The transcriptional landscape of cancer stem-like cell functionality in breast cancer.

BACKGROUND: Cancer stem-like cells (CSCs) have been extensively researched as the primary drivers of therapy resistance and tumor relapse in patients with breast cancer. However, due to lack of specific molecular markers, increased phenotypic plasticity and no clear clinicopathological features, the assessment of CSCs presence and functionality in solid tumors is challenging. While several potential markers, such as CD24/CD44, have been proposed, the extent to which they truly represent the stem cell potential of tumors or merely provide static snapshots is still a subject of controversy. Recent studies have highlighted the crucial role of the tumor microenvironment (TME) in influencing the CSC phenotype in breast cancer. The interplay between the tumor and TME induces significant changes in the cancer cell phenotype, leading to the acquisition of CSC characteristics, therapeutic resistance, and metastatic spread. Simultaneously, CSCs actively shape their microenvironment by evading immune surveillance and attracting stromal cells that support tumor progression. METHODS: In this study, we associated in vitro mammosphere formation assays with bulk tumor microarray profiling and deconvolution algorithms to map CSC functionality and the microenvironmental landscape in a large cohort of 125 breast tumors. RESULTS: We found that the TME score was a significant factor associated with CSC functionality. CSC-rich tumors were characterized by an immune-suppressed TME, while tumors devoid of CSC potential exhibited high immune infiltration and activation of pathways involved in the immune response. Gene expression analysis revealed IFNG, CXCR5, CD40LG, TBX21 and IL2RG to be associated with the CSC phenotype and also displayed prognostic value for patients with breast cancer. CONCLUSION: These results suggest that the characterization of CSCs content and functionality in tumors can be used as an attractive strategy to fine-tune treatments and guide clinical decisions to improve patients therapy response.

Exploring the contrasts: in-depth analysis of human and canine mammary tumors - discoveries at the frontier.

We have examined genomic and transcriptomic abnormalities in human and canine samples to evaluate the canine model's validity for breast cancer research, emphasizing similarities and differences. Both species commonly utilize serum tumor markers and noncoding microRNAs. Immunohistochemistry and immunocytochemistry were employed to illustrate and compare results based on histological diagnoses. In addition to these factors, similarities exist in spontaneous tumor occurrence, age of onset, hormonal influences, and disease progression, including tumor size, clinical stage, and lymph node involvement. Molecular traits such as hormone receptor status, Epidermal Growth Factor Receptor (EGFR), and proliferation markers (Ki67) further endorse the canine model's utility in breast cancer studies. The advancement of technologies facilitates the identification of new cancer-associated molecules, both coding and non-coding genes, underscoring their potential as prognostic/diagnostic biomarkers and therapeutic targets.

Mammographic assessment of breast density as a tool for predicting the response to neoadjuvant therapy in breast cancer patients.

Background and aims: Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer-related death among women worldwide. For locally advanced diseases and high-risk tumors, neoadjuvant therapy (NAT) is the treatment of choice. Some studies show that mammographic density (MD) tumor margins and the presence of microcalcifications play a prognostic role in BC patients. Hence, the objective of this retrospective study was to assess if MD could predict the response to NAT among different molecular subtypes of BC patients undergoing NAT at The "Prof. Dr I. Chiricuta" Oncology Institute of Cluj-Napoca, Romania (IOCN). Furthermore, the association between MD, tumor margins and the presence of microcalcifications with clinico-pathological data was analyzed. Methods: Eighty-four breast cancer patients diagnosed and treated at IOCN were included in this study. The morphological characteristics of the tumors were framed according to the BIRADS lexicon. The presence or absence of microcalcifications was also assessed. First, the significance of associations between breast density, margins and microcalcifications and clinico-pathological parameters of the patients were tested with Fisher or Fisher-Freeman-Halton Exact Test. Next, using multinomial logistic regression, we modelled the associations between the pathological response measured by Miller Payne and Residual cancer burden (RCB) systems and the BI-RADS. Variables having significant univariate tests were selected as candidates for the multivariable analysis (adjusted model). Results: Breast densities were significantly associated with the age of the patients (p=0.01), number of positive lymph nodes (p=0.037), margins (p=0.002) and combined categories of Miller-Payne (p=0.034) and RCB pathological response (p=0.021). Margins was significantly associated with ki67 proliferation index (p=0.029), estrogen receptor (ER) (p=0.007), progesterone receptor (PR) (p=0.019), molecular subtype (p<0.001) and the number of clinically observed positive lymph nodes at diagnosis (p=0.019). Conclusions: In our cohort, BC patients with lower MD had higher odds of achieving pCR following NAT, suggesting the role of MD as a clinical prognostic marker. Larger multicenter studies are warranted to validate the prognostic value of MD, which could aid in patients stratification based on their likelihood to respond to NAT.

