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BACKGROUND: Autologous hematopoietic stem cell transplantation (AHSCT) is currently the backbone of the treatment of multiple myeloma (MM) and relapsed and refractory lymphomas. Notably, infections contribute to over 25% of fatalities among AHSCT recipients within the initial 100 days following the procedure. In this study, we aimed to evaluate three selected miRNAs: hsa-miR-155-5p, hsa-miR-320c, and hsa-miR-361-3p, in identifying AHSCT recipients at high risk of infectious events up to 100 days post-transplantation after discharge. MATERIALS AND METHODS: The study group consisted of 58 patients (43 with MM, 15 with lymphoma) treated with AHSCT. Blood samples were collected from all patients at the same time point: on day +14 after transplantation. RESULTS: Fifteen patients (25.9%) experienced infectious complications after post-transplant discharge within the initial +100 days post-transplantation. The median time to infection onset was 44 days (interquartile range, 25-78). Four patients required hospitalization due to severe infection. High expression of hsa-miR-361-3p (fold change [FC], 1.79; P=0.0139) in the patients experiencing infectious complications and overexpression of hsa-miR-320c (FC, 2.14; P<0.0001) in patients requiring hospitalization were observed. In the multivariate model, both lymphoma diagnosis (odds ratio [OR], 6.88; 95% confidence interval [CI], 1.55-30.56; P=0.0112) and high expression of hsa-miR-361-3p (OR, 3.00; 95% CI, 1.40-6.41; P=0.0047) were independent factors associated with post-discharge infectious complications occurrence. Our model in 10-fold cross-validation preserved its diagnostic potential with an area under the receiver operating characteristic curve of 0.78 (95% CI, 0.64-0.92). CONCLUSION: Elevated serum hsa-miR-361-3p emerges as a promising biomarker for identifying patients at risk of infection during the early post-discharge period, potentially offering optimization of the prophylactic use of antimicrobial agents tailored to the specific risk profile of each AHSCT recipient.
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Autologous hematopoietic stem cell transplantation (AHSCT) remains the most prevalent type of stem cell transplantation. In our study, we investigated the changes in circulating miRNAs in AHSCT recipients and their potential to predict early procedure-related complications. We collected serum samples from 77 patients, including 54 with multiple myeloma, at four key time points: before AHSCT, on the day of transplantation (day 0), and at days + 7 and + 14 post-transplantation. Through serum miRNA-seq analysis, we identified altered expression patterns and miRNAs associated with the AHSCT procedure. Validation using qPCR confirmed deviations in the levels of miRNAs at the beginning of the procedure in patients who subsequently developed bacteremia: hsa-miR-223-3p and hsa-miR-15b-5p exhibited decreased expression, while hsa-miR-126-5p had increased level. Then, a neural network model was constructed to use miRNA levels for the prediction of bacteremia. The model achieved an accuracy of 93.33% (95%CI: 68.05-99.83%), with a sensitivity of 100% (95%CI: 67.81-100.00%) and specificity of 90.91% (95%CI: 58.72-99.77%) in predicting bacteremia with mean of 6.5 ± 3.2 days before occurrence. In addition, we showed unique patterns of miRNA expression in patients experiencing platelet engraftment delay which involved the downregulation of hsa-let-7f-5p and upregulation of hsa-miR-96-5p; and neutrophil engraftment delay which was associated with decreased levels of hsa-miR-125a-5p and hsa-miR-15b-5p. Our findings highlight the significant alterations in serum miRNA levels during AHSCT and suggest the clinical utility of miRNA expression patterns as potential biomarkers that could be harnessed to improve patient outcomes, particularly by predicting the risk of bacteremia during AHSCT.
