Enhancing multiple myeloma staging: a novel cell death risk model approach.

The prognostication of survival trajectories in multiple myeloma (MM) patients presents a substantial clinical challenge. Leveraging transcriptomic and clinical profiles from an expansive cohort of 2,088 MM patients, sourced from the Gene Expression Omnibus and The Cancer Genome Atlas repositories, we applied a sophisticated nested lasso regression technique to construct a prognostic model predicated on 28 gene pairings intrinsic to cell death pathways, thereby deriving a quantifiable risk stratification metric. Employing a threshold of 0.15, we dichotomized the MM samples into discrete high-risk and low-risk categories. Notably, the delineated high-risk cohort exhibited a statistically significant diminution in survival duration, a finding which consistently replicated across both training and external validation datasets. The prognostic acumen of our cell death signature was further corroborated by TIME ROC analyses, with the model demonstrating robust performance, evidenced by AUC metrics consistently surpassing the 0.6 benchmark across the evaluated arrays. Further analytical rigor was applied through multivariate COX regression analyses, which ratified the cell death risk model as an independent prognostic determinant. In an innovative stratagem, we amalgamated this risk stratification with the established International Staging System (ISS), culminating in the genesis of a novel, refined ISS categorization. This tripartite classification system was subjected to comparative analysis against extant prognostic models, whereupon it manifested superior predictive precision, as reflected by an elevated C-index. In summation, our endeavors have yielded a clinically viable gene pairing model predicated on cellular mortality, which, when synthesized with the ISS, engenders an augmented prognostic tool that exhibits pronounced predictive prowess in the context of multiple myeloma.

Liraglutide Attenuates Aortic Valve Calcification in a High-Cholesterol-Diet-Induced Experimental Calcific Aortic Valve Disease Model in Apolipoprotein E-Deficient Mice.

BACKGROUND: Calcific aortic valve disease (CAVD) is a significant cause of morbidity and mortality among elderly people. However, no effective medications have been approved to slow or prevent the progression of CAVD. Here, we examined the effect of liraglutide on aortic valve stenosis. METHODS: Male Apoe-/- mice were fed with a high-cholesterol diet for 24 weeks to generate an experimental CAVD model and randomly assigned to a liraglutide treatment group or control group. Echocardiography and immunohistological analyses were performed to examine the aortic valve function and morphology, fibrosis, and calcium deposition. Plasma Glucagon-like peptide-1 (GLP-1) levels and inflammatory contents were measured via ELISA, FACS, and immunofluorescence. RNA sequencing (RNA-seq) was used to identify liraglutide-affected pathways and processes. RESULTS: Plasma GLP-1 levels were reduced in the CAVD model, and liraglutide treatment significantly improved aortic valve calcification and functions and attenuated inflammation. RNA-seq showed that liraglutide affects multiple myofibroblastic and osteogenic differentiations or inflammation-associated biological states or processes in the aortic valve. Those liraglutide-mediated beneficial effects were associated with increased GLP-1 receptor (GLP-1R) expression. CONCLUSIONS: Liraglutide blocks aortic valve calcification and may serve as a potential therapeutic drug for CAVD treatment.

Circular RNA ciRs-126 promotes hypoxia/reoxygenation cardiac injury possibly through miR-21.

BACKGROUND: This study aimed to analyze the role of circular RNA ciRs-126 in hypoxia/reoxygenation cardiac injury (H/R). METHODS: Expression of ciRs-126 and miR-21 in plasma samples from patients with H/R and healthy controls was determined by RT-qPCR. Correlations were analyzed by linear regression. Overexpression of ciRs-126 and miR-21 was achieved in cardiomyocytes to explore their crosstalk. The roles of ciRs-126 and miR-21 in H/R-induced apoptosis of cardiomyocytes were analyzed using cell apoptosis assay. RESULTS: CiRs-126 was upregulated and miR-21 was downregulated in H/R patients. They were inversely correlated across plasma samples from H/R patients. In H/R cardiomyocytes, ciRs-126 was upregulated and miR-21 was downregulated. In cardiomyocytes, ciRs-126 overexpression decreased miR-21 level and reduced the inhibitory effects of miR-21 overexpression on H/R-induced cell apoptosis. CONCLUSIONS: Circular RNA ciRs-126 may suppress miR-21 expression to promote H/R cardiac injury.

