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IntroductionMixed-phenotype acute leukemia (MPAL) is a rare disease with poor prognosis. So far, no standard approach has been established as the “know-how” of MPAL is based only on retrospective analyses performed on small groups of patients.Materials and methodsIn this study, a retrospective analysis of the outcomes of adult MPAL patients included in the PALG registry between 2005 and 2024 who received the CLAG-M hybrid protocol as induction or salvage therapy was performed.ResultsSixteen of 98 MPAL patients received CLAG-M: eight as first-line and eight as salvage therapy. In the first line, two patients achieved partial response (PR), and six achieved complete remission (CR), of whom four successfully underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). Two patients who did not undergo alloHSCT promptly relapsed. Within the whole group, the overall response rate (ORR) was 75% (n = 12/16). With the median follow-up of 13 months, six out of eight patients remain in CR, however, two of them died due to acute graft versus host disease. Out of eight patients who received CLAG-M in the second line, four patients (50%) obtained CR. AlloHSCT was conducted in seven cases, six of which were in CR. Only two patients remained in CR at the time of the last follow-up. Tolerance to treatment was good. The median times for severe neutropenia and thrombocytopenia were 22 days (range, 16–24) and 17 days (range, 12–24), respectively. Overall, grade 3-4 infections were observed in 12 cases, and all infections presented successful outcomes.ConclusionsCLAG-M is an effective first-line salvage regimen for MPAL with an acceptable safety profile. Early achievement of CR with prompt alloHSCT allows for satisfactory disease control.

In this paper, issues related to the technology of compound castings composed of two parts, i.e., the working layer and the supporting part, made of X46Cr13 high-chromium steel and EN-GJL-HB 255 grey cast iron, respectively, in a liquid–solid system by pre-installing a monolithic insert in the mould cavity are presented. As a part of the research, the mechanism of formation of transitional zones in the bonding area of the above-mentioned two alloys was identified and described. It was shown that the phenomenon that determines the formation of a permanent bond between the joined materials is the transport of C and heat from the “high-carbon and hot” material of the supporting part poured into the mould in the form of liquid cast iron to the “low-carbon and cold” material of the working layer placed in the form of a steel monolithic insert inside the mould cavity. In the paper, the suitability of the compound castings technology developed for use in the coke industry is also presented. Full-size high-chromium steel–grey cast iron compound casting plates designed for the coke quenching car lining were positively verified in real coke plant operating conditions.

This paper presents the results of research conducted in the field of the technology of surface hardening of castings from unalloyed and low-alloy nodular cast iron using the laser remelting method. The range of studies included macro- and microhardness measurements using Rockwell and Vickers methods as well as metallographic microscopic examinations using a scanning electron microscope. Moreover, abrasive wear resistance tests were performed using the pin-on-disk method in the friction pair of nodular cast iron—SiC abrasive paper and the reciprocating method in the friction pair of nodular cast iron—unalloyed steel. Analysis of the test results shows that the casting surface layer remelting by laser for unalloyed nodular cast iron results in a greater improvement in its resistance to abrasive wear in the metal–mineral system, as compared to low-alloy cast iron. Additionally, carrying out the laser hardening treatment of the surface layer made of the tested grades of nodular cast iron is justified only if the tribological system of the cooperating working parts and allowable dimensional changes during their operation are known.

Transplantation of hematopoietic stem cells (HSCT) is a procedure commonly used in treatment of various haematological disorders which is associated with significantly improved survival rates. However, one of its drawbacks is the possibility of development of post-transplant complications, including acute and chronic graft-versus-host disease (GvHD) or CMV infection. Various studies suggested that NK cells and their receptors may affect the transplant outcome. In the present study, patients and donors were found to significantly differ in the distribution of the NKG2A rs7301582 genetic variants – recipients carried the C allele more often than their donors (0.975 vs 0.865, p

The classical BCR::ABL1-negative myeloproliferative neoplasms such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal diseases with the presence of characteristic “driver mutations” in one of the genes: JAK2, CALR, or MPL. The search for mutations in these three genes is required for the diagnosis of MPNs. Nevertheless, the progress that has been made in the field of molecular genetics has opened a new era in medicine. The search for additional mutations in MPNs is helpful in assessing the risk stratification, disease progression, transformation to acute myeloid leukemia (AML), or choosing the right treatment. In some cases, advanced technologies are needed to find a clonal marker of the disease and establish a diagnosis. This review focuses on how the use of new technologies like next-generation sequencing (NGS) helps in the diagnosis of BCR::ABL1-negative myeloproliferative neoplasms.