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Hepatic complications are an acknowledged cause of mortality and morbidity among patients undergoing hematopoietic stem cell transplantation. In this study, we aimed to evaluate the potential role in the prediction of liver injury of five selected microRNAs (miRNAs)-miR-122-5p, miR-122-3p, miR-15b-5p, miR-99b-5p, and miR-125a-5p-in the setting of autologous hematopoietic stem cell transplantation (ASCT). A total of 66 patients were included in the study: 50 patients (75.8%) with multiple myeloma (MM) and 16 (24.2%) with lymphoma. Blood samples were collected after the administration of the conditioning regimen, on the day of transplant (day 0). The expression levels of selected miRNAs were quantified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) using the miRCURY LNA miRNA Custom PCR Panels (QIAGEN). In a multivariate logistic regression analysis adjusted for age, sex, and the administered conditioning regimen, two miRNAs, hsa-miR-122-5p (odds ratio, OR 2.10, 95% confidence interval, CI: 1.29-3.42, p = 0.0029) and hsa-miR-125a-5p (OR 0.27, 95% CI: 0.11-0.71, p = 0.0079), were independent for hepatic toxicity occurrence during the 14 days after transplant. Our model in 10-fold cross-validation preserved its diagnostic potential with a receiver operating characteristics area under the curve (ROC AUC) of 0.75, 95% CI: 0.63-0.88 and at optimal cut-off reached 72.0% sensitivity and 74.4% specificity. An elevated serum level of miR-122-5p and decreased level of miR-125a-5p on day 0 are independent risk factors for hepatotoxicity in ASCT recipients, showing promise in accurately predicting post-ASCT complications. Identifying patients susceptible to complications has the potential to reduce procedure costs and optimize the selection of inpatient or outpatient procedures.
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Transplante de Células-Tronco Hematopoéticas , MicroRNAs , Transplante Autólogo , Humanos , MicroRNAs/sangue , MicroRNAs/genética , Masculino , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pessoa de Meia-Idade , Transplante Autólogo/efeitos adversos , Adulto , Idoso , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Mieloma Múltiplo/sangue , Biomarcadores/sangue , Curva ROC , Linfoma/sangue , Linfoma/genética , Linfoma/terapiaRESUMO
This study aimed to identify microRNAs (miRNAs) whose expression levels are altered by high-risk human papillomavirus (HR-HPV) infection in women with epithelial ovarian neoplasms. MiRNA expression was quantified by real-time polymerase chain reaction, while HR-HPV DNA was quantified using digital-droplet PCR. Analysis of 11 miRNAs demonstrated significantly lower hsa-miR-25-5p expression in HPV-infected compared to uninfected ovarian tissues (p = 0.0405), while differences in miRNA expression in corresponding serum were statistically insignificant. The expression of hsa-miR-218-5p in ovarian tumors was significantly higher in high-grade serous ovarian carcinoma (HGSOC) cases than in other neoplasms (p = 0.0166). In addition, hsa-miR-218-5p was significantly upregulated, whereas hsa-miR-191-5p was significantly downregulated in tissues with stage III/IV FIGO (p = 0.0009 and p = 0.0305, respectively). Using unsupervised clustering, we identified three unique patient groups with significantly varied frequencies of HPV16/18-positive samples and varied miRNA expression profiles. In multivariate analysis, high expression of hsa-miR-16-5p was an independent prognostic factor for poor overall survival (p = 0.0068). This preliminary analysis showed the changes in miRNA expression in ovarian neoplasms during HPV infection and those collected from HGSOCs or patients with advanced disease. This prospective study can provide new insights into the pathogenesis of ovarian neoplasms and host-virus interactions.
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MicroRNAs , Neoplasias Ovarianas , Infecções por Papillomavirus , Humanos , Feminino , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Papillomavirus Humano 16 , Estudos Prospectivos , Papillomavirus Humano 18 , MicroRNAs/genética , Neoplasias Ovarianas/genéticaRESUMO
Infectious complications of autologous hematopoietic stem cell transplantation (AHSCT) are the most common adverse effects of the therapy, resulting in prolonged hospitalization and deterioration of patient well-being. Identifying predictors of these complications is essential for improving patient outcomes and guiding clinical management. This study aimed to examine thrombospondin-1 (THBS-1) serum levels as a potential biomarker for predicting bacteremia in AHSCT recipients. Blood samples were collected from 30 patients undergoing BeEAM/BEAM (bendamustine/carmustine, etoposide, cytarabine, melphalan) conditioning regimen at subsequent time points during AHSCT. THBS-1 levels were quantified using ELISA kits. Patients who developed bacteremia (n = 11) during the AHSCT course had lower THBS-1 concentration compared with those without (n = 19) (22.88 ± 11.53 µg/mL vs. 15.24 ± 5.62 µg/mL, p = .0325). The ROC curve analysis revealed that THBS-1 serum concentration at the first day of BeEAM/BEAM regimen had an area under the curve of 0.732 (95%CI: 0.5390.925, p = .0186) with an optimal cut-off value of 16.5 µg/ml resulting in 82% Sensitivity and 53% Specificity for predicting bacteremia with a median of 11 days before its occurrence. Patients with lower THBS-1 concentrations experienced febrile neutropenia significantly earlier, with a median difference of 5 days (p = .0037). Patients with a low concentration of THBS-1 had a higher risk of bacteremia and a shorter time to febrile neutropenia, indicating its potential value as a complications biomarker. Patients with lower serum THBS-1 concentrations, indicating an increased risk, may be more suitable for an inpatient AHSCT procedure, where close monitoring and immediate intervention are accessible.