Body size influences heart rate in children aged 6 to 18 years old.

Previous research established age-related normal limits for children's heart rates (HRs). However, children of the same age can have significantly different HRs, depending on whether they are overweight or underweight, tall or short. Studies on children HR have failed to find a clear correlation between HR and body size. The goal of our study was to create Z scores for HR based on weight (W), height (H), body mass index (BMI), and body surface area (BSA) and compare them to normal age-related HR limits. Electrocardiograms were recorded from a total of 22,460 healthy children ranging in age from 6 to 18 years old using BTL machines. A comparison was made between different age groups, in function of W, H, BMI, and BSA, based on the HR that was automatically detected by using the digitally stored electrocardiogram. Z scores were computed for each of the categories that were mentioned. Incremental Z score values between -2.5 and 2.5 were calculated to establish upper and lower limits of HR. The BSA's estimation of HR is the most accurate of the available methods and can be utilized with accuracy in clinical practice. Z scores for HR in children differ in function of the age, W, H, BMI and BSA. The best estimation is based on BSA. The novelty of our study is that we developed Z scores for HR in relation to body size, age and sex, producing a standardized, consistent, and reproducible result without requiring practitioners to learn and remember cutoff values for a wide range of variables across age groups and sexes. Z scores minimize observer and institutional bias, hence generating uniform and reproducible standards.

Low Atrial Rhythm in a Large Cohort of Children from Transylvania, Romania.

Low atrial rhythm (LAR) is an ectopic rhythm originating in the lower part of the right or left atrium. Prior observational studies attempted to quantify the prevalence of low atrial rhythm in the pediatric population, but the observed prevalence was highly variable with relatively small sample sizes. We aimed to characterize low atrial rhythm and determine its prevalence in a large population of 24,316 asymptomatic children from northwestern Transylvania. We found a prevalence of 0.6% (145 children) for low atrial rhythm. Children with LAR had a significantly lower heart rate (mean 78.6 ± 8.3 bpm), than the control sinus rhythm group (85.02 ± 4.5 bpm). Furthermore, a shorter PR interval was seen in children with LAR (132.7 ± 12.7 ms) than in the children from the control group (141.7 ± 5.4; p = 0.0001).There was no significant association between gender and the presence of left LAR (LLAR) or right LAR (RLAR) (p = 0.5876). The heart rate of children with LLAR was significantly higher (81.7 ± 11.6 bpm) than that of the children with LRAR (77.6 ± 11.1 bpm) (p = 0.037). Pediatric cardiologists should recognize low atrial rhythm and be aware that asymptomatic, healthy children can exhibit this pattern, which does not require therapeutic intervention.

The Role of miR-375-3p, miR-210-3p and Let-7e-5p in the Pathological Response of Breast Cancer Patients to Neoadjuvant Therapy.