Abstract Objective To investigate the prevalence of histopathological subtypes, the clinical stage at presentation and treatment modalities in Polish patients with orbital lymphoma (OL) and to determine prognostic outcomes. Methods The retrospective study of 107 patients with OL treated in a 14‐year period in Polish hematological centers. The analysis included histopathological subtype, disease clinical advancement, treatment modalities, progression‐free survival (PFS), and overall survival (OS). Results The median patient age was 60 years (range 51–71). Mucosa‐associated lymphoid tissue (MALT) lymphoma accounted for slightly more than half of all cases of orbital lymphoma (51%). The second most common subtype was diffuse large B‐cell lymphoma (DLBCL) (29%). Primary orbital lymphoma was diagnosed in 48% of all patients. According to the Ann Arbor, localized stage IE of orbital lymphoma was diagnosed only in 39% of all patients. Systemic involvement was observed in more than half of all patients (52%). The median follow‐up period was 30 months (range 0–160 months). Patients with non‐MALT lymphoma had a significantly inferior PFS compared to patients with MALT lymphoma, (p = 0.047). Patients with primary orbital lymphoma had a superior PFS compared to patients with secondary orbital lymphoma [median PFS 104.5 months vs. 33.4 months], (p = 0.069). Younger patients with MALT lymphoma were characterized by superior PFS (median PFS not reached) compared to other studied subgroups of patients (older patients with MALT lymphoma, younger and older non‐MALT lymphoma patients) with a median PFS of 30.5, 32.2, 32.6 months respectively (p = 0.039). Patients treated with chemotherapy alone had inferior PFS compared to patients treated with combined therapies (p = 0.034). The median PFS across patients who received chemotherapy alone was 23.7 months, whereas across other patients was 73.9 months. Conclusions Secondary lymphoma accounts for more than half of the orbital lymphoma in Polish population. The advanced clinical stage of the disease (non‐IE according to Ann Arbor) concerns two‐thirds of the overall population of patients with orbital lymphomas and one‐third of MALT lymphoma patients. The high incidence of advanced stages of orbital lymphoma may indicate the need for combined treatment. Combined orbital lymphoma treatment is associated with superior PFS compared to chemotherapy alone in overall population of patients with orbital lymphoma.

Abstract Background Metformin is an inhibitor of oxidative phosphorylation that displays an array of anticancer activities. The interference of metformin with the activity of multi-drug resistance systems in cancer cells has been reported. However, the consequences of the acquired chemoresistance for the adaptative responses of cancer cells to metformin-induced stress and for their phenotypic evolution remain unaddressed. Methods Using a range of phenotypic and metabolic assays, we assessed the sensitivity of human prostate cancer PC-3 and DU145 cells, and their drug-resistant lineages (PC-3_DCX20 and DU145_DCX20), to combined docetaxel/metformin stress. Their adaptation responses have been assessed, in particular the shifts in their metabolic profile and invasiveness. Results Metformin increased the sensitivity of PC-3 wild-type (WT) cells to docetaxel, as illustrated by the attenuation of their motility, proliferation, and viability after the combined drug application. These effects correlated with the accumulation of energy carriers (NAD(P)H and ATP) and with the inactivation of ABC drug transporters in docetaxel/metformin-treated PC-3 WT cells. Both PC-3 WT and PC-3_DCX20 reacted to metformin with the Warburg effect; however, PC-3_DCX20 cells were considerably less susceptible to the cytostatic/misbalancing effects of metformin. Concomitantly, an epithelial–mesenchymal transition and Cx43 upregulation was seen in these cells, but not in other more docetaxel/metformin-sensitive DU145_DCX20 populations. Stronger cytostatic effects of the combined fenofibrate/docetaxel treatment confirmed that the fine-tuning of the balance between energy supply and expenditure determines cellular welfare under metabolic stress. Conclusions Collectively, our data identify the mechanisms that underlie the limited potential of metformin for the chemotherapy of drug-resistant tumors. Metformin can enhance the sensitivity of cancer cells to chemotherapy by inducing their metabolic decoupling/imbalance. However, the acquired chemoresistance of cancer cells impairs this effect, facilitates cellular adaptation to metabolic stress, and prompts the invasive front formation.

Abstract Background Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

The aim of this study was to obtain micropropagation protocol for fibrous, Cannabidiol (CBD) rich, hemp variety Epsilon 68. To fulfil this goal, nodal and tip cutting protocol was developed. In further step, this protocol was compared with several other methods dependent on plant growth regulators with cytokine activity to obtain 4.2 ± 1.43 SD explants per tip. Plants from isolated lines were acclimatized to field conditions, and the content of cannabinoids was evaluated in the inflorescences. Described micropropagation protocol may be useful in breeding of hemp varieties and germplasm conservation.

Abstract Background Acute lymphoblastic leukemia is the most common type of cancer in children. Most often it affects the age group between 2 and 5 years of age. Studies have shown an improvement in general survivability, more than 90% 5-year overall survival (OS). Current treatment protocols for acute lymphoblastic leukemia require verification of the presence of favorable and unfavorable genetic abnormalities, which help qualify patients to the appropriate risk group and select a more suitable treatment. The presence of the BCR/ABL1 fusion gene stratifies the patient into a high-risk group and requires special treatment with tyrosine kinase inhibitors (TKI). The three dominant mRNA transcripts are e1a2, e13a2, and e14a2. Nevertheless, cases of atypical BCR/ABL1 transcripts have also been reported. Case presentation This paper presents the case of a pediatric patient with Ph + B-cell precursor acute lymphoblastic leukemia with rare atypical e8a2 BCR/ABL1 fusion transcript. Our patient achieved complete remission after 33 days of treatment. Molecular and cytogenetic studies in TP1 did not reveal the presence of the BCR/ABL1 transcript. The PCR-MRD test in TP1b was negative, the patient did not require hematopoietic stem cell transplantation. Conclusion Genetic evaluation of the bone marrow sample is crucial in the initial stage of the diagnosis. Fluorescent in situ hybridization and reverse transcriptase polymerase chain reaction with Sanger sequencing are the appropriate methods used in the detection of rare variants of BCR/ABL1 transcripts.