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Neutropenia Febril , Transplante de Células-Tronco Hematopoéticas , Linfoma , Humanos , Carmustina/uso terapêutico , Melfalan/efeitos adversos , Etoposídeo/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante Autólogo/efeitos adversos , Linfoma/terapia , Citarabina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores , Trombospondinas , Condicionamento Pré-Transplante/efeitos adversos , Condicionamento Pré-Transplante/métodosRESUMO
Introduction: AHSCT is the treatment of choice for newly diagnosed patients with transplant-eligible multiple myeloma (MM). However, considerable variability in response to autologous hematopoietic stem cell transplantation (AHSCT) results in only 50% of patients achieving complete response (CR) after AHSCT, which is directly associated with improved progression-free and overall survival (OS). In this study, we aimed to investigate the potential predictive role of selected serum miRNAs in MM patients who underwent AHSCT. Patients and methods: Serum expression level of 6 miRNAs: miR-221-3p, miR-15b-5p, miR-223-3p, miR-320c, miR-361-3p, and miR-150-5p was evaluated in 51 patients who underwent AHSCT. Blood samples were collected at two time points: before conditioning chemotherapy (T1) and fourteen days after transplant (+14) (T2). Results: All selected miRNAs significantly changed their expression level across the procedure- two were up-regulated after AHSCT: hsa-miR-320c (FC 1.42, p<0.0001) and hsa-miR-361-3p (FC 1.35, p=0.0168); four were down-regulated: hsa-miR-15b-5p (FC 0.53, p<0.0001), hsa-miR-221-3p (FC 0.78, p=0.0004), hsa-miR-223-3p (FC 0.74, p=0.0015) and hsa-miR-150-5p (FC 0.75, p=0.0080). Notably, before AHSCT, hsa-miR-223-3p was down-regulated in International Staging System (ISS) III patients (FC=0.76, p=0.0155), and hsa-miR-320c was up-regulated (FC=1.27, p=0.0470). These differences became non-significant after AHSCT. Eight (15.69%) patients achieved CR before AHSCT and 17 patients (33.33%) at +100 days after AHSCT. In multivariate logistic regression analysis, achievement of CR after induction and hsa-miR-223-3p at T1 were independent predictors of CR after AHSCT. In multivariate Cox regression analysis, hsa-miR-223-3p at T1 expression level was associated with prolonged OS (HR 0.06, 95%CI: 0.00 - 0.99, p=0.0488). Conclusion: Serum expression of has-miR-223-3p is a predictor of CR and prolonged OS in MM patients undergoing AHSCT.
