RESUMO
This study aims to gain a deeper understanding of chronic lymphocytic leukemia (CLL) and common variable immunodeficiency (CVID) by studying immune cells and specific immune checkpoint signaling pathways. The analysis of the percentage of selected immune points and their ligands (PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200) on peripheral blood lymphocyte subpopulations was performed using flow cytometry, and additional analyses determining the serum concentration of the above-mentioned molecules were performed using enzyme immunoassay tests. The obtained results indicate several significant changes in the percentage of almost all tested molecules on selected subpopulations of T and B lymphocytes in both CVID and CLL patients in relation to healthy volunteers and between the disease subunits themselves. The results obtained were also supported by the analysis of the serum concentration of soluble molecules tested. By uncovering valuable insights, we hope to enhance our comprehension and management of these conditions, considering both immunodeficiencies and hematological malignancies. Understanding the role of these signaling pathways in disease development and progression may lead to the development of modern, personalized diagnostic and therapeutic strategies. Ultimately, this knowledge may enable the monitoring of the immune system in patients with CVID and CLL, paving the way for improved patient care in the future.
RESUMO
This study delves into the intricate landscape of primary immunodeficiencies, with a particular focus on antibody deficiencies characterized by near-normal immunoglobulin levels or hyperimmunoglobulinemia. Contrary to the conventional focus on genetic dysregulation, these studies investigate the key roles of immune checkpoints, such as PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200, on selected subpopulations of T and B lymphocytes and their serum concentrations of soluble forms in patients recruited for the studies in healthy volunteers. In addition, the studies also show the role of Epstein-Barr virus (EBV) reactivation and interactions with tested pathways of immune checkpoints involved in the immunopathogenesis of this disease. By examining the context of antibody deficiencies, this study sheds light on the nuanced interplay of factors beyond genetics, particularly the immune dysregulations that occur in the course of this type of disease and the potential role of EBV reactivation, which affects the clinical presentation of patients and may contribute to the development of cancer in the future, especially related to hematological malignancies.
RESUMO
Primary immunodeficiencies (PIDs) and secondary immunodeficiencies (SIDs) are characterized by compromised immune function, rendering individuals susceptible to infections and potentially influencing cancer development. Epstein-Barr virus (EBV), a widespread herpesvirus, has been linked to cancer, particularly in those with weakened immune systems. This study aims to compare selected immune parameters, focusing on immune checkpoint molecules (PD-1/PD-L1, CTLA-4/CD86, CD200R/CD200), and EBV reactivation in patients with chronic lymphocytic leukemia (CLL, a representative of SIDs) and common variable immunodeficiency (CVID, a representative of PIDs). We performed a correlation analysis involving patients diagnosed with CLL, CVID, and a healthy control group. EBV reactivation was assessed using specific antibody serology and viral load quantification. Peripheral blood morphology, biochemistry, and immunophenotyping were performed, with emphasis on T and B lymphocytes expressing immune checkpoints and their serum concentrations. Our findings revealed elevated EBV reactivation markers in both CLL and CVID patients compared with healthy controls, indicating increased viral activity in immunodeficient individuals. Furthermore, immune checkpoint expression analysis demonstrated significantly altered percentages of T and B lymphocytes expressing PD-1/PD-L1, CTLA-4/CD86, and CD200R/CD200 in CLL and CVID patients. This suggests a potential interplay between immune checkpoint dysregulation and EBV reactivation in the context of immunodeficiency. In conclusion, our study underscores the intricate relationship between immune dysfunction, EBV reactivation, and immune checkpoint modulation in the context of immunodeficiency-associated cancers. The altered expression of immune checkpoints, along with heightened EBV reactivation, suggests a potential mechanism for immune evasion and tumor progression. These findings provide insights into the complex interactions that contribute to cancer development in immunocompromised individuals, shedding light on potential therapeutic targets for improved management and treatment outcomes. Further investigations are warranted to elucidate the underlying mechanisms and to explore potential interventions to mitigate cancer risk in these patient populations.