Myeloproliferative neoplasms (MPNs) are a group of hematologic disorders characterized by clonal proliferation of myeloid lineage cells. The diagnostic criteria are based on morphological features of bone marrow and peripheral blood cells but also include specific genomic mutations. In some patients, co-occurrence of hematologic and rheumatic diseases could be observed. To date, most of the reported cases concerned patients with myelodysplastic syndrome (MDS) or essential thrombocythemia (ET). In this paper, we present a case of a patient with a complicated diagnostic process leading to the diagnosis of unclassified MPN and giant cell arteritis (GCA). Routine tests did not reveal any mutations typical for MPNs such as JAK-2, CALR, MPL or BCR-ABL. Targeted next-generation sequencing (NGS) helped to confirm the diagnosis by demonstrating the presence of heterozygous ASXL1, TET2, SRSF2, and CBL mutations. The second important issue was the overlapping of symptoms of MPN and seronegative rheumatic disease, which finally was diagnosed as GCA. Leukocytosis and musculoskeletal pain, which were present at the time of diagnosis, resolved after allogeneic hematopoietic stem cell transplantation but recurred after a few months along with decreasing donor cell chimerism. Differentiation of the causes of recurrence of the symptoms was an important issue. This case shows the diagnostic challenge posed by co-incidence of MPN and rheumatic disease, especially its atypical variants.

Myelodysplastic syndromes (MDSs) belong to a group of clonal bone marrow malignancies. In light of the emergence of new molecules, a significant contribution to the understanding of the pathogenesis of the disease is the study of the B-cell CLL/lymphoma 2 (BCL-2) and the programmed cell death receptor 1 (PD-1) protein and its ligands. BCL-2-family proteins are involved in the regulation of the intrinsic apoptosis pathway. Disruptions in their interactions promote the progression and resistance of MDSs. They have become an important target for specific drugs. Bone marrow cytoarchitecture may prove to be a predictor of response to its use. The challenge is the observed resistance to venetoclax, for which the MCL-1 protein may be largely responsible. Molecules with the potential to break the associated resistance include S63845, S64315, chidamide and arsenic trioxide (ATO). Despite promising in vitro studies, the role of PD-1/PD-L1 pathway inhibitors has not yet been established. Knockdown of the PD-L1 gene in preclinical studies was associated with increased levels of BCL-2 and MCL-1 in lymphocytes T, which could increase their survival and promote tumor apoptosis. A trial (NCT03969446) is currently underway to combine inhibitors from both groups.

The article presents the results of research on the properties of molding sands in Alphaset technology (alkaline-phenolic). These sands are often used in steel foundries, producing large castings. However, knowledge about them, and especially about the changeability of their properties with the change of environmental conditions (seasons), is still insufficient. Various compositions of molding sand were analyzed based on fresh chromite sand and reclaimed sand. A binder and hardener in various mass ratios were used to prepare the mass. The research methodology included, among others, tests of tensile and bending strength, permeability, abrasion, gas emissivity, and ignition losses. These tests were carried out for summer and winter conditions. The results showed the optimal proportions of resin and hardener, showed the influence of ambient temperature on the properties of the molding sand, and the possible ratio of reclaimed sand in relation to fresh sand. However, you should always remember to verify them under the conditions of a specific foundry.

We aimed to identify miRNAs and pathways specifically deregulated in adolescent and young adult (AYA) T-ALL patients. Small RNA-seq showed no major differences between AYA and pediatric T-ALL, but it revealed downregulation of miR-143-3p in T-ALL patients. Prediction algorithms identified several known and putative oncogenes targeted by this miRNA, including KRAS, FGF1, and FGF9. Pathway analysis indicated signaling pathways related to cell growth and proliferation, including FGFR signaling and PI3K-AKT signaling, with the majority of genes overrepresented in these pathways being predicted targets of hsa-miR-143-3p. By luciferase reporter assays, we validated direct interactions of this miRNA with KRAS, FGF1 and FGF9. In cell proliferation assays, we showed reduction of cell growth upon miR-143-3p overexpression in two T-ALL cell lines. Our study is the first description of the miRNA transcriptome in AYA T-ALL patients and the first report on tumor suppressor potential of miR-143-3p in T-ALL. Downregulation of this miRNA in T-ALL patients might contribute to enhanced growth and viability of leukemic cells. We also discuss the potential role of miR-143-3p in FGFR signaling. Although this requires more extensive validation, it might be an interesting direction, since FGFR inhibition proved promising in preclinical studies in various cancers.

Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) are major elements of the innate immune system that recognize pathogen-associated molecular patterns. Single-nucleotide polymorphisms (SNPs) in the TLR, NLR, and RLR genes may lead to an imbalance in the production of pro- and anti-inflammatory cytokines, changes in susceptibility to infections, the development of diseases, and carcinogenesis. Acute myeloid leukemia (AML) is a bone marrow malignancy characterized by uncontrolled proliferation of transformed myeloid precursors. We retrospectively analyzed 90 AML patients. We investigated the effect of fifteen SNPs located in the genes coding for RLR1 (rs9695310, rs10738889, rs10813831), NOD1 (rs2075820, rs6958571), NOD2 (rs2066845, rs2066847, rs2066844), TLR3 (rs5743305, rs3775296, 3775291), TLR4 (rs4986791, rs4986790), and TLR9 (rs187084, rs5743836). We observed that TLR4 rs4986791, TLR9 rs5743836, and NOD2 rs2066847 were associated with CRP levels, while RLR-1 rs10738889 was associated with LDH level. Furthermore, we found TLR3 rs5743305 AA to be more common in patients with infections. We also found TLR9 rs187084 C to be associated with more favorable risk, and RLR-1 rs9695310 GG with higher age at diagnosis. In conclusion, the current study showed that SNPs in the genes encoding TLRs, NLRs, and RLRs may be potential biomarkers in patients with AML.