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Pediatric multi-system inflammatory syndrome temporally associated with COVID-19 (PIMS-TS) is a serious complication of a previous SARS-CoV-2 infection. The disease causes multiple organ failure, but in some patients, a more severe course of the disease is observed. The treatment is multidirectional and depends on the severity and course of the disease, as some patients do not respond to the recommended treatment. The aim of this study was to identify laboratory risk factors affecting the more severe course of the disease and resistance to standard therapy. It is a single-center retrospective study considering 51 patients with PIMS-TS. Clinical features, laboratory results, and additional imaging tests data were taken into account. Fifty-one patients with PIMS-TS were hospitalized within a 16-month observation period. In the studied group, 26/51 children (51%) were girls. The mean age of patients was 7 years. Sex of the patient was not a risk factor for changes in cardiovascular system or severe course of the disease. Sixteen patients (31.3%) required transfer to the intensive care unit. Children with initially higher concentrations of NT-proBNP, troponin, creatinine, triglycerides, C-reactive protein, procalcitonin, ferritin, D-dimers and lower hematocrit, platelet count, lymphocytes, and ejection fraction should be strictly observed as they have a higher risk of severe course of the disease. CONCLUSIONS: Laboratory parameters especially markers of myocardial damage, markers of inflammation, blood count, as wells as biochemical parameters are significant risk indicators of severe course of PIMS -TS and their concentration can be defined as predictor of disease severity. WHAT IS KNOWN: ⢠Pediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS) is a serious complication of a previous SARS-CoV-2 infection in the group of pediatric patients ⢠Course of the disease may be severe, which may cause long-term complications and the need for longitudinal patient care. WHAT IS NEW: ⢠Children with higher concentrations of NT-proBNP, troponin, creatinine, TG, CRP, PCT, ferritin, D-dimers and lower hematocrit, PLT, lymphocytes, and EF have a higher risk of a severe course of the disease. ⢠Patients with high concentration of NT-proBNP, troponin, CRP, lactates, ferritin, D-dimers, creatinine and a lower concentration of PLT, albumin, leukocytes; lymphopenia, hyponatremia are at risk for intravenous immunoglobulin resistance.
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COVID-19 , Proteína C-Reativa , COVID-19/complicações , Criança , Creatinina , Feminino , Ferritinas , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Lactatos , Masculino , Pró-Calcitonina , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2 , Síndrome , Síndrome de Resposta Inflamatória Sistêmica , Triglicerídeos , TroponinaRESUMO
Background Pediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS) is a serious complication of a previous SARS-CoV-2 infection in the group of pediatric patients. Despite the fact that this disease affects only about 1 of 1000 children, it may be severe, and changes in the cardiovascular system may cause long-term complications and the need for longitudinal patient care. Methods It is a single-center retrospective study considering 51 patients with PIMS-TS. The aim of this study was to analyze patients with PIMS-TS, taking into account demographic data, clinical course, laboratory tests and cardiovascular system assessment (electrocardiography, echocardiography, etc.). Results From June 2020 to October 2021, 51 patients with PIMS-TS were hospitalized in our center. In the studied group, 26/51 children (51%) were girls. The mean age of patients was 7 years. Changes in electrocardiograms were found in 21/51 patients. Echocardiography revealed pericardial fluid in most patients. In addition, heart valve insufficiency was found. Changes in the coronary vessels in the form of dilatations and even aneurysms were found in 42 patients. Myocardial hypokinesis was visualized in more than 1/4 of the patients. Sixteen patients (31.3%) required transfer to the intensive care unit (ICU) due to severe hypotension. Laboratory tests revealed increased levels of markers of heart failure and enzymes of myocardial damage. Conclusions Changes in the cardiovascular system in the course of PIMS-TS are of various nature, but in most patients they require close cardiac supervision and long-term follow-up.
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COVID-19 , Sistema Cardiovascular , COVID-19/complicações , COVID-19/diagnóstico , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica/diagnósticoRESUMO
Neonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome (MIM# 610199) is a rare disease caused by autosomal recessive mutations in the GLIS3 gene. GLIS3 is an important transcription factor that might acts as both a repressor and activator of transcription. To date, 22 cases of NDH syndrome from 16 families and 11 countries have been described. Herein, we report a child who developed diabetes during the first week of age. Additionally, she suffered from congenital hypothyroidism, cardiac abnormalities, and polycystic kidney disease. Genetic analysis revealed that patient is a carrier of two novel heterozygous mutations, p.Pro444fsdelG (c.1330delC) and p.His647Arg (c.1940A > G) in the GLIS3 gene. Each was inherited from clinically healthy father and mother, respectively. Bioinformatic tools (SIFT, PolyPhen2, PROVEAN and SWISS-MODEL) declared that the p.His647Arg (c.1940A > G) variant has strong detrimental effect and disturbs Kruppel-like zinc finger domain. All but one so far described cases of NDH syndrome have been caused by homozygous of GLIS3, making the described case the second case of pathogenic, compound heterozygosity of GLIS3 worldwide posing substantial clinical novelty and detailing an interesting interplay between the observed variants and GLIS3 expression, which seems to be autoregulated. Hence, the damaging missense mutation may further reduce the expression of any remaining functional alleles. This case report expands our understanding of the clinical phenotype, treatment approaches, and outcome of infants with GLIS3 mutations and indicates the need for further research to deepen our understanding of the role of GLIS3.
