The development of immunoassays enables more sophisticated studies of the associations between protein concentrations and pregnancy outcomes, allowing early biomarker identification that can improve neonatal outcomes. The aim of this study was to explore associations between selected mid-trimester amniotic fluid proteins and (1) overall gestational duration and (2) spontaneous preterm delivery. A prospective cohort study, including women undergoing mid-trimester transabdominal genetic amniocentesis, was performed in Gothenburg, Sweden, 2008-2016 (n = 1072). A panel of 27 proteins related to inflammation was analyzed using Meso-Scale multiplex technology. Concentrations were adjusted for gestational age at sampling, experimental factors, year of sampling, and covariates (maternal age at sampling, parity (nulliparous/multiparous), smoking at first prenatal visit, and in vitro fertilization). Cox regression analysis of the entire cohort was performed to explore possible associations between protein concentrations and gestational duration. This was followed by Cox regression analysis censored at 259 days or longer, to investigate whether associations were detectable in women with spontaneous preterm delivery (n = 47). Finally, linear regression models were performed to analyze associations between protein concentrations and gestational duration in women with spontaneous onset of labor at term (n = 784). HMG-1, IGFBP-1, IL-18, MIP-1α, MIP-1β, S100A8, and thrombospondin-1 were significantly associated with gestational duration at term, but not preterm. Increased concentrations of thrombospondin-1, MIP-1β, and S100A8, respectively, were significantly associated with decreased gestational duration after the Holm-Bonferroni correction in women with spontaneous onset of labor at term. This adds to the concept of a pregnancy clock, where our findings suggest that such a clock is also reflected in the amniotic fluid at early mid-trimester, but further research is needed to confirm this.

• Klíčová slova
• Amniotic fluid, Gestational duration, Inflammation, Mid-trimester, Proteins,
• MeSH
• amniocentéza MeSH
• chemokin CCL4 analýza   MeSH
• dospělí MeSH
• gestační stáří MeSH
• kalgranulin A analýza   MeSH
• lidé MeSH
• nástup porodu MeSH
• plodová voda chemie   MeSH
• prospektivní studie MeSH
• těhotenství metabolismus   MeSH
• thrombospondin 1 analýza   MeSH
• trimestry těhotenství * MeSH
• výsledek těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství metabolismus   MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chemokin CCL4 MeSH
• kalgranulin A MeSH
• S100A8 protein, human MeSH Prohlížeč
• thrombospondin 1 MeSH

S100 proteins are currently being investigated as potential diagnostic and prognostic biomarkers of several cancers and inflammatory diseases. The aims of this study were to analyse the plasma levels of S100A4, S100A8/9 and S100A12 in patients with incomplete systemic lupus erythematosus (iSLE), in patients with established SLE and in healthy controls (HCs) and to investigate the potential utility of the S100 proteins as diagnostic or activity-specific biomarkers in SLE. Plasma levels were measured by ELISA in a cross-sectional cohort study of 44 patients with SLE, 8 patients with iSLE and 43 HCs. Disease activity was assessed using the SLEDAI-2K. The mean levels of all S100 proteins were significantly higher in SLE patients compared to HCs. In iSLE patients, the levels of S100A4 and S100A12 but not S100A8/9 were also significantly higher compared to HCs. There were no significant differences in S100 levels between the iSLE and SLE patients. Plasma S100 proteins levels effectively discriminated between SLE patients and HCs. The area under the curve (AUC) for S100A4, S100A8/9 and S100A12 plasma levels was 0.989 (95% CI 0.976-1.000), 0.678 (95% CI 0.563-0.792) and 0.807 (95% CI 0.715-0.899), respectively. S100 levels did not differentiate between patients with high and low disease activity. Only the S100A12 levels were significantly associated with SLEDAI-2K and with cSLEDAI-2K. S100 proteins were significantly higher in SLE patients compared HCs and particularly S100A4 could be proposed as a potential diagnostic biomarker for SLE.

