The combination of JAK/STAT and HDAC inhibitors exerted beneficial effects in haematological malignancies, presenting promising therapeutic CTCL targets. We aim to investigate the efficacy of JAK1/2i ...ruxolitinib in combination with HDACi resminostat in CTCL in vitro.
Non-toxic concentrations of ruxolitinib and/or resminostat were administered to MyLa (MF) and SeAx (SS) cells for 24h. Cytotoxicity, cell proliferation and apoptosis were estimated through MTT, BrdU/7AAD and Annexin V/PI assay. Multi-pathway analysis was performed to investigate the effect of JAK1/2i and/or HDACi on JAK/STAT, Akt/mTOR and MAPK signalling pathways.
Both drugs and their combination were cytotoxic in MyLa (p<0.05) and in SeAx cell line (p<0.001), inhibited proliferation of MyLa (p<0.001) and SeAx (p<0.001) at 24h, compared to untreated cells. Moreover, combined drug treatment induced apoptosis after 24h (p<0.001) in MyLa, and SeAx (p<0.001). The combination of drugs had a strong synergistic effect with a CI<1. Importantly, the drugs' combination inhibited phosphorylation of STAT3 (p<0.001), Akt (p<0.05), ERK1/2 (p<0.001) and JNK (p<0.001) in MyLa, while it reduced activation of Akt (p<0.05) and JNK (p<0.001) in SeAx.
The JAKi/HDACi combination exhibited substantial anti-tumor effects in CTCL cell lines, and may represent a promising novel therapeutic modality for CTCL patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Increasing evidence foresees the
of neural stem cells (NSCs) to confer superimposable beneficial properties as exogenous NSC transplants in experimental treatments of traumas and diseases of the ...central nervous system (CNS). Naturally produced
biologics include membrane-free signaling molecules and extracellular membrane vesicles (EVs) capable of regulating broad functional responses. The development of high-throughput screening pipelines for the identification and validation of NSC
targets is still in early development. Encouraging results from pre-clinical animal models of disease have highlighted
-based (acellular) therapeutics as providing significant improvements in biochemical and behavioral measurements. Most of these responses are being hypothesized to be the result of modulating and promoting the restoration of key inflammatory and regenerative programs in the CNS. Here, we will review the most recent findings regarding the identification of NSC-secreted factors capable of modulating the immune response to promote the regeneration of the CNS in animal models of CNS trauma and inflammatory disease and discuss the increased interest to refine the pro-regenerative features of the NSC
into a clinically available therapy in the emerging field of Regenerative Neuroimmunology.
MicroRNAs (miRNAs) represent a class of small non-coding RNAs bearing regulatory potency. The implication of miRNAs in physiological cellular processes has been well documented so far. A typical ...process orchestrated by miRNAs is the normal B-cell development. A stage-specific expression pattern of miRNAs has been reported in the developmental procedure, as well as interactions with transcription factors that dictate B-cell development. Besides their involvement in normal hematopoiesis, miRNAs are severally implicated in hematological malignancies, a typical paradigm of which is B-cell chronic lymphocytic leukemia (B-CLL). B-CLL is a highly heterogeneous disease characterized by the accumulation of abnormal B cells in blood, bone marrow, lymph nodes, and spleen. Therefore, timely, specific, and sensitive assessment of the malignancy is vital. Several studies have attempted to highlight the remarkable significance of miRNAs as regulators of gene expression, biomarkers for diagnosis, prognosis, progression, and therapy response prediction, as well as molecules with potential therapeutic utility. This review seeks to outline the linkage between miRNA function in normal and malignant hematopoiesis by demonstrating the main benchmarks of the implication of miRNAs in the regulation of normal B-cell development, and to summarize the key findings about their value as regulators, biomarkers, or therapeutic targets in B-CLL.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Chronic neutrophilic leukemia (CNL) represents a rare disease, that has been classified among the BCR/ABL-negative myeloproliferative neoplasms. The disease is characterized by marked leukocytosis ...with absolute neutrophilia and its clinical presentation may vary from asymptomatic to highly symptomatic with massive splenomegaly and constitutional symptoms. CNL prognosis remains relatively poor, as most patients succumb to disease complications or transform to acute myeloid leukemia. Recent studies have demonstrated that
mutations drive the disease, albeit the presence of other secondary mutations perplex the genetic landscape of the disease. Notably, the presence of
mutations has been adopted as a criterion for diagnosis of CNL. Despite the vigorous research, the management of the disease remains suboptimal. Allogeneic stem cell transplantation represents the only treatment that could lead to cure; however, it is accompanied by high rates of treatment-related mortality. Recently, ruxolitinib has shown significant responses in patients with CNL; however, emergence of resistance might perturbate long-term management of the disease. The aim of this review is to summarize the clinical course and laboratory findings of CNL, highlight its pathogenesis and complex genetic landscape, and provide the context for the appropriate management of patients with CNL.