The role of immune dysregulation in the course and prognosis of COVID-19 is not clearly established. In particular, immune status in specific populations such as haematological patients, who have an impaired immunological system, has not been described so far. Here, we performed a comprehensive analysis of peripheral blood lymphocyte subsets in 27 SARS-CoV-2-infected patients, including 16 patients with haematological malignancies. We identified T cell subpopulations, B cells, NK cells and TCR α/ß and ɣ/ƍ-expressing T cells during COVID-19 infection, with significant changes observed in immune profiles during the course of disease, especially in haematological patients. We observed an increase in activated T lymphocytes (CD3+HLA-DR+ and CD3+CD8+HLA-DR+) in the early stages of SARS-CoV-2 infection with a concomitant decrease in the CD4/CD8 ratio in haematological patients compared to non-haematological patients affected by COVID-19. We also found a decrease in ɣ/ƍ T cells in both studied groups of patients, with lower numbers of CD25+ T cells and CD16+CD56+ NK cells in haematological patients compared to non-haematological patients with COVID-19. Our findings demonstrate, for the first time, impaired adaptive immunity in patients with haematological malignancies infected with COVID-19, resulting in impaired cellular immune responses to SARS-CoV-2. This warrants further investigation of this disease group in COVID-19 patient cohorts

Background. Platelet reactivity and response to antiplatelet drugs, acetylsalicylic acid (ASA) and clopidogrel, in patients with thrombocytopenia and thrombocythemia can have a potentially important effect on the outcome. The effectiveness and safety of antiplatelet drugs in such patients has not been well examined. Measuring the effect of ASA and clopidogrel on platelets could help guide the therapy. Nevertheless, platelet response to antiplatelet drugs is not routinely measured in platelet count disorders and relevant evidence is scarce. Aims. The study aimed to measure platelet reactivity and response to ASA and clopidogrel in patients with platelet count disorders. Materials and Methods. This was a cross-sectional study of consecutive patients hospitalized in cardiology and hematology departments in the years 2018–2019. The study included patients with thrombocytopenia (PLT 450 G/L) on ASA or dual antiplatelet therapy (DAPT; ASA plus clopidogrel). Controls included patients on antiplatelet drugs with normal platelet count. Platelet reactivity was measured in whole blood (Multiplate aggregometer, Roche, Switzerland) using arachidonic acid (AA), adenosine-5′-diphosphate (ADP), and thrombin receptor agonist peptide-6 (TRAP) as agonists. Platelet aggregation was expressed in arbitrary units (AU). AA-induced aggregation was used as a measure of response to ASA with a cut-off above 30 AU showing high on-treatment platelet reactivity to ASA (HTPR-A). ADP-induced aggregation measured response to clopidogrel with a cut-off above 48 AU for high on-treatment platelet reactivity to clopidogrel (HTPR-C). TRAP-induced aggregation measured baseline platelet reactivity not affected by oral antiplatelet drugs. Results. The study included 174 patients. There were 64 patients with thrombocytopenia, 30 patients with chronic thrombocythemia, and 80 controls. All patients were on 75 mg of ASA and 32% of them additionally on 75 mg of clopidogrel due to a history of recent coronary artery angioplasty. AA- and ADP-induced aggregation was comparable between thrombocytopenic patients and controls (median (IQR) 19 (7–28) vs. 23 (15–38) for AA AU and 32 (16–44) vs. 50 (32–71) for ADP AU, respectively), while it was significantly higher in thrombocythemic patients (median (IQR) 80 (79–118) for AA AU and 124 (89–139) for ADP AU). TRAP-induced aggregation showed significantly lowest aggregation in thrombocytopenic (median (IQR) 41 (34–60) for TRAP AU) and highest in thrombocythemic patients (median (IQR) 137 (120–180) for TRAP AU). HTPR-A was frequent in thrombocythemic patients in comparison with thrombocytopenic patients and controls (60% vs. 4% vs. 15%, respectively; p

Acute graft-versus-host disease (aGvHD) reduces the efficiency and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In recent years, attempts have been made to transplant fecal microbiota from healthy donors to treat intestinal GvHD. This study presented two cases of patients undergoing allo-HSCT who were later selected for fecal microbiota transplantation (FMT). In the first patient, FMT resulted in the complete resolution of symptoms, whereas therapeutic efficacy was not achieved in the second patient. FMT eliminated drug-resistant pathogens, namely very drug-resistant Enterococcus spp., but not multidrug-resistant Acinetobacter baumannii or Candida spp. Further research is needed, particularly on the safety of FMT in patients with intestinal steroid-resistant GvHD and on the distant impact of transplanted microflora on the outcomes of allo-HSCT. FMT appears promising for the treatment of patients with steroid-resistant GvHD.