• Klíčová slova
• Biomarkers, Disease activity, S100 proteins, SLE,
• MeSH
• dospělí MeSH
• kalgranulin A krev   MeSH
• kalgranulin B krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• protein S100A12 krev   MeSH
• proteiny S100 krev   MeSH
• průřezové studie MeSH
• S100 kalcium vázající protein A4 krev   MeSH
• studie případů a kontrol MeSH
• systémový lupus erythematodes krev   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• kalgranulin A MeSH
• kalgranulin B MeSH
• protein S100A12 MeSH
• proteiny S100 MeSH
• S100 kalcium vázající protein A4 MeSH
• S100A12 protein, human MeSH Prohlížeč
• S100A4 protein, human MeSH Prohlížeč
• S100A8 protein, human MeSH Prohlížeč
• S100A9 protein, human MeSH Prohlížeč

Toll-like receptor (TLR) agonists demonstrate therapeutic promise as immunological adjuvants for anticancer immunotherapy. To date, three TLR agonists have been approved by US regulatory agencies for use in cancer patients. Additionally, the potential of hitherto experimental TLR ligands to mediate clinically useful immunostimulatory effects has been extensively investigated over the past few years. Here, we summarize recent preclinical and clinical advances in the development of TLR agonists for cancer therapy.

• Klíčová slova
• Ampligen®, Hiltonol®, SD-101, bacillus Calmette-Guérin, imiquimod, motolimod,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Approximately half of patients with rheumatoid arthritis (RA) have normal C-reactive protein (CRP) levels. Calprotectin is a promising and likely more specific biomarker of disease activity than conventionally used acute phase reactants. We aimed to analyse the levels of serum calprotectin in RA patients with clinically active disease and with normal/low CRP. A total of 160 RA patients underwent clinical examination (DAS28-ESR and CDAI). The levels of calprotectin were analysed in patients with moderate to high disease activity with normal/low CRP levels and in 32 healthy subjects. The discriminatory capacity of calprotectin to identify clinically active patients in spite of normal/low CRP was assessed using ROC curves. Out of all RA patients, 74/160 (46.3%) were in remission or had low disease activity according to DAS28 and had normal/low CRP levels. However, 51/160 (32%) had normal/low CRP levels despite having moderate to high disease activity. In these patients, calprotectin levels were significantly higher than those in patients who had normal/low CRP and were in remission or showed low disease activity (2.7 ± 1.5 vs. 2.1 ± 1.2 μg/mL, p = 0.043), which differed from those in healthy subjects (2.7 ± 1.5 vs. 1.9 ± 1.2 μg/mL, p = 0.011). The discriminatory capacity for calprotectin to distinguish clinically active vs. inactive disease despite normal/low CRP using AUC of the DAS28 was 0.607 (95% CI 0.503 to 0.711, p = 0.043). The present study demonstrates that calprotectin may reflect inflammatory activity in RA patients where CRP fails to do so.

• Klíčová slova
• C-reactive protein, Calprotectin, Inflammation, Rheumatoid arthritis,
• MeSH
• biologické markery krev   MeSH
• C-reaktivní protein analýza   MeSH
• krevní sedimentace MeSH
• leukocytární L1-antigenní komplex krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• referenční hodnoty MeSH
• revmatoidní artritida krev   MeSH
• stupeň závažnosti nemoci MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Finsko MeSH
• Názvy látek
• biologické markery MeSH
• C-reaktivní protein MeSH
• leukocytární L1-antigenní komplex MeSH

BACKGROUND: Major abdominal surgery (MAS) is high-risk intervention usually accompanied by tissue injury leading to a release of signaling danger molecules called alarmins. This study evaluates the surgical injury caused by two fundamental types of gastrointestinal surgical procedures (open surgery and laparoscopy) in relation to the inflammation elicited by alarmins. PATIENTS AND METHODS: Patients undergoing MAS were divided into a mixed laparoscopy group (LPS) and an open surgery group (LPT). Serum levels of alarmins (S100A8, S100A12, HMGB1, and HSP70) and biomarkers (leukocytes, C-reactive protein [CRP], and interleukin-6 [IL-6]) were analyzed between the groups. The secondary objectives were to compare LPT and LPS cancer subgroups and to find the relationship between procedure and outcome (intensive care unit length of stay [ICU-LOS] and hospital length of stay [H-LOS]). RESULTS: A total of 82 patients were analyzed. No significant difference was found in alarmin levels between the mixed LPS and LPT groups. IL-6 was higher in the LPS group on day 2 (p=0.03) and day 3 (p=0.04). Significantly higher S100A8 protein levels on day 1 (p=0.02) and day 2 (p=0.01) and higher S100A12 protein levels on day 2 (p=0.03) were obtained in the LPS cancer subgroup. ICU-LOS and H-LOS were longer in the LPS cancer subgroup. CONCLUSION: The degree of surgical injury elicited by open MAS as reflected by alarmins is similar to that of laparoscopic procedures. Nevertheless, an early biomarker of inflammation (IL-6) was higher in the laparoscopy group, suggesting a greater inflammatory response. Moreover, the levels of S100A8 and S100A12 were higher with a longer ICU-LOS and H-LOS in the LPS cancer subgroup.