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Hipotireoidismo Congênito , Diabetes Mellitus , Doenças do Recém-Nascido , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/genética , Proteínas de Ligação a DNA/genética , Diabetes Mellitus/congênito , Diabetes Mellitus/genética , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/genética , Mutação , Proteínas Repressoras/genética , Transativadores/genética , Transativadores/metabolismoRESUMO
WHO has declared COVID-19 as a worldwide, public health emergency. The elderly, pregnant women, and people with associated co-morbidities, including pulmonary disease, heart failure, diabetes, and cancer are the most predisposed population groups to infection. Cell-free DNA is a very commonly applied marker, which is elevated in various pathological conditions. However, it has a much higher sensitivity than standard biochemical markers. cfDNA appears to be an effective marker of COVID-19 complications, and also serves as a marker of certain underlying health conditions and risk factors of severe illness during COVID-19 infection. We aimed to present the possible mechanisms and sources of cfDNA released during moderate and severe infections. Moreover, we attempt to verify how efficiently cfDNA increase could be applied in COVID-19 risk assessment and how it corresponds with epidemiological data.
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COVID-19/diagnóstico , Ácidos Nucleicos Livres/análise , Ácidos Nucleicos Livres/sangue , SARS-CoV-2/patogenicidade , COVID-19/sangue , COVID-19/complicações , Morte Celular/genética , Feminino , Marcadores Genéticos , Humanos , Gravidez , Gestantes , Medição de Risco , Fatores de RiscoRESUMO
We aimed to summarize the current knowledge about the trends in cfDNA application based on the analysis of clinical trials registered until April 2021. International Clinical Trials Registry Platform (ICTRP) and Clinicaltrials.gov were searched with the keywords: "cf-DNA"; "Circulating DNA"; "Deoxyribonucleic Acid"; and "Cell-Free Deoxyribonucleic Acid". Of 605 clinical trials, we excluded 237 trials, and 368 remaining ones were subject to further analysis. The subject, number of participants, and study design were analyzed. Our scoping review revealed three main trends: oncology (n = 255), non-invasive prenatal diagnostic (n = 48), and organ transplantation (n = 41), and many (n = 22) less common such as sepsis, sport, or autoimmune diseases in 368 clinical trials. Clinical trials are translating theory into clinical care. However, the diagnostic value of cfDNA remains controversial, and diagnostic accuracy still needs to be evaluated. Thus, further studies are necessary until cfDNA turns into a standard in clinical practice.
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Numerous studies have shown that cf nDNA significantly rises in stress caused by exercise. However, during nuclear decondensation, released DNA is followed by histones. Histones are also a common disease marker. After PAD4 mediated hypercitrullination extracellular H3Cit exhibits high toxicity contributing to tissue damage which, in cases of systemic inflammation, may lead to multiorgan failure and finally to death. We tested whether circulating histones rise in response to strenuous exercise. Eleven average-trained men performed three treadmill exercise tests to exhaustion at speed corresponding to 70% VO2max separated by 72 h of resting. Blood was collected before and just after each bout of exercise and plasma proteins were measured using enzyme-linked immunosorbent assay, whereas platelet activity was estimated with Light Transmission Aggregometry. Both, circulating histones and PAD4 raised in response to exercise. Plasma citrullinated histones increased from 3.1 ng/mL to 5.96 ng/mL (p = 0.0059), from 3.65 ng/mL to 6.37 ng/mL (p = 0.02), and from 3.86 ng/mL to 4.75 ng/mL (p = 0.033) after the first, second, and third treadmill run, respectively. However despite the parallel increase, no significant correlation between citrullinated histone and aggregation or cell-free nDNA was found. Furthermore, positive correlations of cf nDNA with aggregation and PAD4, lactate with aggregation, and lactate with citrullinated histone have been observed.