Aquagenic pruritus is one of the main clinical features of polycythemia vera. The aim of this study was to analyse the clinical characteristics of aquagenic pruritus. The study group comprised 102 patients with molecularly confirmed polycythemia vera. Demographic data, data on disease history, polycythemia vera status and treatment modalities were collected. Moreover, various clinical features of aquagenic pruritus (including intensity, localization, quality, descriptors) and the most common factors responsible for its aggravation or alleviation were examined. Aquagenic pruritus was observed in 41.2% of individuals, mean duration 6.6 ± 8.6 years, and its onset was noticed in the majority of patients (52.4%) before the diagnosis of polycythemia vera. The mean intensity of aquagenic pruritus was 4.8 ± 1.9 points (visual analogue scale). One-third of patients with aquagenic pruritus avoided any contact with water. Antipruritic treatment was received only by 3 patients. Aquagenic pruritus seems to be an important, but frequently neglected, symptom in patients with polycythemia vera.

The innate immune system plays a pivotal role in the first line of host defense against infections and is equipped with patterns recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Several classes of PRRS, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) recognize distinct microbial components and directly activate immune cells. TLRs are transmembrane receptors, while NLRs and RLRs are intracellular molecules. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. The innate immune system also influences pathways involved in cancer immunosurveillance. Natural and synthetic agonists of TLRs, NLRs, or RLRs can trigger cell death in malignant cells, recruit immune cells, such as DCs, CD8+ T cells, and NK cells, into the tumor microenvironment, and are being explored as promising adjuvants in cancer immunotherapies. In this review, we provide a concise overview of TLRs, NLRs, and RLRs: their structure, functions, signaling pathways, and regulation. We also describe various ligands for these receptors and their possible application in treatment of hematopoietic diseases.

In our previous study, while chronic lymphocytic leukemia (CLL) cases showed higher levels of B and T lymphocyte attenuator (BTLA) mRNA compared to controls, lower BTLA protein expression was observed in cases compared to controls. Hence we hypothesize that micro RNA (miR) 155-5p regulates BTLA expression in CLL. In line with earlier data, expression of BTLA mRNA and miR-155-5p is elevated in CLL (p = 0.034 and p = 0.0006, respectively) as well as in MEC-1 cell line (p = 0.009 and 0.016, respectively). Inhibition of miR-155-5p partially restored BTLA protein expression in CLL patients (p = 0.01) and in MEC-1 cell lines (p = 0.058). Additionally, we aimed to evaluate the significance of BTLA deficiency in CLL cells on proliferation and IL-4 production of B cells. We found that secretion of IL-4 is not dependent on BTLA expression, since fractions of BTLA positive and BTLA negative B cells expressing intracellular IL-4 were similar in CLL patients and controls. We demonstrated that in controls the fraction of proliferating cells is lower in BTLA positive than in BTLA negative B cells (p = 0.059), which was not observed in CLL. However, the frequency of BTLA positive Ki67+ B cells in CLL was higher compared to corresponding cells from controls (p = 0.055) while there were no differences between the examined groups regarding frequency of BTLA negative Ki67+ B cells. Our studies suggest that miR-155-5p is involved in BTLA deficiency, affecting proliferation of CLL B cells, which may be one of the mechanisms responsible for CLL pathogenesis.

The paper discusses a potential composite produced using the casting method, where the matrix is gray cast iron with flake graphite. The reinforcement is provided by granular carborundum (β-SiC). The article presents model studies aimed at identifying the phenomena at the contact boundary resulting from the interaction of the liquid matrix with solid reinforcement particles. The scope of the research included, primarily, the metallographic analysis of the microstructure of the resulting composite, carried out by using light (LOM) and scanning electron (SEM) microscopy with energy dispersive X-ray spectroscopy (EDS) analysis. The occurrence of metallic phases in the boundary zone was indicated, the contents and morphology of which can be optimized in order to achieve favorable functional properties, mainly the tribological properties of the composite. In addition, the results obtained confirm the possibility of producing similar composites based on selected iron alloys.

This article collects several published cases in which immune thrombocytopenic purpura (ITP) is followed by essential thrombocythemia (ET) and vice versa. This surprising clinical condition is possible, but very rare and difficult to diagnose and manage. We have made an attempt to analyse the possible causes of the sequential appearance of ITP and ET taking into consideration the following: alteration of the thrombopoietin (TPO) receptor, the role of autoimmunity and inflammation, and cytokine modulation. A better understanding of these interactions may provide opportunities to determine predisposing factors and aid in finding new treatment modalities both for ITP and ET patients.

Non-Hodgkin B-cell lymphomas (NHL) are a heterogeneous group of lymphoid neoplasms with complex etiopathology, rich symptomatology, and a variety of clinical courses, therefore requiring different therapeutic approaches. The hypothesis that an infectious agent may initiate chronic inflammation and facilitate B lymphocyte transformation and lymphogenesis has been raised in recent years. Viruses, like EBV, HTLV-1, HIV, HCV and parasites, like Plasmodium falciparum, have been linked to the development of lymphomas. The association of chronic Helicobacter pylori (H. pylori) infection with mucosa-associated lymphoid tissue (MALT) lymphoma, Borrelia burgdorferi with cutaneous MALT lymphoma and Chlamydophila psittaci with ocular adnexal MALT lymphoma is well documented. Recent studies have indicated that other infectious agents may also be relevant in B-cell lymphogenesis such as Coxiella burnettii, Campylobacter jejuni, Achromobacter xylosoxidans, and Escherichia coli. The aim of the present review is to provide a summary of the current literature on infectious bacterial agents associated with B-cell NHL and to discuss its role in lymphogenesis, taking into account the interaction between infectious agents, host factors, and the tumor environment.