Background and Objectives: Prediction of response to therapy remains a continuing challenge in treating breast cancer, especially for identifying molecular tissue markers that best characterize resistant tumours. Microribonucleic acids (miRNA), known as master modulators of tumour phenotype, could be helpful candidates for predicting drug resistance. We aimed to assess the association of miR-375-3p, miR-210-3p and let-7e-5p in breast cancer tissues with pathological response to neoadjuvant therapy (NAT) and clinicopathological data. Material and methods: Sixty female patients diagnosed with invasive breast cancer at The Oncology Institute "Ion Chiricuța", Cluj-Napoca, Romania (IOCN) were included in this study. Before patients received any treatment, fresh breast tissue biopsies were collected through core biopsy under echographic guidance and processed for total RNA extraction and miRNA quantification. The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) database was used as an independent external validation cohort. Results: miR-375-3p expression was associated with more differentiated tumours, hormone receptor presence and lymphatic invasion. According to the Miller-Payne system, a higher miR-375-3p expression was calculated for patients that presented with intermediate versus (vs.) no pathological response. Higher miR-210-3p expression was associated with an improved response to NAT in both Miller-Payne and RCB evaluation systems. Several druggable mRNA targets were correlated with miR-375-3p and miR-210-3p expression, with upstream analysis using the IPA knowledge base revealing a list of possible chemical and biological targeting drugs. Regarding let-7e-5p, no significant association was noticed with any of the analysed clinicopathological data. Conclusions: Our results suggest that tumours with higher levels of miR-375-3p are more sensitive to neoadjuvant therapy compared to resistant tumours and that higher miR-210-3p expression in responsive tumours could indicate an excellent pathological response.

Circulating Small EVs miRNAs as Predictors of Pathological Response to Neo-Adjuvant Therapy in Breast Cancer Patients.

Neo-adjuvant therapy (NAT) is increasingly used in the clinic for the treatment of breast cancer (BC). Pathological response to NAT has been associated with improved patients' survival; however, the current techniques employed for assessing the tumor response have significant limitations. Small EVs (sEVs)-encapsulated miRNAs have emerged as promising new biomarkers for diagnosis and prediction. Therefore, our study aims to explore the predictive value of these miRNAs for the pathological response to NAT in BC. By employing bioinformatic tools, we selected a set of miRNAs and evaluated their expression in plasma sEVs and BC biopsies. Twelve miRNAs were identified in sEVs, of which, miR-21-5p, 221-3p, 146a-5p and 26a-5p were significantly associated with the Miller-Payne (MP) pathological response to NAT. Moreover, miR-21-5p, 146a-5p, 26a-5p and miR-24-3p were independent as predictors of MP response to NAT. However, the expression of these miRNAs showed no correlation between sEVs and tissue samples, indicating that the mechanisms of miRNA sorting into sEVs still needs to be elucidated. Functional analysis of miRNA target genes and drug interactions revealed that candidate miRNAs and their targets, can be regulated by different NAT regimens. This evidence supports their role in governing the patients' therapy response and highlights their potential use as prediction biomarkers.

Anatomical-MRI Correlations in Adults and Children with Hypertrophic Cardiomyopathy.

Hypertrophic Cardiomyopathy (HCM) is the most frequent hereditary cardiovascular disease and the leading cause of sudden cardiac death in young individuals. Advancements in CMR imaging have allowed for earlier identification and more accurate prognosis of HCM. Interventions aimed at slowing or stopping the disease's natural course may be developed in the future. CMR has been validated as a technique with high sensitivity and specificity, very few contraindications, a low risk of side effects, and is overall a good tool to be employed in the management of HCM patients. The goal of this review is to evaluate the magnetic resonance features of HCM, starting with distinct phenotypic variants of the disease and progressing to differential diagnoses of athlete's heart, hypertension, and infiltrative cardiomyopathies. HCM in children has its own section in this review, with possible risk factors that are distinct from those in adults; delayed enhancement in children may play a role in risk stratification in HCM. Finally, a number of teaching points for general cardiologists who recommend CMR for patients with HCM will be presented.

Formula to estimate left atrial volume using antero-posterior diameter in patients with catheter ablation of atrial fibrillation.

