Fascin Is Critical for the Maintenance of Breast Cancer Stem Cell Pool Predominantly via the Activation of the Notch Self-Renewal Pathway.

An emerging dogma shows that tumors are initiated and maintained by a subpopulation of cancer cells that hijack some stem cell features and thus referred to as "cancer stem cells" (CSCs). The exact mechanism that regulates the maintenance of CSC pool remains largely unknown. Fascin is an actin-bundling protein that we have previously demonstrated to be a major regulator of breast cancer chemoresistance and metastasis, two cardinal features of CSCs. Here, we manipulated fascin expression in breast cancer cell lines and used several in vitro and in vivo approaches to examine the relationship between fascin expression and breast CSCs. Fascin knockdown significantly reduced stem cell-like phenotype (CD44hi /CD24lo and ALDH+ ) and reversal of epithelial to mesenchymal transition. Interestingly, expression of the embryonic stem cell transcriptional factors (Oct4, Nanog, Sox2, and Klf4) was significantly reduced when fascin expression was down-regulated. Functionally, fascin-knockdown cells were less competent in forming colonies and tumorspheres, consistent with lower basal self-renewal activity and higher susceptibility to chemotherapy. Fascin effect on CSC chemoresistance and self-renewability was associated with Notch signaling. Activation of Notch induced the relevant downstream targets predominantly in the fascin-positive cells. Limiting-dilution xenotransplantation assay showed higher frequency of tumor-initiating cells in the fascin-positive group. Collectively, our data demonstrated fascin as a critical regulator of breast CSC pool at least partially via activation of the Notch self-renewal signaling pathway and modification of the expression embryonic transcriptional factors. Targeting fascin may halt CSCs and thus presents a novel therapeutic approach for effective treatment of breast cancer. Stem Cells 2016;34:2799-2813 Video Highlight: https://youtu.be/GxS4fJ_Ow-o.

Antimicrobial resistance and virulence markers in methicillin sensitive Staphylococcus aureus isolates associated with nasal colonization.

Most Staphylococcus aureus infections occur in previously colonized persons who also act as reservoirs for continued dissemination. This study aimed to investigate the carriage of antimicrobial resistance and virulence markers in S. aureus isolates associated with nasal colonization. The study was conducted from December 2013-April 2014. Nasal swabs were collected and questionnaires administered to 97 medical students in Riyadh Saudi Arabia. Bacterial culture, identification and antimicrobial susceptibility testing were performed by conventional methods and chromogenic agar was used for methicillin resistant S. aureus (MRSA) screening. Molecular characterization of isolates was carried out using the StaphyType DNA microarray. Thirty two students (43%) had S. aureus nasal carriage (MSSA = 31; MRSA = 1). Seventeen clonal complexes (CC) were identified namely: CC15-MSSA (n = 5), CC1-MSSA-SCCfus (n = 4), CC8-MSSA (n = 3), CC22-MSSA (n = 3), CC25-MSSA (n = 3), CC101-MSSA (n = 2). Other CC found as single isolates were CC5-MSSA, CC6-MSSA, CC30-MSSA, CC45-MSSA, CC96-MSSA, CC188-MSSA, CC398-MSSA, CC942-MSSA/PVL+, CC1290-MSSA, ST2482-MSSA, CC80-MRSA-IV/PVL+. The CC1-SCCfus isolates harbored the Staphylococcal cassette chromosome (SCC) with ccrA-1; ccrB-1 and ccrB-3 genes plus the putative fusidic acid resistance marker Q6GD50. One MSSA isolate was genotyped as coagulase negative Staphylococcus spp with an irregular composite SCCmec element. Majority of the isolates harbored various virulence genes including the hemolysin, enterotoxin, and exfoliative genes as well as various adhesive protein producing genes. Although there was low carriage of MRSA, the MSSA isolates harbored various resistance and virulence genes including those usually seen in MRSA isolates. The presence of isolates with incomplete SCCmec elements plus putative resistance and virulence genes is of concern.

Pathophysiologic Mechanisms in Cardiac Autonomic Nervous System and Arrhythmias.