Aquagenic pruritus (AP) has a significant influence on quality of life (QoL) in patients with polycythaemia vera. This study analysed the impact of AP on patient well-being in 102 patients with polycythaemia vera. Intensity of pruritus was evaluated using a visual analogue scale (VAS), verbal rating scale (VRS) and a 4-item Itch Questionnaire. Psychosocial aspects of AP were assessed with the Hospital Anxiety and Depression Scale (HADS), EQ-5D and itch-specific QoL questionnaire (ItchyQoL). AP of mean duration 6.6 ± 8.6 years and intensity 4.8 ± 1.9 points (VAS) was present in 42/102 individuals. The prevalence of depression and anxiety among patients with AP was 23.8% and 9.5%, respectively. Depression was more frequent in the AP group (vs. non-AP). Moreover, patients with AP had higher HADS-anxiety scoring than those without pruritus (p = 0.005). A negative correlation was found between duration of AP and EQ-5D-VAS. The ItchyQol score of 37.3 ± 12.3 points was influenced by the extent (p =0.01) and duration of episodes of AP (p = 0.02). In conclusion, AP places an additional burden on patients with polycy­thaemia vera, negatively influencing their QoL.

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The dysregulation of both the innate and adaptive responses to SARS-CoV-2 have an impact on the course of COVID-19, and play a role in the clinical outcome of the disease. Here, we performed a comprehensive analysis of peripheral blood lymphocyte subpopulations in 82 patients with COVID-19, including 31 patients with a critical course of the disease. In COVID-19 patients who required hospitalization we analyzed T cell subsets, including Treg cells, as well as TCRα/β and γ/δ, NK cells, and B cells, during the first two weeks after admission to hospital due to the SARS-CoV-2 infection, with marked reductions in leukocytes subpopulations, especially in critically ill COVID-19 patients. We showed decreased levels of Th, Ts cells, Treg cells (both naïve and induced), TCRα/β and γ/δ cells, as well as CD16+CD56+NK cells in ICU compared to non-ICU COVID-19 patients. We observed impaired function of T and NK cells in critically ill COVID-19 patients with extremely low levels of secreted cytokines. We found that the IL-2/INFγ ratio was the strongest indicator of a critical course of COVID-19, and was associated with fatal outcomes. Our findings showed markedly impaired innate and adaptive responses in critically ill COVID-19 patients, and suggest that the immunosuppressive state in the case of a critical course of SARS-CoV-2 infection might reflect subsequent clinical deterioration and predict a fatal outcome.

Glioblastoma multiforme (GBM) recurrences after temozolomide (TMZ) treatment result from the expansion of drug-resistant and potentially invasive GBM cells. This process is facilitated by O6-Methylguanine-DNA Methyltransferase (MGMT), which counteracts alkylating TMZ activity. We traced the expansion of invasive cell lineages under persistent chemotherapeutic stress in MGMTlow (U87) and MGMThigh (T98G) GBM populations to look into the mechanisms of TMZ-induced microevolution of GBM invasiveness. TMZ treatment induced short-term, pro-invasive phenotypic shifts of U87 cells, in the absence of Snail-1 activation. They were illustrated by a transient induction of their motility and followed by the hypertrophy and the signs of senescence in scarce U87 sub-populations that survived long-term TMZ stress. In turn, MGMThigh T98G cells reacted to the long-term TMZ treatment with the permanent induction of invasiveness. Ectopic Snail-1 down-regulation attenuated this effect, whereas its up-regulation augmented T98G invasiveness. MGMTlow and MGMThigh cells both reacted to the long-term TMZ stress with the induction of Cx43 expression. However, only in MGMThigh T98G populations, Cx43 was directly involved in the induction of invasiveness, as manifested by the induction of T98G invasiveness after ectopic Cx43 up-regulation and by the opposite effect after Cx43 down-regulation. Collectively, Snail-1/Cx43-dependent signaling participates in the long-term TMZ-induced microevolution of the invasive GBM front. High MGMT activity remains a prerequisite for this process, even though MGMT-related GBM chemoresistance is not necessary for its initiation.

The use of convalescent plasma in the treatment of COVID-19 may lead to a milder course of infection and has been associated with improved outcomes. Determining optimal treatments in high risk populations is crucial, as is the case in those with hematological malignancies. We analyzed a cohort of 23 patients with hematological malignancies and COVID-19 who had received plasma 48–72 h after the diagnosis of infection and compared it with a historical group of 22 patients who received other therapy. Overall survival in those who received convalescent plasma was significantly higher than in the historical group (p = 0.03460). The plasma–treated group also showed a significantly milder course of infection (p = 0.03807), characterized by less severe symptoms and faster recovery (p = 0.00001). In conclusion, we have demonstrated that convalescent plasma is an effective treatment and its early administration leads to clinical improvement, increased viral clearance and longer overall survival in patients with hematological malignancies and COVID-19. To our knowledge, this is the first report to analyze the efficacy of convalescent plasma in a cohort of patients with hematological malignancies.