RESUMO
Infection with Epstein-Barr virus (EBV) worsens the prognosis in chronic lymphocytic leukemia (CLL), but the underlying mechanisms are not yet established. We intended to assess whether EBV affects the course of CLL by the deregulation of the CTLA-4/CD86 signaling pathway. We used polymerase chain reaction to measure the load of EBV DNA in the blood of 110 newly diagnosed patients with CLL. The expression of CTLA-4 and CD86 antigen on lymphocytes was assessed with flow cytometry. Additionally, CTLA-4 and CD86 serum concentrations were measured through enzyme-linked immunosorbent assays. Fifty-four percent of the patients had detectable EBV DNA [EBV(+)]. In EBV(+) patients the CTLA-4 and CD86 serum concentrations and their expressions on investigated cell populations were significantly higher than in EBV(-) patients. EBV load correlated positively with unfavorable prognostic markers of CLL and the expression of CTLA-4 on CD3+ lymphocytes (r = 0.5339; p = 0.027) and CD86 on CD19+ cells (r = 0.6950; p < 0.001). During a median follow-up period of 32 months EBV(+) patients were more likely to require treatment or have lymphocyte doubling (p < 0.001). Among EBV(+) but not EBV(-) patients, increased expressions of CTLA-4 lymphocytes were associated with elevated risks of progression. We propose that EBV coinfection may worsen prognosis in CLL patients, partly due to EBV-induced up-regulation of CTLA-4 expression.
RESUMO
AL (light-chain) amyloidosis is a systemic disease in which amyloid fibers are formed from kappa or lambda immunoglobulin light chains, or fragments thereof, produced by a neoplastic clone of plasmocytes. The produced protein is deposited in tissues and organs in the form of extracellular deposits, which leads to impairment of their functions and, consequently, to death. Despite the development of research on pathogenesis and therapy, the mortality rate of patients with late diagnosed amyloidosis is 30%. The diagnosis is delayed due to the complex clinical picture and the slow progression of the disease. This is the type of amyloidosis that most often contributes to cardiac lesions and causes cardiac amyloidosis (CA). Early diagnosis and correct identification of the type of amyloid plays a crucial role in the planning and effectiveness of therapy. In addition to standard histological studies based on Congo red staining, diagnostics are enriched by tests to determine the degree of cardiac involvement. In this paper, we discuss current diagnostic methods used in cardiac light chain amyloidosis and the latest therapies that contribute to an improved patient prognosis.
RESUMO
Ovarian cancer is a global problem that affects women of all ages. Due to the lack of effective screening tests and the usually asymptomatic course of the disease in the early stages, the diagnosis is too late, with the result that less than half of the patients diagnosed with ovarian cancer (OC) survive more than five years after their diagnosis. In this study, we examined the expression of TLR2 in the peripheral blood of 50 previously untreated patients with newly diagnosed OC at various stages of the disease using flow cytometry. The studies aimed at demonstrating the usefulness of TLR2 as a biomarker in the advanced stage of ovarian cancer. In this study, we showed that TLR2 expression levels were significantly higher in women with more advanced OC than in women in the control group. Our research sheds light on the prognostic potential of TLR2 in developing new diagnostic approaches and thus in increasing survival in patients with confirmed ovarian cancer.
Assuntos
Carcinoma Epitelial do Ovário , Neoplasias Ovarianas , Receptor 2 Toll-Like/sangue , Idoso , Biomarcadores Tumorais/sangue , Carcinoma Epitelial do Ovário/diagnóstico , Carcinoma Epitelial do Ovário/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/metabolismo , PrognósticoRESUMO
Multiple myeloma (MM) is a plasma cell neoplasm characterized by an abnormal proliferation of clonal, terminally differentiated B lymphocytes. Current approaches for the treatment of MM focus on developing new diagnostic techniques; however, the search for prognostic markers is also crucial. This enables the classification of patients into risk groups and, thus, the selection of the most optimal treatment method. Particular attention should be paid to the possible use of immune factors, as the immune system plays a key role in the formation and course of MM. In this review, we focus on characterizing the components of the immune system that are of prognostic value in MM patients, in order to facilitate the development of new diagnostic and therapeutic directions.