The autonomic nervous system, including the central nervous system and the cardiac plexus, maintains cardiac physiology. In diseased states, autonomic changes through neuronal remodeling generate electrical mechanisms of arrhythmia such as triggered activity or increased automaticity. This article will focus on the pathophysiological mechanisms of arrhythmia to highlight the role of the autonomic nervous system in disease and the related therapeutic interventions.

Outcomes of Octogenarian Patients Treated with Tafamidis for Transthyretin Amyloid Cardiomyopathy.

Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) benefit from disease-modifying agents such as tafamidis. However, the survival benefit of tafamidis in elderly patients (age ≥80 years) is not reported. This study aimed to assess the survival of patients with ATTR-CM aged 80 years and older who were treated with tafamidis compared with patients aged <80 years. We conducted a retrospective analysis of patients with ATTR-CM who underwent tafamidis treatment, aged 45 to 97 years at the time of diagnosis between January 1, 2008, and May 31, 2021. A total of 484 patients were included, with 208 in the ≥80 years group and 276 in the <80 years group. The cohort was followed up for mortality outcomes, and hazard ratios with 95% confidence intervals were calculated. After a median follow-up of 18.5 months, 72 deaths were recorded in the entire cohort. Kaplan-Meier curves showed no differences in survival probability between the 2 groups at 30 months (p for log-rank test = 0.76). The survival rates for patients aged ≥80 years who underwent treatment at 1, 2, 3, 4, and 5 years were 94.7%, 86.0%, 77.0%, 77.0%, and 38.5%, respectively. The corresponding rates for patients aged <80 years who underwent treatment were 93.2, 84.8, 74.4, 68.2, and 64.6%, respectively. In the multivariable analysis, the hazard ratio (95% confidence interval) of the mortality comparing treatment patients aged ≥80 years with those aged <80 years was 0.81 (0.41 to 1.61). In conclusion, tafamidis treatment is associated with similar reductions in mortality in older and younger patients with ATTR-CM.

Advancing the care of individuals with cancer through innovation & technology: Proceedings from the cardiology oncology innovation summit 2020 and 2021.

As cancer therapies increase in effectiveness and patients' life expectancies improve, balancing oncologic efficacy while reducing acute and long-term cardiovascular toxicities has become of paramount importance. To address this pressing need, the Cardiology Oncology Innovation Network (COIN) was formed to bring together domain experts with the overarching goal of collaboratively investigating, applying, and educating widely on various forms of innovation to improve the quality of life and cardiovascular healthcare of patients undergoing and surviving cancer therapies. The COIN mission pillars of innovation, collaboration, and education have been implemented with cross-collaboration among academic institutions, private and public establishments, and industry and technology companies. In this report, we summarize proceedings from the first two annual COIN summits (inaugural in 2020 and subsequent in 2021) including educational sessions on technological innovations for establishing best practices and aligning resources. Herein, we highlight emerging areas for innovation and defining unmet needs to further improve the outcome for cancer patients and survivors of all ages. Additionally, we provide actionable suggestions for advancing innovation, collaboration, and education in cardio-oncology in the digital era.

Utility of Intracardiac Echocardiography for Infective Endocarditis and Cardiovascular Device-Related Endocarditis: A Contemporary Systematic Review.

The diagnosis of infective endocarditis (IE) can pose a significant challenge, particularly in cases of prosthetic valve endocarditis (PVE) or cardiac device-related endocarditis (CDIE) (1). While echocardiography remains a crucial diagnostic tool for identifying IE, including PVE and CDIE, there are certain circumstances where transesophageal echocardiography (TEE) may not be conclusive or practically feasible (2). Recently, intracardiac echocardiography (ICE) has emerged as a promising alternative for diagnosing IE and evaluating intracardiac infections, especially in cases where transthoracic echocardiography (TTE) has not been revealing, and TEE has been contraindicated. Furthermore, ICE has been found to be useful in guiding transvenous lead extractions in infected implantable cardiac devices (3). This systematic review aims to comprehensively explore the various applications of ICE in the diagnosis of IE and assess its efficacy in comparison to traditional diagnostic methods.