• Klíčová slova
• alarmins, gastrointestinal surgery, laparoscopy, major surgery, open surgery, surgical injury,
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: Neutrophil extracellular traps (NETs) are formed by activated neutrophils during the process of NETosis in which the nuclear material is released into extracellular space, including DNA molecules, citrullinated histones, and neutrophil granule enzymes, such as elastase. This material forms networks that are able not only to physically entrap bacteria but also to provide elevated concentration of bactericidal components. Over the last years, it has become clear that NETs can also be formed under numerous sterile inflammatory conditions, i.e., thrombosis, cancer, SLE, atherosclerosis, and diabetes. METHOD: We reviewed studies published until July 2016 to find possible associations between elevated cell-free DNA levels in dialyzed patients and the process of NETosis and its consequences. RESULTS: The process of NETosis, its elevated activation, or impaired clearance provides the link between clinical conditions and elevated levels of cell-free DNA found in plasma after the hemodialytic procedure which itself is able to activate neutrophils via platelets and ROS formation. NETs stimulate thrombosis and endothelial damage, and their formation may contribute to the development of spectrum of comorbidities described in dialyzed patients. CONCLUSION: The study of plasma cell-free DNA levels together with markers of NETosis could contribute to the evaluation of the influence of hemodialysis on the immune system of patients.

• Klíčová slova
• Atherosclerosis, Cell-free DNA, Diabetes, Hemodialysis, NETosis, Neutrophil extracellular trap, Thrombosis,
• MeSH
• dialýza ledvin * MeSH
• extracelulární pasti * MeSH
• komorbidita MeSH
• lidé MeSH
• membrány umělé MeSH
• neutrofily MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• membrány umělé MeSH

The mechanisms of immunogenicity underlying mild heat-shock (mHS) treatment < 42°C of tumor cells are largely attributed to the action of heat-shock proteins; however, little is known about the immunogenicity of tumor cells undergoing severe cytotoxic heat-shock treatment (sHS > 43°C). Here, we found that sHS, but not mHS (42°C), induces immunogenic cell death in human cancer cell lines as defined by the induction of ER stress response and ROS generation, cell surface exposure of calreticulin, HSP70 and HSP90, decrease of cell surface CD47, release of ATP and HMGB1. Only sHS-treated tumor cells were efficiently killed and phagocytosed by dendritic cells (DCs), which was partially dependent on cell surface calreticulin. DCs loaded with mHS or sHS-treated tumor cells displayed similar level of maturation and stimulated IFNγ-producing CD8+ T cells without any additional adjuvants in vitro. However, only DCs loaded with sHS-treated tumor cells stimulated antigen-specific CD4+ T cells and induced higher CD8+ T-cell activation and proliferation. sHS-treated murine cells also exposed calreticulin, HSP70 and HSP90 and activated higher DC maturation than mHS treated cells. Vaccination with sHS-treated tumor cells elicited protective immunity in mice. In this study, we defined specific conditions for the sHS treatment of human lung and ovarian tumor cells to arrive at optimal ratio between effective cell death, immunogenicity and content of tumor antigens for immunotherapeutic vaccine generation.

• Klíčová slova
• Antitumor immunity, calreticulin, cancer immunotherapy, dendritic cells, heat-shock treatment, hyperthermia, immunogenic cell death,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs). The emission of DAMPs and other immunostimulatory factors by cells succumbing to immunogenic cell death (ICD) favors the establishment of a productive interface with the immune system. This results in the elicitation of tumor-targeting immune responses associated with the elimination of residual, treatment-resistant cancer cells, as well as with the establishment of immunological memory. Although ICD has been characterized with increased precision since its discovery, several questions remain to be addressed. Here, we summarize and tabulate the main molecular, immunological, preclinical, and clinical aspects of ICD, in an attempt to capture the essence of this phenomenon, and identify future challenges for this rapidly expanding field of investigation.