WITHDRAWN: Severe Pulmonary Embolism Secondary to Cement Embolism in the Inferior Vena Cava after Percutaneous Vertebroplasty.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.avsg.2018.01.003. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy.

Severe Pulmonary Embolism was Secondary to Cement Inferior Vena Cava Embolism after Percutaneous Vertebroplasty.

Cement pulmonary embolism (cPE) and inferior vena cava embolism (cIE) are rare but potentially life-threatening complications of percutaneous vertebroplasty (PVP). Most cPE and cIE occurred simultaneously. In this case, a 65-year-old woman complained of dyspnea after PVP for 4 days. Patient's symptom and image tests manifest that the cPE was secondary to cIE. Although cIE was found at the first day after PVP, the local surgeons treat the patient with a regular anticoagulant without another more effective therapeutic measure. Eventually, the long cement inferior vena cava embolus was broken and result in left pulmonary embolism via the systemic circulation. She was admitted to our hospital and performed with embolectomy surgery by cardiopulmonary bypass and discharged after 7 days. We report this case to show that cIE embolism is still underestimated by some spine surgeons in China, and cIE may be developed to severe cPE during conservation management with anticoagulation.

Effects of David I operation in the treatment of aortic root disease combined with aortic insufficiency.

BACKGROUND: We compared the effects of the new David I operation and classical Bentall operation in the treatment of aortic root disease combined with aortic insufficiency. METHODS: A total of 60 cases of patients with aortic root disease combined with aortic insufficiency diagnosed at our hospital from January 2010 to January 2016 were analyzed retrospectively, including 32 cases of aortic root aneurysm, 18 cases of aortic dissection, 5 cases of hypertension combined with atherosclerosis, 2 cases of retrogression, 2 cases of rheumatic heart disease and 1 case of Takayasu arteritis. Twenty-four cases that underwent the David I operation and 36 cases that underwent the Bentall operation were selected and their therapeutic effects were compared. The operation success rate, operation time, cardiopulmonary bypass time, cross-clamp time and blood infusion of both groups were compared; there were no significant differences (P>0.05). RESULTS: Two patients in the David I group and 3 patients in the Bentall operation group died of multiple organ dysfunction. The LVEDd and LVEF of both groups postoperation had no difference when compared with those parameters of before operation. The diameter of the valve annulus after the operation was shorter than before the operation. The severity of valve regurgitation of both groups had no difference. However, the ratio of severe regurgitation of the David I group increased and the mild regurgitation decreased. The incidence rate of complications of the David I group was significantly lower than that of the Bentall operation group. The differences were statistically significant (P<0.05). CONCLUSIONS: Both David I operation and Bentall operation have better short-term and long-term effects in the treatment of aortic root disease when combined with aortic insufficiency; however, David I operation had less long-term complications.

Direct Activation of Angiotensin II Type 2 Receptors Enhances Muscle Microvascular Perfusion, Oxygenation, and Insulin Delivery in Male Rats.

Angiotensin II receptors regulate muscle microvascular recruitment and the delivery of nutrients, oxygen, and insulin to muscle. Although angiotensin type 1 receptor antagonism increases muscle microvascular perfusion and insulin action, angiotensin type 2 receptor blockade markedly restricts muscle microvascular blood volume and decreases muscle delivery of insulin. To examine the effects of direct type 2 receptor stimulation using Compound 21 (C21) on microvascular perfusion, insulin delivery and action, and tissue oxygenation in muscle, overnight-fasted adult male rats were infused with C21 systemically. C21 potently increased microvascular blood volume without altering microvascular flow velocity or blood pressure, resulting in a net increase in microvascular blood flow in muscle. This was associated with a substantial increase in muscle interstitial oxygen saturation and insulin delivery into the skeletal and cardiac muscle. These effects were neutralized by coinfusion of the type 2 receptor antagonist or nitric oxide synthase inhibitor. Superimposing C21 infusion on insulin infusion increased insulin-mediated whole body glucose disposal by 50%. C21 significantly relaxed the preconstricted distal saphenous artery ex vivo. We have concluded that direct type 2 receptor stimulation markedly increases muscle microvascular perfusion through nitric oxide biosynthesis and enhances insulin delivery and action in muscle. These findings provide a physiologic mechanistic insight into type 2 receptor modulation of insulin action and suggest that type 2 receptor agonists might have therapeutic potential in the management of diabetes and its associated complications.