Trends and Outcomes of Left Atrial Appendage Occlusion in Renal and Liver Transplant Recipients: Insights From the United States National Inpatient and Readmission Database.

Left atrial appendage occlusion using the Watchman device has emerged as an alternative treatment strategy for preventing strokes in patients with atrial fibrillation. However, there is no data on its safety and clinical outcomes in prior renal or liver transplant recipients. We included a total of 61,995 patients from the National Inpatient Sample (NIS, in-hospital outcomes) and 55,048 patients from the National Readmission Database (NRD, 30-day outcomes) who underwent percutaneous left atrial appendage occlusion (LAAO). From this group, 0.65% (n=405) and 0.62% (n=339) were renal and liver transplant recipients in NIS and NRD respectively. Transplant recipients were younger compared with non-transplant recipients (mean age 69 vs 77 years, P=<0.01). There was little difference in terms of in-hospital mortality (0% vs 0.2%, P=0.43), major complications (6.2% vs 5.6%, P=0.61), cardiovascular complications (2.5% vs 2.8%, P=0.73), neurological complications (1.2% vs 0.7%, P=0.21) or bleeding complications (1.2% vs 0.7%, P=0.99) between transplant vs. non-transplant patients. Based on the NRD database, 30-day readmission rate was not meaningfully different for transplant recipients undergoing LAAO (9.44%) when compared to non-transplant patients (8.12%, [log-rank, P=0.56]). There was no difference between 30-day major or cardiovascular complications, however vascular complication rates were significantly higher for transplant recipients (OR 2.56, 95% CI [(1.66-3.47]). Our study findings suggest that LAAO may be safe for patients with a prior renal or liver transplant in terms of major complications, cardiovascular complications, and all-cause readmission rates. However vascular complications may be higher in transplant recipients. Further large-scale studies are needed to confirm these findings.

Cardio oncology: Digital innovations, precision medicine and health equity.

The rapid emergence of cardio-oncology has resulted in a rapid growth of cardio-oncology programs, dedicated professional societies sections and committees, and multiple collaborative networks that emerged to amplify the access to care in this new subspecialty. However, most existing data, position statements and guidelines are limited by the lack of availability of large clinical trials to support these recommendations. Furthermore, there are significant challenges regarding proper access to cardio-oncology care and treatment, particularly in marginalized and minority populations. The emergence and evolution of personalized medicine, artificial intelligence (AI), and machine learning in medicine and in cardio-oncology provides an opportunity for a more targeted, personalized approach to cardiovascular complications of cancer treatment. The proper implementation of these new modalities may facilitate a more equitable approach to adequate and universal access to cardio-oncology care, improve health related outcomes, and enable health care systems to eliminate the digital divide. This article reviews and analyzes the current status on these important issues.

'Minimalist approach' for transcatheter mitral valve replacement using intracardiac echocardiography and conscious sedation: a case series.

BACKGROUND: Transcatheter aortic valve implantation operators have adapted to a less invasive technique by foregoing the use of general anaesthesia and transoesophageal echocardiography. This is known as a 'minimalist approach'. This approach has yet to be explored in transcatheter mitral valve replacement (TMVR). Two patients with high perioperative risk underwent TMVR using only monitored conscious sedation (CS) and intracardiac echocardiography (ICE). CASE SUMMARY: The patients were symptomatic and required treatment of severe mitral regurgitation and severe mitral stenosis in a mitral valve ring and prosthetic mitral valve, respectively. With the use of an antegrade transseptal approach, the procedure was conducted under CS using ICE only. After placement of the prosthetic mitral valve, the valve was assessed by advancing the ICE catheter through the interatrial septal defect and no significant paravalvular leak occurred. In one case, ad hoc treatment of right to left shunting was successfully pursued. Valve function was excellent immediately and at 24 h after implantation and resulted in significant haemodynamic improvement. CONCLUSION: With more TMVR cases being conducted, the 'minimalist approach' with CS and ICE may be considered in selected cases.

