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The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite the constantly growing number of cancer survivors, little is known about the transcriptional mechanisms which progress in the time leading to a severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations related to doxorubicin use are similar to transcriptomic patterns present in patients suffering from other cardiomyopathies. Here we have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 childhood acute lymphoblastic leukemia survivors treated with doxorubicin and 61 healthy controls (254 samples in total). We analyzed processes regulated by differentially expressed miRNA and cross-validated our results with the data of patients with clinically manifested cardiomyopathies. Our analyses indicate that the circulating compartment used for inspection should be selected with particular attention. miRNAs contained within EVs may be particularly informative in terms of cardiomyopathy development and may regulate pathways related to neurotrophin, transforming growth factor beta or epidermal growth factor receptors (ErbB). Among miRNAs differentially expressed in vesicles, which additionally are also most variable between groups, we identified those correlated with echocardiographic parameters, including miR-144-3p and miR-423-3p and respectively for plasma miRNAs: let-7g-5p, miR-16-2-3p. Among these, vesicular miR-144-3p correlates with the highest number of echocardiographic parameters and is also differentially expressed in the circulation of patients with dilated cardiomyopathy. We also show that in ALL survivors' distribution of particular miRNAs, e.g., miR-184 between plasma and EVs is different than in healthy controls. This suggests persistent alterations within the cellular sorting and exporting system.

The use of doxorubicin is associated with an increased risk of acute and long-term cardiomyopathy. Despite that the number of cancer survivors is growing constantly, little is known about the transcriptional mechanisms which progress in time leading to severe cardiac outcome. It is also unclear whether long-term transcriptomic alterations are related to an acute response to doxorubicin. We have sequenced miRNA from total plasma and extracellular vesicles (EVs) from 66 acute lymphoblastic leukemia (ALL) survivors treated with doxorubicin and 61 healthy controls (254 samples in total). We identified 94 and 33 TFs regulating differentially expressed miRNA in plasma and EVs compartments, respectively. For total plasma we found: HEY1, NRF2, HIF1A, NOTCH1, and for EVs: TGFB, ZEB1, ASCL2, PELP1, SIP1, TWIST1. Analysis of the data from patients with dilated and idiopathic cardiomyopathy revealed similarities with our data from EVs, especially in the activity of TFs related to epithelial-to-mesenchymal transition (EMT). To verify if similarities exist between acute and long-term response to doxorubicin, we performed experiments on cultured as well as we studied the role of NRF2, previously considered as an important player in acute response, in transcriptomic network upon doxorubicin treatment). KEGG analysis of miRNA targets for EVs indicates development of cardiomyopathy, whereas among GO process we found terms related to cardiac septum. In vitro experiments revealed that NRF2 is co-regulated with NOTCH effectors from HEY family, with known role in muscle regeneration. NRF2 and doxorubicin treatment contribute also to the dysregulation of TWIST family, important for the process of EMT.

Common variable immunodeficiency (CVID) is a primary immunodeficiency disorder related to recurrent infections, as well as a range of non-infectious manifestations including autoimmune and inflammatory disorders. We hypothesized that patients with CVID and different clinical phenotypes would demonstrate alterations in lymphocyte T subsets, including T lymphocytes expressing programmed cell death protein 1 (PD-1), and regulatory T lymphocytes. We performed flow cytometry in two CVID groups: group 1 with infections only, and group 2 with infections and concomitant noninfectious manifestations. Patients were 18-59 years old (mean 35.8 years of age). Increased proportions of CD8+PD-1+ T cells and reduced regulatory T cells were associated with lymphadenopathy. Amount of regulatory T cells correlated with CD8+PD-1+ T lymphocytes (r = 0.54; p = 0.013), and with CRP (r = -0.64; p = 0.004). Forty percent of patients expressed manifestations in addition to infections (group 2), and they had reduction in number of regulatory T cells [8 (3-12) vs. 24 (11-26)/μl; p = 0.034), naive CD4+ T lymphocytes [36 (27-106) vs. 149 (81-283)/μl; p = 0.034], and elevated C-reactive protein (CRP) [5.33 (3.15-8.82) vs. 1 (1-2.16) mg/l; p = 0.003] in comparison to group 1. In conclusion, the amount of CD8+ T cells expressing PD-1 is associated with lymphadenopathy and number of regulatory T cells in patients with CVID. Patients with CVID and non-infectious complications have increased level of inflammation and alterations in regulatory T cells.