DNA methylation dysregulations in valvular atrial fibrillation.

BACKGROUND: The epigenetic changes underlying the development of atrial fibrillation (AF) remain incompletely understood. Limited evidence suggests that abnormal DNA methylation might be involved in the pathogenesis of AF. In the present study, we evaluated the methylation status of genomic DNA from myocardial tissue in AF patients and sinus rhythm (SR) patients systematically. HYPOTHESIS: DNA methylation dysregulations will be associated with valvular AF. METHODS: Right atrial myocardial tissue was obtained from rheumatic valvular patients who had undergone valve replacement surgery (SR group, n = 10; AF group, n = 10). The global DNA methylation level, the promoter methylation level of the natriuretic peptide receptor-A gene (NPRA), and its correlation with the mRNA expression level of DNA methyltransferase genes were detected. RESULTS: The global DNA methylation level was significantly higher in the AF group than in the SR group (P < 0.05). The NPRA mRNA expression was decreased and the NPRA gene was hypermethylated in the AF group (P < 0.05). Meanwhile, the NPRA mRNA expression level has a negative correlation with the mean methylation level in the promoter region of the NPRA gene. CONCLUSIONS: DNA methylation dysregulations may be relevant in the pathogenesis of AF. DNA methyltransferase 3B likely plays an essential role in the DNA methylation dysregulations in AF.

The Relationship between Galectin-3 and Different Patterns of Ventricular Geometry Remodelling in Aortic Valve Stenosis.

BACKGROUND: This study was conducted to assess expression of Galectin-3 (Gal-3) in patients with different types of left ventricle (LV) hypertrophy geometry, and the relationship between Gal-3 expression and LV remodelling in patients with aortic valve stenosis (AS). METHODS: Galectin-3 expression was measured in the plasma and myocardia of AS patients who underwent an aortic valve replacement procedure. RESULTS: The study enrolled 77 consecutive patients with severe AS. Fifty-five (71.43%) of the enrolled patients had concentric hypertrophy (CH group), and had the highest degree of fibrosis (27.10±5.25%; p<0.001) and expression of Gal-3 in both plasma (19.11±2.06 ng/mL) and myocardial tissue (3.01±0.79). There was a strong positive correlation between the levels of fibrosis and Gal-3 expression in both plasma (r=0.584, p<0.001) and myocardium (r=0.522, p<0.001). Relative wall thickness (RWT) was strongly correlated with Gal-3 expression in both myocardium (r=0.594, p<0.001) and plasma (r=0.323, p=0.005). Additionally, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were positively correlated with both fibrosis (r=0.313, p=0.036) and LV mass index (r=0.559, p<0.001). CONCLUSIONS: Concentric hypertrophy geometry was the most common type of myocardium remodelling, and AS patients with CH geometry showed the highest levels of Gal-3 expression. Galectin-3 levels were positively correlated with fibrosis and RWT, both of which are crucial indicators of geometric remodelling. Galectin-3 and NT-proBNP levels may be valuable prognostic predictors in AS patients with myocardial remodelling.

[Diagnostic experience in 3 cases of cardiac occupying lesion].

The clinic symptoms of cardiac occupying lesions are complex and difficult to diagnose currently. In this study, three cases of atrial angiosarcoma, left ventricular aneurysm and left ventricular diverticulum were selected, respectively. The clinical characteristics, imaging features (echocardiogram, cardiac CT and MRI) and the postoperative and pathological results for patients were studied. We compared the differences in clinical symptoms, morphology, histology and haemodynamics among the three patients. The diagnosis were confirmed by intraoperative and postoperative pathological examination. We conclude that proper imaging approaches would be beneficial to diagnose the cardiac occupying lesions. Accurate preoperative diagnosis is beneficial to preoperative preparation as well as the decrease in operative risks.