ABSTRACT: In patients undergoing atrial fibrillation (AF) ablation, an enlarged left atrium (LA) is a predictor of procedural failure as well as AF recurrence on long term. The most used method to assess LA size is echocardiography-measured diameter, but the most accurate remains computed tomography (CT).The aim of our study was to determine whether there is an association between left atrial diameters measured in echocardiography and the left atrial volume determined by CT in patients who underwent AF ablation.The study included 93 patients, of whom 60 (64.5%) were men and 64 (68.8%) had paroxysmal AF, who underwent AF catheter ablation between January 2018 and June 2019. Left atrial diameters in echocardiography were measured from the long axis parasternal view and the LA volume in CT was measured on reconstructed three-dimensional images.The LA in echocardiography had an antero-posterior (AP) diameter of 45.0 ±â€Š6 mm (median 45; Inter Quartile Range [IQR] 41-49, range 25-73 mm), longitudinal diameter of 67.5 ±â€Š9.4 (median 66; IQR 56-88, range 52-100 mm), and transversal diameter of 42 ±â€Š8.9 mm (IQR 30-59, range 23-64.5 mm). The volume in CT was 123 ±â€Š29.4 mL (median 118; IQR 103-160; range 86-194 mL). We found a significant correlation (r = 0.702; P < .05) between the AP diameter and the LA volume. The formula according to which the AP diameter of the LA can predict the volume was: LA volume = AP diam3 + 45 mL.There is a clear association between the left atrial AP diameter measured on echocardiography and the volume measured on CT. The AP diameter might be sufficient to determine the increase in the volume of the atrium and predict cardiovascular outcomes.

Anatomical-MRI Correlations in Adults and Children with Arrhythmogenic Right Ventricular Cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare disease in which the right ventricular myocardium is replaced by islands of fibro-adipose tissue. Therefore, ventricular re-entry circuits can occur, predisposing the patient to ventricular tachyarrhythmias, as well as dilation of the right ventricle that eventually leads to heart failure. Although it is a rare disease with low prevalence in Europe and the United States, many patients are addressed disproportionately for cardiac magnetic resonance imaging (MRI). The most severe consequence of this condition is sudden cardiac death at a young age due to untreated cardiac arrhythmias. The purpose of this paper is to revise the magnetic resonance characteristics of ARVC, including the segmental contraction abnormalities, fatty tissue replacement, decrease of the ejection fraction, and the global RV dilation. Herein, we also present several recent improvements of the 2010 Task Force criteria that are not included within the ARVC diagnosis guidelines. In our opinion, these features will be considered in a future Task Force Consensus.

Game of "crowning" season 8: RAS and reproductive hormones in COVID-19 - can we end this viral series?

The outbreak of a newly identified coronavirus, the SARS-CoV-2 (alternative name 2019-nCoV), capable of jumping across species causing zoonosis with severe acute respiratory syndromes (SARS), has alerted authorities worldwide. Soon after the epidemic was first detected in the city of Wuhan in the Hubei Province of China, starting in late December 2019, the virus spread over multiple countries in different continents, being declared a pandemic by March 2020. The demographic characteristics of the infected patients suggest that age, sex, and comorbidities are predictive factors for the fatality of the infection. The mechanisms of viral entry into the human host cells seem to be in a close relationship with the mechanisms of regulating the renin-angiotensin system (RAS), which may explain the pathogenesis associated with the infection. This brings new insights into the possibilities of exploiting viral entry mechanisms to limit associated complications by means of enhancing the resistance of the infected patients using methods of regulating the RAS and strategies of modulating ACE2 expression. In this perspective article we exploit the mechanisms of COVID-19 pathogenesis based on the demographic characteristics of the infected patients reported in the recent literature and explore several approaches of limiting the initial steps of viral entry and pathogenesis based on viral interactions with ACE2 and RAS. We further discuss the implications of reproductive hormones in the regulation of the RAS and investigate the premise of using endocrine therapy against COVID-19.

ECG Markers of Cardiovascular Toxicity in Adult and Pediatric Cancer Treatment.

When a cardiologist is asked to evaluate the cardiac toxic effects of chemotherapy, he/she can use several tools: ECG, echocardiography, coronary angiography, ventriculography, and cardiac MRI. Of all these, the fastest and easiest to use is the ECG, which can provide information on the occurrence of cardiac toxic effects and can show early signs of subclinical cardiac damage. These warning signs are the most desired to be recognized by the cardiologist, because the dose of chemotherapeutics can be adjusted so that the clinical side effects do not occur, or the therapy can be stopped in time, before irreversible side effects. This review addresses the problem of early detection of cardiotoxicity in adult and pediatric cancer treatment, by using simple ECG recordings.