Unraveling the pathophysiology of COVID-19 disease is of crucial importance for designing treatment. The purpose of this study is to investigate the effects of the disease on erythrocytes (RBCs) and ...to correlate the findings with disease severity.
Hospitalized patients (
= 36) with COVID-19 and control group of healthy volunteers (
= 18) were included in the study. Demographic data, clinical, laboratory and chest Computed Tomography (CT) findings at time of admission were recorded. Laboratory measurements included: Hemoglobin (H b), indirect billirubin, LDH, D-Dimers, and plasma free hemoglobin (plasma free-Hb). On RBCs were performed: osmotic fragility (MCF), Free-Hb after mechanical stress (Free-Hb-MECH), intracellular RBC concentration of calcium ions (iCa
), intracellular ROS (iROS), G6PD, intracellular active caspase-3 (RBC-caspase-3), IgG immunoglobulins (RBC-IgGs), which are bound on RBCs' senescent neo-antigen proteins and RBC surface phosphatidylserine (RBC-PS).
The percentage of males was 50 and 66% and the mean age was 65.16 ± 14.24 and 66.33 ± 13.48 years among patients and controls respectively (mean ± SD,
= 0.78). Upon admission patients' PO
/FiO
ratio was 305.92 ± 76.75 and distribution of infiltration extend on chest CT was: 0-25% (
= 19), 25-50%: (
= 7), and 50-75% (
= 9). Elevated hemolysis markers (LDH and plasma free-Hb) were observed in patients compared to the control group. Patients' RBCs were more sensitive to mechanical stress, and exhibited significantly elevated apoptotic markers (iCa
, RBC-PS). Plasma free Hb levels correlated with the extend of pulmonary infiltrates on chest CT in COVID-19 patients. Surprisingly, patients' RBC-iROS were decreased, a finding possibly related with the increased G6PDH levels in this group, suggesting a possible compensatory mechanism against the virus. This compensatory mechanism seemed to be attenuated as pulmonary infiltrates on chest CT deteriorated. Furthermore, RBC-IgGs correlated with the severity of pulmonary CT imaging features as well as the abnormality of lung function, which are both associated with increased disease severity. Lastly, patients' D-Dimers correlated with RBC surface phosphatidylserine, implying a possible contribution of the red blood cells in the thrombotic diathesis associated with the SARS-CoV-2 disease.
This pilot study suggests that SARS-CoV-2 infection has an effect on red blood cells and there seems to be an association between RBC markers and disease severity in these patients.
In-depth understanding of the immune response provoked by SARS-CoV-2 infection is necessary, as there is a great risk of reinfection and a difficulty in achieving herd immunity due to a decline in ...both antibody concentration and avidity. Avidity testing, however, could overcome variability in the immune response associated with sex or clinical symptoms, and thus differentiate between recent and past infections. In this context, here, we analyzed SARS-CoV-2 antibody kinetics and avidity in Greek hospitalized (26%) and non-hospitalized (74%) COVID-19 patients (N = 71) in the course of up to 15 months after their infection to improve the accuracy of the serological diagnosis in dating the onset of the infection. The results showed that IgG-S1 levels decline significantly at four months (p = 0.0239) in both groups of patients and are higher in hospitalized ones (up to 2.1-fold, p < 0.001). Additionally, hospitalized patients’ titers drop greatly and are equalized to non-hospitalized ones only at a time-point of twelve to fifteen months. Antibody levels of women in total remain more stable months after infection, compared to men. Furthermore, we examined the differential maturation of IgG avidity after SARS-CoV-2 infection, showing an incomplete maturation of avidity that results in a plateau at four months after infection. We also defined 38.2% avidity (sensitivity: 58.9%, specificity: 90.91%) as an appropriate “cut-off” that could be used to determine the stage of infection before avidity reaches a plateau.