Background The long‐term consequences of chemotherapy and radiotherapy result in a high prevalence and early onset of age‐related chronic diseases in survivors. We aimed to examine whether childhood and adolescent cancer survivors (CS) demonstrate biomarkers of accelerated aging. Methods We evaluated 50 young adult CS at 11 [8–15] years after cancer diagnosis, and 30 healthy, age and sex‐matched controls, who were unexposed to cancer therapy. Using a machine‐learning approach, we assessed factors discriminating CS from controls and compared selected biomarkers and lymphocyte subpopulations with data from the Framingham Heart Study (FHS) cohort and the Genotype Tissue Expression (GTEx) project. Results Survivors compared with controls had higher levels of C‐reactive protein and fibrinogen. The surface expression of CD38 on T cells was increased, and there was an increase in the percentage of memory T cells in survivors, compared with the unexposed group. The relationships between above cell subpopulations and age were consistent in CS, FHS, and GTEx cohorts, but not in controls. Conclusions Young pediatric cancer survivors differ from age‐related controls in terms of activation of the adaptive immune system and chronic, low‐grade inflammation. These changes resemble aging phenotype observed in older population. Further research in biomarkers of aging in young, adult childhood cancer survivors is warranted, as it may facilitate screening and prevention of comorbidities in this population., Young, adult pediatric cancer survivors are different from age‐matched controls in terms of activation of the adaptive immune system and chronic, low‐grade inflammation. These changes resemble aging phenotype observed in older population.

Increased incidence of lymphomas in patients with rheumatoid arthritis has been reported and may be associated with several factors, including genetic factors, chronic inflammation, and immunosuppressive treatment. Intravascular large cell lymphoma (ILCL) is a rare subtype of large cell lymphoma with undetectable lymphoma cells in peripheral blood and without any extravascular localisation. Diag- nosis is often delayed because bone marrow, spleen, and cerebrovascular fluid may not be involved and there are no specific laboratory studies for intravascular large cell lymphoma. We report the case of a 63-year-old woman with a 10-year history of seropositive rheumatoid arthritis and intravascular large cell lymphoma recognised at autopsy. The patient presented with progressive central nervous system-related symptoms mimicking vasculitis without lymphadenopathy or bone marrow involvement. Malignant lymphoproliferative disorders should be considered in RA patients with varying clinical presentation, even in the absence of lymphadenopathy and bone marrow involvement. JRCD 2018; 4 (1): 15-17.

Poor knowledge on rare diseases (RD) results in a significant delay in their diagnosis and treatment. So far there are no standards of university education in RD. We assessed knowledge on RD among healthcare students and the effectiveness of targeted education.We conducted an internet-based survey among students of the faculty of medicine, pharmacy and health sciences. Questions regarded personal information, definition and epidemic data on RD. The survey was used to assess the effect of targeted education about RD in an additional group of students.We enrolled 270 students (females: n=181; 67%), aged 22±1.7 years. Most of them (87.8%) declared to be familiar with the term RD. However only 20.7% knew the correct definition of RD, 14% knew that RD affect a significant (6-8%) proportion of population, 21.4% that there are 5-8 thousands of different RD’ entities, 73.7% recognized the most common cause of RD. 12.6% knew, that the RD most frequently occur in the adulthood. Targeted education applied in the additional group of 18 students resulted in a significant improvement of students’ knowledge on RD: definition (by 33%; p=0.007), percentage of population affected by RD (by 67%; p=0.001 ), total number of different RD (by 61%; p=0.003), time of onset of RD (by 61% p=0.003).Despite the declared recognition of the term: RD, knowledge on RD among medical students is poor independently on the year of study. However it can be improved with use of targeted education.