Chronologic and Climatic Factors of Acute Aortic Dissection: Study of 1642 Patients in Two Continents.

BACKGROUND: The purpose of this study was to examine whether chronologic and climatic factors and lunar phases affect the onset of acute aortic dissection (AAD). METHODS: The frequencies of AAD were analyzed with regard to the chronologic and climatic factors and lunar phases on the day when AAD occurred for 1642 patients with AAD from two aortic referral centers in the United States and China. RESULTS: Mean age of patients was 51.6 ± 13.1 years, and 1260 (76.7%) were men. Dissection was type A in 1125 patients (68.5%) and type B in 517 (31.5%). Early mortality rate was 11.6% (190 of 1642), including 89 aortic ruptures before operation and 101 operative deaths. There was a winter peak in occurrence (33.6%, P < .01) with a relative risk of 1.519. In a week, the frequency was highest on Wednesday (15.5%) and Monday (15.2%), and lowest on Sunday (12.8%). Month-specific incidence was significantly inversely correlated to the mean temperature (rho = -0.650, P = .022) and directly correlated to the atmospheric pressure (rho = 0.706, P = .001). The proportion of type A dissection was significantly higher in the full moon phase compared with type B dissection (73.7% vs 66.9%, P = .012). CONCLUSIONS: Acute aortic dissection exhibits significant chronologic variation in the frequency of occurrence, with a peak in winter and on Wednesdays, and nadir in summer and on Sundays. The incidence is significantly correlated to the mean temperature and atmospheric pressure. The proportion of type A dissection is higher in the full moon phase. These results are important for understanding the mechanisms involved in triggering AAD events and helpful for improving disease prevention and patient care.

When "Blue Babies" Grow Up: Complications After Surgical Repair of Tetralogy of Fallot.

Tetralogy of Fallot (TOF) is a complex congenital cardiac defect. Surgical correction is well established as the treatment of choice and has resulted in a rapidly growing group of adults living with TOF. We describe potential complications of patients who have undergone TOF repair and were lost to follow-up. (Level of Difficulty: Intermediate.).

No-fistula vs. fistula type anorectal malformation: Outcome comparative study.

INTRODUCTION: Anorectal malformation (ARM) is a congenital defect that exists in varying presentations and no-fistula type (NFT) ARM is a rare high-type category. We aim to report our experience with management of this anomaly and its outcome, compared to the more common fistula-type (FT) ARM. METHODS: A retrospective review of medical records of patients diagnosed with high ARM and 3years and older, for the period between September 2000 and January 2015 was conducted. Demographic, anatomic, and outcome data were obtained for each group and compared. Quality of life data were collected using the Krickenbeck classification and assessed as documented at clinic visits as well as phone interviews. RESULTS: There were 100 patients managed for ARM during that period and were 3years or older. Sixteen of them were NFT (16%). For comparison purposes each NFT patient was matched with 3 FT patients. We have analyzed data on 44 patients with FT (44 males), and 16 with NFT (12 males and 4 females). The occurrence of Down syndrome in NFT patients was 56.2% compared to 0% in the FT patients (p=<0.0001). Quality of Life data showed no significant differences between the two groups with p-values of 0.39, 1.0, and 1.0 for Voluntary Bowel Movement, Soiling, and Constipation respectively. CONCLUSION: NFT ARM represents a significant number at our population (16%). There is a strong association between NFT ARM and Down syndrome. NFT ARM has similar outcomes compared to the FT ARM. TYPE OF STUDY: Clinical research paper. LEVEL OF EVIDENCE: Level III.

Advanced Glycation End Products and its Soluble Receptors in the Pathogenesis of Thoracic Aortic Aneurysm.