Field Cancerization in NSCLC: A New Perspective on MicroRNAs in Macrophage Polarization.

Lung cancer is currently the first cause of cancer-related death. The major lung cancer subtype is non-small cell lung cancers (NSCLC), which accounts for approximatively 85% of cases. The major carcinogenic associated with lung cancer is tobacco smoke, which produces long-lasting and progressive damage to the respiratory tract. The progressive and diffuse alterations that occur in the respiratory tract of patients with cancer and premalignant lesions have been described as field cancerization. At the level of tumor cells, adjacent tumor microenvironment (TME) and cancerized field are taking place dynamic interactions through direct cell-to-cell communication or through extracellular vesicles. These molecular messages exchanged between tumor and nontumor cells are represented by proteins, noncoding RNAs (ncRNAs) and microRNAs (miRNAs). In this paper, we analyze the miRNA roles in the macrophage polarization at the level of TME and cancerized field in NSCLC. Identifying molecular players that can influence the phenotypic states at the level of malignant cells, tumor microenvironment and cancerized field can provide us new insights into tumor regulatory mechanisms that can be further modulated to restore the immunogenic capacity of the TME. This approach could revert alterations in the cancerized field and could enhance currently available therapy approaches.

Catheter ablation of a latent accessory pathway under continuous infusion of adenosine: A case report.

RATIONALE: In absence of conduction over the accessory pathway (AP) during the electrophysiological study, mapping and ablation is impossible. Various techniques can be used to activate absent conduction. In this presentation we describe the first case of latent AP ablation performed under continuous infusion of adenosine. PATIENT CONCERNS: A 65-year-old man, presented to emergency department with atrial fibrillation and antegrade conduction through a left lateral AP. He had palpitations and lightheadedness that occurred every 2 to 3 weeks. DIAGNOSIS: The electrophysiological study confirmed a latent left-side AP. INTERVENTIONS: Catheter ablation could not be performed because of absent conduction through AP. Therefore, a continuous infusion of adenosine was used to activate AP. Ablation was performed at the left lateral mitral ring. OUTCOMES: After catheter ablation and a new adenosine bolus there was no conduction through AP. LESSONS: In case of a latent AP when ablation is difficult to perform because of absent conduction at the time of electrophysiological study, adenosine can be used in doses of 1.5 mg/kg over 5 minutes continuous infusion.

Human Chorionic Gonadotropin Improves the Proliferation and Regenerative Potential of Bone Marrow Adherent Stem Cells and the Immune Tolerance of Fetal Microchimeric Stem Cells In Vitro.

Nongonadal tissues express luteinizing hormone-chorionic gonadotropin receptors (LHCG-R) which are essential for their growth during fetal development. Adult mesenchymal stem/stromal cells (MSCs) have been shown to express functional LHCG-R outside pregnancy conditions, making them susceptible to hCG stimulation. In the present study we tested the effect of hCG treatment on bone marrow (BM) derived adherent stem cells in vitro, isolated from a parous women, mother of male sons, in order to evaluate its effect on maternal MSCs and in the same time on fetal microchimeric stem cells (FMSCs), to better understand the outcomes of this safe and affordable treatment on cell proliferation and expression of pluripotency genes. Our study highlights the beneficial effects of hCG exposure on gene regulation in bone marrow adherent stem cells through the upregulation of pluripotency genes and selection of more primitive mesenchymal stem cells with a better differentiation potential. Validation of these effects on MSCs and FMSCs long after parturition in vivo represents a close perspective as it could set the premises of a new mobilization strategy for the stem cell transplantation procedures in the clinical setting.

Intraductal papillary mucinous neoplasia--a challenging diagnosis in a patient with paraneoplastic rheumatoid arthritis. Case report.

Intraductal papillary mucinous neoplasias (IPMNs) of the pancreas are potentially malignant tumors, and associated also with extrapancreatic carcinomas. We present the case of a 80 year old man with IPMN and late onset of rheumatoid arthritis. The particularity of this case is the discordance between the clinical picture and the imaging worrisome features, together with the surgery-requiring mixed-type of IPMN, despite the late possible paraneoplastic onset of rheumatoid arthritis.