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Various agents are currently under evaluation as potential treatments in the fight against coronavirus disease 2019 (COVID‐19). Plasma from patients that have overcome COVID‐19 infection, referred to ...as convalescent plasma, is a treatment option with considerable background in viral diseases such as Spanish influenza, H1N1, Ebola, Severe Acute Respiratory Syndrome (SARS), and Middle East Respiratory Syndrome (MERS). Although convalescent plasma has historically proven beneficial in the treatment of some viral diseases, its use is still explorative in the context of COVID‐19. To date, preliminary evidence from case series is favorable as significant clinical, biochemical improvement and hospital discharge have been reported. A detailed overview of randomized as well non‐randomized trials of treatment with convalescent plasma, which have been registered worldwide, is provided in this review. Based on these studies, data from thousands of patients is anticipated in the near future. Convalescent plasma seems to be a safe option, but potential risks such as transfusion‐related acute lung injury and antibody‐dependent enhancement are discussed. Authorities including the Food and Drug Administration (FDA), and scientific associations such as the International Society of Blood Transfusion (ISBT) and the European Blood Alliance (EBA), have provided guidance into the selection criteria for donors and recipients. A debatable, pivotal issue pertains to the optimal timing of convalescent plasma transfusion. This treatment should be administered as early as possible to maximize efficacy, but at the same time be reserved for severe cases. Emerging risk stratification algorithms integrating clinical and biochemical markers to trace the cases at risk of significant deterioration can prove valuable in this direction.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The combination of Resminostat (HDACi) and Ruxolitinib (JAKi) exerted cytotoxic effects and inhibited proliferation of CTCL cell lines (MyLa, SeAx) in previously published work. A xenograft tumor ...formation was produced by implanting the MyLa or SeAx cells on top of the chick embryo chorioallantoic membrane (CAM). The CAM assay protocol was developed to monitor the metastatic properties of CTCL cells and the effects of Resminostat and/or Ruxolitinib in vivo. In the spontaneous CAM assays, Resminostat and Ruxolitinib treatment inhibited the cell proliferation (
< 0.001) of MyLa and SeAx, and induced cell apoptosis (
< 0.005,
< 0.001, respectively). Although monotherapies reduced the size of primary tumors in the metastasis CAM assay, the drug combination exhibited a significant inhibition of primary tumor size (
< 0.0001). Furthermore, the combined treatment inhibited the intravasation of MyLa (
< 0.005) and SeAx cells (
< 0.0001) in the organs, as well as their extravasation to the liver (
< 0.0001) and lung (
< 0.0001). The drug combination also exerted a stronger inhibitory effect in migration (
< 0.0001) rather in invasion (
< 0.005) of both MyLa and SeAx cells. It further reduced p-p38, p-ERK, p-AKT, and p-STAT in MyLa cells, while it decreased p-ERK and p-STAT in SeAx cells in CAM tumors. Our data demonstrated that the CAM assay could be employed as a preclinical in vivo model in CTCL for pharmacological testing. In agreement with previous in vitro data, the combination of Resminostat and Ruxolitinib was shown to exert antitumor effects in CTCL in vivo.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Introduction
Patients who undergo coronary angiography experience a rather stressful situation. They need information about this invasive procedure which most of the times find either from the ...internet, their referring physicians, acquaintances or friends with past experience of an invasive procedure.
Aim
The aim of the study was on the one hand to test the potential beneficial effects of an information brochure on undergoing a cardiac catheterization for the first time and on the other hand to highlight the importance of informing patients before coronary angiography and its beneficial effects on both reducing their fear and anxiety.
Methods
Patients were randomly assigned to an experimental group receiving the brochure at least 1 day before the cardiac catheterization (N = 44), or to a control group not receiving the brochure (N = 44). The SFQ, ISQ and STAI tools were distributed to both groups.
Results
All experimental subjects in the intervention group read the brochure. The intervention group had significantly lower scores on both short-term and overall fear compared to the control group. However, the fear of the long-term consequences of cardiac catheterization was similar in both groups. Women had higher fear of the short-term consequences of catheterization than men. The control group experienced a mean satisfaction score of 10.9 points (SD= 2.5 points) while the intervention group had a score of 11.1 points respectively (SD= 2.3 points). In addition, 95, 5% of the control group and 88, 6% of the intervention group patients considered that the provision of information could have been improved. In terms of stress, patients with co-morbidities scored 7.39 points higher, meaning they experienced more symptoms of permanent anxiety, compared to patients who did not have an underlying disease. In addition, the more the patients were satisfied with the information provided, the fewer the symptoms of transient anxiety they experienced.
Conclusions
Providing information in the form of a brochure regarding cardiac catheterization before the procedure, is of great importance and constitutes an efficient intervention.
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