BACKGROUND: Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of thoracic aortic aneurysms (TAAs). Cytokines [Interleukin (IL)-Iß, IL-2, IL-6, and TNF-α)] increase the expression of MMP-2 and -3. Advanced glycation end products (AGEs) interact with cell receptors to increase the release of cytokines. Circulating soluble receptors for AGEs (sRAGE) and endogenous secretory RAGE (esRAGE) compete with membrane bound RAGE for binding with AGEs and reduce the production of cytokines. It is hypothesized that low levels of serum sRAGE and esRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE would increase the levels of cytokines that would increase the levels MMPs, thus contributing to the formation of TAAs. METHODS: The study population was composed of 17 control subjects and 20 patients with TAA. Blood samples were collected for measurement of serum sRAGE, esRAGE, AGEs, cytokines, and MMPs. AGEs, sRAGE, and esRAGE were measured using ELISA kits, whereas the remaining parameters were measured using the Luminex Multi-Analyte system. RESULTS: The levels of sRAGE were lower, while the levels of AGEs, AGEs/sRAGE, AGEs/esRAGE, cytokines and MMPs were higher in patients with TAA compared to controls. The levels of sRAGE were inversely correlated with cytokines and MMPs, while AGEs, AGEs/sRAGE and AGEs/esRAGE were positively correlated with cytokines and MMPs. Cytokines were positively correlated with MMPs. CONCLUSIONS: The data suggest that the AGE-RAGE axis may be involved in the pathogenesis of TAA and that low levels of sRAGE and high levels of AGEs, AGEs/sRAGE, and AGEs/esRAGE are risk factors for TAA.

Self-reported breast feeding practices and the Baby Friendly Hospital Initiative in Riyadh, Saudi Arabia: prospective cohort study.

BACKGROUND: The Baby Friendly Hospital Initiative (BFHI) is a practice guideline for healthcare providers to promote breastfeeding and increase breastfeeding rates. OBJECTIVE: This study aimed to examine reported experiences and views on breastfeeding of women using prenatal and postnatal services, and opinions of staff, in the context of the BFHI programme in Riyadh, Saudi Arabia. DESIGN: Prospective cohort study. SETTING: This prospective, longitudinal study was conducted from December 2013 to September 2015 at two healthcare facilities (BFHI and non-BFHI) in Riyadh Saudi Arabia. METHODS: Women 36-40 weeks gestation receiving antenatal care at the hospitals were enrolled. Questionnaires were administered prenatally, at 1, 3 and 6 months postnatal and to the administrator and maternity staff. RESULTS: We recruited 277 women with an estimated 80% response rate. 156 (BFHI=78/139, non-BFHI=78/138, 56%) participants completed all questionnaires. Most BFHI-hospital participants (77.9%, n=8 for this question) acknowledged seeing the breast feeding policy compared to 23.5% (n=23) at the non-BFHI-hospital (p<0.01). Breast feeding education and encouragement was higher at the BFHI-hospital (93.3%) compared to the non-BFHI-hospital (48.2%; p<0.01). At postpartum discharge, 51% (n=53) of mothers in the BFHI-hospital were breast feeding exclusively versus 29.6% (n=29) at the non-BFHI-hospital. Where formula feed was introduced, women in the BFHI-hospital more often practiced mixed feeding rather than exclusive formula feeding with some switching from mixed feeding to exclusive breast feeding between 3 and 6 months postpartum. Exclusive breast feeding rates declined in both hospitals at 3 and 6 months postpartum with lack of community services for lactation being a major reason. Although BFHI-hospital staff (n=9) were more conversant with BFHI principles, defects in adherence to the BFHI 10 Steps were identified. CONCLUSIONS: This is the first study assessing the effectiveness of BFHI implementation in Saudi Arabia. Although women reported increased breast feeding rates, we identified important weaknesses that could be improved through strict compliance with BFHI practices.

Reasons to Investigate the Soluble Receptor for Advanced Glycation End-Product (sRAGE) Pathway in Aortic Disease.

Aortic disease has a high rate of morbidity and mortality, and there are no documented screening methods to date. Yet biochemical research does show a significant link between soluble receptor for advanced glycation end-products (sRAGE) protein and cardiovascular disease. Therefore, it can be hypothesized that sRAGE plasma levels may help differentiate patients with aortic disease from the general population, which this paper will review and present.