In our study, we describe the outcomes of the intercalation of different anthracycline antibiotics in double-stranded DNA at the nanoscale and single molecule level. Atomic force microscopy analysis revealed that intercalation results in significant elongation and thinning of dsDNA molecules. Additionally, using optical tweezers, we have shown that intercalation decreases the stiffness of DNA molecules, that results in greater susceptibility of dsDNA to break. Using DNA molecules with different GC/AT ratios, we checked whether anthracycline antibiotics show preference for GC-rich or AT-rich DNA fragments. We found that elongation, decrease in height and decrease in stiffness of dsDNA molecules was highest in GC-rich dsDNA, suggesting the preference of anthracycline antibiotics for GC pairs and GC-rich regions of DNA. This is important because such regions of genomes are enriched in DNA regulatory elements. By using three different anthracycline antibiotics, namely doxorubicin (DOX), epirubicin (EPI) and daunorubicin (DAU), we could compare their detrimental effects on DNA. Despite their analogical structure, anthracyclines differ in their effects on DNA molecules and GC-rich region preference. DOX had the strongest overall effect on the DNA topology, causing the largest elongation and decrease in height. On the other hand, EPI has the lowest preference for GC-rich dsDNA. Moreover, we demonstrated that the nanoscale perturbations in dsDNA topology are reflected by changes in the microscale properties of the cell, as even short exposition to doxorubicin resulted in an increase in nuclei stiffness, which can be due to aberration of the chromatin organization, upon intercalation of doxorubicin molecules.

Abnormal secretion of epidermal growth factor (EGF) by non-neuronal cells (e.g., glioma-associated microglia) establishes a feedback loop between glioblastoma multiforme (GBM) invasion and a functional disruption of brain tissue. Considering the postulated significance of this vicious circle for GBM progression, we scrutinized mechanisms of EGF-dependent pro-invasive signaling in terms of its interrelations with energy metabolism and reactive oxygen species (ROS) production. The effects of EGF on the invasiveness of human glioblastoma T98G cells were estimated using time-lapse video microscopy, immunocytochemistry, cell cycle assay, immunoblot analyses, and Transwell® assay. These techniques were followed by quantification of the effect of EGFR (Epidermal Growth Factor Receptor) and ROS inhibitors on the EGF-induced T98G invasiveness and intracellular ROS, ATP, and lactate levels and mitochondrial metabolism. The EGF remarkably augmented the proliferation and motility of the T98G cells. Responses of these cells were accompanied by cellular rear–front polarization, translocation of vinculin to the leading lamellae, and increased promptness of penetration of micropore barriers. Erlotinib (the EGFR inhibitor) significantly attenuated the EGF-induced T98G invasiveness and metabolic reprogramming of the T98G cells, otherwise illustrated by the increased mitochondrial activity, glycolysis, and ROS production in the EGF-treated cells. In turn, ROS inhibition by N-acetyl-L-cysteine (NAC) had no effect on T98G morphology, but considerably attenuated EGF-induced cell motility. Our data confirmed the EGFR/ROS-dependent pro-neoplastic and pro-invasive activity of EGF in human GBM. These EGF effects may depend on metabolic reprogramming of GBM cells and are executed by alternative ROS-dependent/-independent pathways. The EGF may thus preserve bioenergetic homeostasis of GBM cells in hypoxic regions of brain tissue.

This work attempts to process AlCu4MgSi (AW 2017A) alloy continuous ingots by means of the equal channel angular pressing (ECAP) method. The equal channel angular pressing (ECAP) technique has been widely investigated in recent years as the most promising severe plastic deformation (SPD) method. The presented research was focused on the precise determination of the phase composition of the precipitates formed in the AlCu4MgSi alloy and its influence on intensive plastic deformation. In the second stage, the research was focused on explaining the recrystallization process. With the use of the high-temperature X-ray diffraction (HT-XRD) technique, the changes in the dislocation substructure at various recrystallization annealing temperatures were analyzed.

The study was designed to determine the associations of asymmetric (ADMA) and symmetric (SDMA) dimethylarginines plasma concentrations with all-cause mortality in patients with hematological malignancies. 33 patients with acute myeloid leukemia (AML), 31 patients with non-Hodgkin's lymphoma (nHL), 32 patients with chronic lymphocytic leukemia (CLL) and 48 patients without malignancy were enrolled into the study. Each patient was followed until death or for at least 14.5 months (range: 14.5-53). Median ADMA and SDMA were significantly elevated in AML, nHL and CLL compared to controls (ADMA: 1.36, 1.24, 1.03, 0.55 μmol/l respectively, p

The migration, survival and proliferation of cells is the basis for all physiologic and pathologic processes in the human body. All these reactions are regulated by a complex chemokine network that guides lymphocytes homing, chemotaxis, adhesion and interplay between immunologic system response cells. Chemokines are also responsible for metastatic dissemination of cancers, including Hodgkin’s and non-Hodgkin’s lymphomas. The purpose of this study was to determine chemokine gene expression (CXCL8, CXCL10, CCL2, CCL3, CCL4 and CCL5) in lymphoma lymph nodes compared to their expression in reactive lymph nodes. We also analyzed the influence of chemokine gene expression on the survival of lymphoma patients. Chemokine gene expression was evaluated in 37 lymphoma lymph nodes and in 25 samples of reactive lymph nodes. Gene expression of chemokines CXCL8, CXCL10, CCL2, CCL3, CCL4 and CCL5 was measured using the PCR method. Statistical analysis was performed using CSS Statistica for Windows (version 7.0) software. Probability values < < 0.05 were considered statistically significant and those between 0.05 and 0.1 as indicative of a trend. We found lower CXCL8 and CXCL10 gene expression in lymphoma lymph nodes compared to reactive lymph nodes. In the cases of CCL2 and CCL3, expression in lymphomas was higher than in reactive lymph nodes. Patients with high expression of CCL2 and CXCL10 had shorter survival. (Folia Histochemica et Cytobiologica 2011; Vol. 49, No. 2, pp. 240–247)