Apelin attenuates the osteoblastic differentiation of aortic valve interstitial cells via the ERK and PI3-K/Akt pathways.

Aortic valve calcification (AVC), which used to be recognized as a passive and irreversible process, is now widely accepted as an active and regulated process characterized by osteoblastic differentiation of aortic valve interstitial cells (AVICs). Apelin, the endogenous ligand for G-protein-coupled receptor APJ, was found to have protective cardiovascular effects in several studies. However, the effects and mechanisms of apelin on osteoblastic differentiation of AVICs have not been elucidated. Using a pro-calcific medium, we devised a method to produce calcific human AVICs. These cells were used to study the relationship between apelin and the osteoblastic calcification of AVICs and the involved signaling pathways. Alkaline phosphatase (ALP) activity/expression and runt-related transcription factor 2 (Runx2) expression were examined as hallmark proteins in this research. The involved signaling pathways were studied using the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, and the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002. The results indicate that apelin attenuates the expression and activity of ALP, the expression of Runx2, and the formation of mineralized nodules. This protective effect was dependent on the dose of apelin, reaching the maximum at 100 pM, and was connected to activity of ERK and Akt (a downstream effector of PI3-K). The activation of ERK and PI3-K initiated the effects of apelin on ALP activity/expression and Runx2, but PD98059 and LY294002 abolished the effect. These results demonstrate that apelin attenuates the osteoblastic differentiation of AVICs via the ERK and PI3-K/Akt pathway.

Effectiveness of YouTube as a Source of Medical Information on Heart Transplantation.

BACKGROUND: In this digital era, there is a growing tendency to use the popular Internet site YouTube as a new electronic-learning (e-learning) means for continuing medical education. Heart transplantation (HTx) remains the most viable option for patients with end-stage heart failure or severe coronary artery disease. There are plenty of freely accessible YouTube videos providing medical information about HTx. OBJECTIVE: The aim of the present study is to determine the effectiveness of YouTube as an e-learning source on HTx. METHODS: In order to carry out this study, YouTube was searched for videos uploaded containing surgical-related information using the four keywords: (1) "heart transplantation", (2) "cardiac transplantation", (3) "heart transplantation operation", and (4) "cardiac transplantation operation". Only videos in English (with comments or subtitles in English language) were included. Two experienced cardiac surgeons watched each video (N=1800) and classified them as useful, misleading, or recipients videos based on the HTx-relevant information. The kappa statistic was used to measure interobserver variability. Data was analyzed according to six types of YouTube characteristics including "total viewership", "duration", "source", "days since upload", "scores" given by the viewers, and specialized information contents of the videos. RESULTS: A total of 342/1800 (19.00%) videos had relevant information about HTx. Of these 342 videos, 215 (62.8%) videos had useful information about specialized knowledge, 7/342 (2.0%) were found to be misleading, and 120/342 (35.1%) only concerned recipients' individual issues. Useful videos had 56.09% of total viewership share (2,175,845/3,878,890), whereas misleading had 35.47% (1,375,673/3,878,890). Independent user channel videos accounted for a smaller proportion (19% in total numbers) but might have a wider impact on Web viewers, with the highest mean views/day (mean 39, SD 107) among four kinds of channels to distribute HTx-related information. CONCLUSIONS: YouTube videos on HTx benefit medical professionals by providing a substantial amount of information. However, it is a time-consuming course to find high-quality videos. More authoritative videos by trusted sources should be posted for dissemination of reliable information. With an improvement of ranking system and content providers in future, YouTube, as a freely accessible outlet, will help to meet the huge informational needs of medical staffs and promote medical education on HTx.

MiR-133a modulates osteogenic differentiation of vascular smooth muscle cells.

Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease, and peripheral vascular disease. A hallmark of this pathological process is the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with ß-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression, and mineralized nodule formation. Conversely, the knockdown of miR-133a using an miR-133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion, and Runx2 expression. Runx2 was identified as a direct target of miR-133a by a cotransfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3'-untranslated region sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2-knockdown cells, and the inhibition of osteogenic differentiation by pre-miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs.