycle, and RT-qPCR for the expression of interested genes. Megakaryocytes at different stages in marrow smear were checked under microscope. RESULTS: When added in MEG-01 cultures at 200 µg/ml, BSA-AGEs increased proliferation of cells and enhanced mRNA expression of RAGE, VEGFα and PF4 in the cells. None of cell cycle distribution, PMA-induced platelet-like particles production, expression of GATA1/NF-E2/PU-1/IL-6/OPG/PDGF in MEG-01 cells nor TPO/SCF/IL-3 induced umbilical cord blood cells differentiation into megakaryocyte was affected by BSA-AGEs. In the ob/ob diabetic mice, MKs percentages in marrow cells and platelets in peripheral blood were significantly increased compared with control mice. In streptozotocin-induced diabetic mice, however, MKs percentage in marrow cells was decreased though peripheral platelet counts were not altered. Gene expression assay showed that the change in MKs in these two diabetic conditions might be explained by the alteration of GATA1 and NF-E2 expression, respectively. CONCLUSIONS: Diabetic condition in animals might exert its influence on hematopoiesis via megakaryocytes-the newly identified modulator of hematopoietic stem cells in bone marrow.

Matrix Remodeling Associated 7 Deficiency Alleviates Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

Matrix remodeling associated 7 (MXRA7) was first noted to co-express with a group of matrix remodeling related genes, and its biological functions had remained unclear. In this study, we investigated the presumed function of MXRA7 in a carbon tetrachloride (CCl4)-induced acute liver injury model in mice. Wild-type, MXRA7-/- mice, and mice that were pulsed with hydrodynamic injection of vehicle or MXRA7-harboring plasmids were challenged with a single dose of CCl4 for injury induction. The sera, spleens, and livers were harvested from mice for assay of cytokines/chemokines expression, cellular responses, or histological features. We found that MXRA7 deficiency alleviated, and MXRA7 overexpression aggravated liver damage in CCl4-challenged mice. FACS analysis showed that MXRA7 deficiency reduced the recruitment of neutrophils through downregulation the expression of CXCL1 and CXCL2 in liver, decreased the number of CD8+ T cells in liver and spleen, suppressed the release of IFNγ and TNFα from T cells, and decreased IFNγ in serum and liver. Western blot assay demonstrated that MXRA7 deficiency suppressed the activation of MAPK pathway and AKT/NF-κB pathway, respectively. Lastly, MXRA7 deficiency or overexpression regulated the expression of two matrix remodeling-related genes (fibronectin and TIMP1) in the liver. We concluded that MXRA7 was an active player in CCl4-induced liver injury, hypothetically by mediating the inflammation or immune compartments and matrix remodeling processes. Further exploration of MXRA7 as a possible new therapeutic target for management of inflammation-mediated liver injury was discussed.

Identification of a novel gene fusion RNF213­SLC26A11 in chronic myeloid leukemia by RNA-Seq.

Chronic myeloid leukemia (CML) was the first hematological malignancy to be associated with a specific genetic lesion. The Philadelphia translocation, producing a BCR­ABL hybrid oncogene, is the most common mechanism of CML development. However, in the present study, b3a2, b2a2 and ela2 fusion junctions of the breakpoint cluster region (BCR)-V-abl Abelson murine leukemia viral oncogene homolog 1 (ABL) gene were not detected in patients diagnosed with CML three and four years previously. RNA-Seq technology, with an average coverage of ~30­fold, was used to detect gene fusion events in a patient with a 6-year history of CML, identified to be in the chronic phase of the disease. Using deFuse and TopHat­fusion programs with improved filtering methods, we identified two reliable gene fusions in a blood sample obtained from the CML patient, including extremely low expression levels of the classic BCR­ABL1 gene fusion. In addition, a novel gene fusion involving the ring finger protein 213 (RNF213)-solute carrier family 26, member 11 (SLC26A11) was identified and validated by reverse transcription polymerase chain reaction. Further bioinformatic analysis revealed that specific domains of SLC26A11 were damaged, which may affect the function of sulfate transportation of the normal gene. The present study demonstrated that, in specific cases, alternative gene fusions, besides BCR­ABL, may be associated with the development of CML.