Long-term survivors of acute lymphoblastic leukemia (ALL), the most common childhood malignancy, are at remarkably increased risk of heart failure (HF) in middle age, most likely due anthracycline cardiotoxicity. The role of cranial radiation therapy (CRT) in the development of left ventricular (LV) dysfunction, a predecessor of overt HF, remains unclear. Our aim was to compare LV function and systemic arterial properties according to past CRT in young adult survivors of anthracycline-treated ALL. We studied young adult survivors of childhood ALL at a median of 16 years from diagnosis treated with anthracycline-based chemotherapy, with (n = 12) or without (n = 30) CRT. In addition to fractional shortening (FS) and ejection fraction (EF), LV function was quantified by tissue Doppler imaging of the mitral annulus. Aortic strain/distensibility and arterial compliance were derived from echocardiography and simultaneously recorded pulse pressure. Despite similar FS and EF, peak mitral annular systolic velocity (median (interquartile range): 9.0 (7.5&ndash, 10.0) vs. 10.0 (8.8&ndash, 11.5) cm/s, p = 0.05), and early diastolic velocity (13.8 (13.0&ndash, 14.8) vs. 15.5 (14.0&ndash, 17.3), p = 0.01) were decreased after chemotherapy combined with CRT compared to chemotherapy without CRT. Systemic arterial compliance was lower in post-CRT subjects (1.0 (0.8&ndash, 1.2 vs. 1.4 (1.1&ndash, 1.7) mL/mmHg, p = 0.002). Aortic strain and distensibility were similar regardless of prior CRT. In conclusion, lower arterial compliance and subclinical LV dysfunction may be possible late consequences of past CRT in adult survivors of childhood ALL. Whether arterial stiffening is associated with future HF development in CRT-exposed ALL survivors remains to be investigated.

Mycobacteria is a large group of pathogens that are common in environment, in soil and tap water. Although mycobacteria [non tuberculosis mycobacteria] can inhabit body surface without causing any disease in the circumstances of primary or secondary immunodeficiency can cause clinically significant organ or systemic damage. Defect of IL-12/INFgamma axis is an example of primary immunodeficiency that predispose to mycobacterial infections while protection against other microorganisms is not damaged. We present review of known defects of IL-12/IFNgamma axis and brief presentation of our own experience.

138 Background: Survivors of childhood cancer are at increased risk of early cardiovascular (CV) diseases related to previous cancer therapy, chronic stress and unhealthy behaviors, as well as traditional cardiovascular risk factors. The aim of the study was to assess the prevalence of cardiovascular risk factors in young adult survivors of childhood malignancies. Methods: Medical records of 155 adult childhood cancer survivors were analyzed to extract data on cancer treatment, demographical characteristics, family history, smoking, blood pressure (BP), lipids, fasting glucose, creatinine measured during a routine visit in our follow-up clinic for adult childhood cancer survivors. Results: The prevalence of traditional CV risk factors was high, with 55% of patients presenting with prehypertension (office systolic BP 120-139 mmHg or diastolic 80-89 mmHg) and 15,4% with hypertension (BP ≥ 140 mmHg and/or ≥ 90 mmHg or being on antihypertensive drugs). The prevalence of overweight and obesity was 23,5% and 3,7%, respectively. A classic “atherogenic lipid profile” (28% patients with elevated total cholesterol and 27% with elevated LDL cholesterol) was more common than a dyslipidemic pattern (elevated triglycerides 11% and reduced HDL cholesterol 7,8%). Two or more CV risk factors were found in 50% of patients and only 16% did not have any of traditional risk factors. Conclusions: Major CV risk factors are common in very young adults with cancer history in the childhood and may substantially increase risk for future CV events in this population. These finding support the need for screening of adult survivors of childhood malignancy for early detection and treatment of modifiable risk factors. [Table: see text]