• Klíčová slova
• anti-tumor immunity, immunogenicity, immunotherapy, molecular medicine, oncoimmunology, patient prognosis, translational medicine,
• Publikační typ
• časopisecké články MeSH

The concept of immunogenic cancer cell death (ICD), as originally observed during the treatment with several chemotherapeutics or ionizing irradiation, has revolutionized the view on the development of new anticancer therapies. ICD is defined by endoplasmic reticulum (ER) stress response, reactive oxygen species (ROS) generation, emission of danger-associated molecular patterns and induction of antitumor immunity. Here we describe known and emerging cancer cell death-inducing physical modalities, such as ionizing irradiation, ultraviolet C light, Photodynamic Therapy (PDT) with Hypericin, high hydrostatic pressure (HHP) and hyperthermia (HT), which have been shown to elicit effective antitumor immunity. We discuss the evidence of ICD induced by these modalities in cancer patients together with their applicability in immunotherapeutic protocols and anticancer vaccine development.

• Klíčová slova
• ATP, Adenosine triphosphate, CRT, calreticulin, DAMPs, danger-associated molecular patterns, DC, dendritic cells, EGFR, endothelial growth factor receptor, ER, endoplasmic reticulum, HHP, high hydrostatic pressure, HMGB1, high-mobility group box 1, HSP, heat shock protein, HT, hyperthermia, Hyp-PDT, Hypericin-based Photodynamic therapy, ICD, immunogenic cell death, IFNγ, interferon-γ, NDV, Newcastle Disease Virus, ROS, reactive oxygen species, RT, radiotherapy, TLR, Toll-like receptor, UVC, ultraviolet C light, cancer immunotherapy, eIF2α, eukaryotic translation initiation factor 2α, high hydrostatic pressure, hyperthermia, immunogenic cell death, ionizing irradiation, photodynamic therapy with hypericin,
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

INTRODUCTION: The aim of this study was to examine the serum levels of S100 proteins and to evaluate their role in patients with recent-onset rheumatoid arthritis (RA). METHODS: Serum levels of S100A8/9 and S100A12 were analysed in 43 patients with recent-onset RA, both before and three months after the initiation of conventional treatment, as well as in 32 healthy individuals. Disease activity was assessed based on serum levels of C-reactive protein (CRP), the Disease Activity Score for 28 joints (DAS28) and the total number of swollen joints count for 66 joints (SJC). RESULTS: The levels of serum S100A8/9 and S100A12 were significantly higher in patients with recent-onset RA compared to the levels in healthy individuals (P < 0.0001) and normalised after three months of treatment. Using age- and sex-adjusted analysis, S100A8/9 levels were correlated with CRP (r = 0.439, P < 0.01), DAS28 (r = 0.501, P = 0.002) and SJC (r = 0.443, P = 0.007), while S100A12 was less significantly correlated with these parameters. Higher levels of S100A8/9 at baseline predicted improvement in the levels of CRP and SJC over time. Moreover, decreases in serum S100A8/9 were associated with decreased serum levels of CRP (r = 0.459, P = 0.005) and improvements in SJC (r = 0.459, P = 0.005). In multiple linear regression analyses, decreases in S100A8/9 but not CRP were significant predictors for improvements in SJC (P = 0.001). CONCLUSIONS: This study is the first to show normalisation of elevated S100 proteins in patients with recent-onset RA after the initiation of conventional treatment. Therefore, S100A8/9 might potentially be a predictive marker for improvement in the total number of swollen joints in patients in the early phase of RA.

• MeSH
• antirevmatika terapeutické užití   MeSH
• biologické markery krev   MeSH
• ELISA MeSH
• kalgranulin A krev   MeSH
• kalgranulin B krev   MeSH
• klouby patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• revmatoidní artritida krev   farmakoterapie   patologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antirevmatika MeSH
• biologické markery MeSH
• kalgranulin A MeSH
• kalgranulin B MeSH