Patients with multiple myeloma (MM) treated with conventional chemotherapy have an averagesurvival of approximately three years. High dose chemotherapy followed by autologous stem cell transplantation(ASCT), first introduced in the mid-1980s, is now considered the standard therapy for almost all patientswith multiple myeloma, because it prolongs overall survival and disease free survival. Between November 1997and October 2006, 122 patients with MM (58 females, 64 males, median age 51.0 years [± 7.98] range: 30–66years) were transplanted in the Department of Hematooncology and Bone Marrow Transplantation at the MedicalUniversity of Lublin: 47 patients were in complete remission or in unconfirmed complete remission,66 patients were in partial remission, and nine had stable disease. Of these, there were 95 patients with IgG myeloma,16 with IgA myeloma, one with IgG/IgA, one with IgM myeloma, five with non secretory type, two withsolitary tumor and two with LCD myeloma. According to Durie-Salmon, 62 patients had stage III of the disease,46 had stage II and four had stage I. Most patients (69/122) were transplanted after two or more cycles ofchemotherapy, 48 patients were transplanted after one cycle of chemotherapy, one patient after surgery and rtg--therapy and four patients had not been treated. In mobilisation procedure, the patients received a single infusionof cyclophosphamide (4–6 g/m2) or etoposide 1.6 g/m2 followed by daily administration of G-CSF until theperipheral stem cells harvest. The number of median harvest sessions was 2.0 (± 0.89) (range: 1–5). An averageof 7.09 (± 33.28) × 106 CD34+ cells/kg were collected from each patient (range: 1.8–111.0 × 106/kg). Conditioningregimen consisted of high dose melphalan 60–210 mg/m2 without TBI. An average of 3.04 (± 11.59) × 106CD34+ cells/kg were transplanted to each patient. Fatal complications occured in four patients (treatment--related mortality = 3.2%). In all patients there was regeneration of hematopoiesis. The median number of daysfor recovery to ANC > 0.5 × 109/l was 13 (± 4.69) (range: 10–38) and platelets recovery to > 50 × 109/l was 25days (± 11.65) (range: 12–45). Median time of hospitalization was 22 days (± 7.14) (range: 14–50). Patientswere evaluated on day 100 after transplantation: 74.9% achieved CR and nCR, 14.3% were in PR, 5.4% had SDand 5.4% had progressed. Median of OS was 45 months (± 30.67). OS at 3-years was 84% and at 7-years 59%.Median PFS was 25 months (± 26.13). PFS at 3-years was 68%, and at 7-years was 43%. At present (November2009) 52 patients (42%) are still alive. High-dose chemotherapy followed by autologous stem cell transplantationis a valuable, well tolerated method of treatment for patients with MM that allows the achievement of long--lasting survival.

Angiogenesis is important in development, maintenance and progression of haematological malignancies. Some clinical observations have indicated that in non-Hodgkin's lymphoma (nHL) tumour microvessel density (MVD) may correlate with tumour staging and outcome. The aim of the study was to examine relationship between MVD as a parameter of tumour angiogenesis measured by expression of CD34 and the grade of nHL histological malignancy as determined by REAL classification. 40 lymph node samples of patients with newly diagnosed nHL (17 women, 23 men; aged 48-70 yrs, median age 64 yrs; stage III and IV) and treated at the Department of Haematology, WrocĹaw Medical University in 1999-2002 were fixed in 10% buffered formalin and embedded in paraffin. In all the studied cases, sections were incubated with antibodies against CD34. The slides were stained with hematoxylin and eosin and evaluated histopathologically. Patients were divided into two groups according to histological malignancy: indolent nHL (19 patients) and aggressive nHL (21 patients). Mean MVD measured by expression of CD34 in aggressive and indolent nHL groups amounted to 19.45 +/- 11.24 vessels/0.375 mm2 and 21.7 +/- 12.4 vessels/0.375 mm2, respectively. Statistical analysis of microvessel staining demonstrated no correlation between tumour MVD and grade of histological malignancy in lymph nodes of nHL patients. Nevertheless, angiogenesis observed in nHL provides rationale for use of angiogenesis inhibitors in lymphoma therapy.

Syndecan-1 (CD138) is a transmembrane heparin sulfate proteoglycan expressed on distinct stages of differentiation of B-lymphoid cells. Its prognostic value in B-cell chronic lymphocytic leukemia (B-CLL) has not been evaluated so far. The serum concentration of sCD138 and some angiogenesis-involved cytokines: vascular endothelial growth factor (VEGF), basis fibroblast growth factor (bFGF), and endostatin were studied in 52 previously untreated patients with B-CLL. We found that bFGF and sCD138 levels were significantly higher in B-CLL patients than in controls. In patients with sCD138 level or endostatin level below the median value the lymphocyte count was higher than in patients with serum level of those cytokines above the median value. In patients with progressive disease bFGF level was significantly higher and sCD138 level significantly lower than in patients with stable one. Moreover, high sCD138 level was associated with longer lymphocyte doubling-free survival, and, on the limit of statistical significance, a high endostatin level was associated with shorter progression-free survival. We conclude that serum sCD138 level is increased in early stage B-CLL patients and may have a positive prognostic value as to the dynamics of the disease.