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It is believed that neutrophils extracellular traps (NETs) formation is responsible for the increase in cf DNA after exercise. Since T1DM is accompanied by enhanced NETs generation, we compared exercise-induced increase in cf DNA in 14 men with T1DM and 11 healthy controls and analyzed its association with exercise load. Subjects performed a treadmill run to exhaustion at speed corresponding to 70% of their personal VO2max. Blood was collected before and just after exercise for determination of plasma cf nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) by real-time PCR, blood cell count and metabolic markers. Exercise resulted in the increase in median cf n-DNA from 3.9 ng/mL to 21.0 ng/mL in T1DM group and from 3.3 ng/mL to 28.9 ng/mL in controls. Median exercise-induced increment (∆) in cf n-DNA did not differ significantly in both groups (17.8 ng/mL vs. 22.1 ng/mL, p = 0.23), but this variable correlated with run distance (r = 0.66), Δ neutrophils (r = 0.86), Δ creatinine (r = 0.65) and Δ creatine kinase (r = 0.77) only in controls. Pre- and post-exercise cf mt-DNA were not significantly different within and between groups. These suggest low usefulness of Δ cf n-DNA as a marker of exercise intensity in T1DM men.
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Ácidos Nucleicos Livres/sangue , Diabetes Mellitus Tipo 1/fisiopatologia , Exercício Físico , Adulto , Estudos de Casos e Controles , DNA Mitocondrial/metabolismo , Diabetes Mellitus Tipo 1/sangue , Humanos , MasculinoRESUMO
Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The present study examines the influence on progression-free survival (PFS) and overall survival (OS) by the serum levels of 27 selected cytokines in 61 newly diagnosed MM patients receiving first-line therapy with bortezomib-based regimens. The measurements were performed using a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay and a MAGPIX Multiplex Reader, based on the Bio-Plex® 200 System (Bio-Rad). The following levels were determined: IL-1ß, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1ß, PDGF-BB, RANTES, TNF-α, and VEGF. Most patients received a VCD chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone). In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240-0.8291, p = 0.0302) and ASCT (HR 0.3722, 95% CI: 0.1826-0.7585, p = 0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046-0.438, p = 0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471-9.949, p = 0.0059), and two cytokine levels-IL-1Ra (HR 1.017, 95% CI: 1.004-1.030, p = 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037-0.698, p = 0.0147)-were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Endometriosis is a chronic gynecological disease, affecting up to 10% of reproductive-age women. The exact cause of the disease is unknown; however, it is a heritable condition affected by multiple genetic, epigenetic, and environmental factors. Previous studies reported variations in the epigenetic patterns of numerous genes known to be involved in the aberrant modulation of cell cycle steroidogenesis, abnormal hormonal, immune and inflammatory status in endometriosis, apoptosis, adhesion, angiogenesis, proliferation, immune and inflammatory processes, response to hypoxia, steroidogenic pathway and hormone signaling are involved in the pathogenesis of endometriosis. Accumulating evidence suggest that various epigenetic aberrations may contribute to the pathogenesis of endometriosis. Among them, DNA methyltransferases, histone deacetylators, and non-coding microRNAs demonstrate differential expression within endometriotic lesions and in the endometrium of patients with endometriosis. It has been indicated that the identification of epigenetic differences within the DNA or histone proteins may contribute to the discovery of a useful prognostic biomarker, which could aid in the future earlier detection, timely diagnosis, and initiation of a new approach to the treatment of endometriosis, as well as inform us about the effectiveness of treatment and the stage of the disease. As the etiology of endometriosis is highly complex and still far from being fully elucidated, the presented review focuses on different approaches to identify the genetic and epigenetic links of endometriosis and its pathogenesis.
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The most common histological type of thyroid cancer is papillary thyroid carcinoma (PTC). Radical resection of the thyroid gland is currently the recommended method of treatment. Almost 75% of thyroidectomies performed just for diagnostic purposes are benign. Thus, the confirmation of innovative and more precise noninvasive biomarkers holds promise for the detection of PTC, which may decrease the number of unnecessary thyroid lobectomies. In this work, using the droplet digital PCR (ddPCR) method, we have analyzed the level of five miRNAs (let-7a, let-7c, let-7d, let-7f, and let-7i) in the plasma of patients with PTC and compared them with those of a healthy control group to investigate whether miRNAs also have value in the management of PTC. Levels of four miRNAs, namely let-7a, let-7c, let-7d, and let-7f, were significantly higher in PTC patients than healthy controls. Thus, the analysis of circulating let-7 can be a useful tool and support the currently used methods for PTC diagnosis. However, our observation requires further research on a larger patient group.
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Strenuous exercise increases circulating cell free DNA (cfDNA) and stimulates blood phagocytes to generate reactive oxygen species (ROS) which may induce DNA strand breaks. We tested whether: (A) elevated cfDNA in response to three repeated bouts of exhaustive exercise has decreased integrity; (B) each bout of exercise increases luminol enhanced whole blood chemiluminescence (LBCL) as a measure of ROS production by polymorphonuclear leukocytes. Eleven men performed three treadmill exercise tests to exhaustion separated by 72 hours of resting. Pre- and post-exercise concentrations and integrity of cf nuclear and mitochondrial DNA (cf n-DNA, cf mt-DNA) and resting (r) and fMLP (n-formyl-methionyl-leucyl-phenylalanine)-stimulated LBCL were determined. Each bout increased concentrations of cf n-DNA by more than 10-times which was accompanied by about 2-times elevated post-exercise rLBCL and fMLP-LBCL. Post-exercise cf n-DNA integrity (integrity index, I229/97) decreased after the first (0.59 ± 0.19 vs. 0.48 ± 0.18) and second (0.53 ± 0.14 vs. 0.44 ± 0.17) bout of exercise. There were negative correlations between I229/97 and rLBCL (Æ = -0.37), and I229/97 and fMLP-LBCL (Æ = -0.40) - analysis of pooled pre- and post-exercise data (n = 66). cf mt- DNA integrity (I218/78) did not alter in response to exercise. This suggests an involvement of phagocyte ROS in cf n-DNA strand breaks in response to exhaustive exercise.
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Papillary thyroid cancer is the most common thyroid cancer type. However, diagnostics based on fine needle biopsy cannot make a definitive diagnosis in 25% of thyroid nodules. Additionally, approximately 70% to 80% of thyroid lobectomies performed just for diagnostic purposes are benign. Despite this, biopsy still remains the main method of evaluation of thyroid nodules. Cell-free DNA (cf-DNA) measurement could give a new diagnostic opportunities which may reduce the number of unnecessary thyroid procedures. In this study, using a qPCR, we have examined the nuclear cf-DNA and mitochondrial cf-DNA in the plasma of 32 patients. We have found that the level of nuclear cf-DNA is almost 2-fold increased (median 3 089 vs. 1 872, p = 0.022), whereas mitochondrial cf-DNA content was significantly decreased in respect to healthy controls (median 44 992 vs. 92 220, p = 0.010). The ROC curve analysis showed high specificity for nuclear cf-DNA and mitochondrial cf-DNA, which may serve as a useful tool to decrease the number of unneeded surgeries. Our study reports the first epidemiological evidence for lower mitochondrial cf-DNA content in the patient group, what suggests that apart from nuclear cf-DNA also mitochondrial cf-DNA is affected by disease development.
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DNA Mitocondrial/sangue , DNA/sangue , Câncer Papilífero da Tireoide/sangue , Neoplasias da Glândula Tireoide/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular , Ácidos Nucleicos Livres/sangue , Feminino , Humanos , Linfonodos , Masculino , Pessoa de Meia-Idade , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Adulto JovemRESUMO
Analysis of the problem of surgical pain is important in view of the fact that the success of surgical treatment depends largely on proper pain management during the first few days after a cardiosurgical procedure. Postoperative pain is due to intraoperative damage to tissue. It is acute pain of high intensity proportional to the type of procedure. The pain is most intense during the first 24 hours following the surgery and decreases on subsequent days. Its intensity is higher in younger subjects than elderly and obese patients, and preoperative anxiety is also a factor that increases postoperative pain. Ineffective postoperative analgesic therapy may cause several complications that are dangerous to a patient. Inappropriate postoperative pain management may result in chronic pain, immunosuppression, infections, and less effective wound healing. Understanding and better knowledge of physiological disorders and adverse effects resulting from surgical trauma, anesthesia, and extracorporeal circulation, as well as the development of standards for intensive postoperative care units are critical to the improvement of early treatment outcomes and patient comfort.