Assuntos
Mieloma Múltiplo/imunologia , Mieloma Múltiplo/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Quimiocinas , Citocinas , Humanos , Fatores Imunológicos/uso terapêutico , Peptídeos e Proteínas de Sinalização Intercelular , Interferon gama , Mieloma Múltiplo/tratamento farmacológico , Prognóstico , Fatores de Necrose TumoralRESUMO
Secondary immunodeficiency is observed in all patients with chronic lymphocytic leukemia (CLL) in varying degrees. The aim of the study was to review the available literature data on patients with CLL, with particular regard to the pathogenesis of the disease and the impact of humoral immunity deficiency on the clinical and therapeutic approach. A systematic literature review was carried out by two independent authors who searched PubMed databases for studies published up to January 2020. Additionally, Google Scholar was used to evaluate search results and support manual research. The search resulted in 240 articles eligible for analysis. After all criteria and filters were applied, 22 studies were finally applied to the analysis. The data analysis showed that the clinical heterogeneity of CLL patients correlates with the diversity of molecular abnormalities determining the clinical picture of the disease, the analysis of which enables setting therapeutic targets. Additionally, in improving the therapeutic method, it is worth introducing supportive therapies with the use of vaccines, antibiotics and/or immunoglobins. Moreover, humoral immunodeficiency in CLL has a strong influence on the risk of infection in patients for whom infections are a major cause of morbidity and mortality.
Assuntos
Imunidade Humoral , Terapia de Imunossupressão , Leucemia Linfocítica Crônica de Células B/imunologia , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , PrognósticoRESUMO
Gastric cancer (GC) is one of the most commonly diagnosed malignancies and, unfortunately, still has a high mortality rate. Recent research points to CAR-T immunotherapy as a promising treatment for this disease. Using genetically engineered T cells designed to target a previously selected antigen, researchers are able to harness the natural anti-tumor activity of T cells. For therapy to be successful, however, it is essential to choose antigens that are present on tumor cells but not on healthy cells. In this review, we present an overview of the most important targets for CAR-T therapy in the context of GC, including their biologic function and therapeutic application. A number of clinical studies point to the following as important markers in GC: human epidermal growth factor receptor 2, carcinoembryonic antigen, mucin 1, epithelial cell adhesion molecule, claudin 18.2, mesothelin, natural-killer receptor group 2 member D, and folate receptor 1. Although these markers have been met with some success, the search for new and improved targets continues. Key among these novel biomarkers are the B7H6 ligand, actin-related protein 2/3 (ARP 2/3), neuropilin-1 (NRP-1), desmocollin 2 (DSC2), anion exchanger 1 (AF1), and cancer-related antigens CA-72-4 and CA-19-9.
RESUMO
Despite the significant progress of modern anticancer therapies, multiple myeloma (MM) is still incurable for the majority of patients. Following almost three decades of development, chimeric antigen receptor (CAR) T-cell therapy now has the opportunity to revolutionize the treatment landscape and meet the unmet clinical need. However, there are still several major hurdles to overcome. Here we discuss the recent advances of CAR T-cell therapy for MM with an emphasis on future directions and possible risks. Currently, CAR T-cell therapy for MM is at the first stage of clinical studies, and most studies have focused on CAR T cells targeting B cell maturation antigen (BCMA), but other antigens such as cluster of differentiation 138 (CD138, syndecan-1) are also being evaluated. Although this therapy is associated with side effects, such as cytokine release syndrome and neurotoxicity, and relapses have been observed, the benefit-risk balance and huge potential drive the ongoing clinical progress. To fulfill the promise of recent clinical trial success and maximize the potential of CAR T, future efforts should focus on the reduction of side effects, novel targeted antigens, combinatorial uses of different types of CAR T, and development of CAR T cells targeting more than one antigen.
Assuntos
Antígeno de Maturação de Linfócitos B/imunologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Imunoterapia Adotiva/métodos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Antígenos CD1d/imunologia , Antígeno de Maturação de Linfócitos B/metabolismo , Humanos , Cadeias beta de Integrinas/metabolismo , Receptores de Antígenos Quiméricos/metabolismo , Medição de Risco , Sindecana-1/imunologia , Sindecana-1/metabolismoRESUMO
Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p = .0055, Bonferroni corrected p = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p = .0063, Bonferroni corrected p = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p = .0054, Bonferroni corrected p = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM.
Assuntos
Mieloma Múltiplo , Proteínas Adaptadoras de Transdução de Sinal/genética , Humanos , Lenalidomida , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Peptídeo Hidrolases/genética , Testes Farmacogenômicos , Polimorfismo Genético , Intervalo Livre de Progressão , Talidomida/uso terapêutico , Ubiquitina-Proteína LigasesRESUMO
PURPOSE: Patients with monoclonal gammopathy of undetermined significance (MGUS) have an increased risk of developing infections. Streptococcus pneumoniae vaccinations are recommended for immunocompromised patients, including patients with lymphoproliferative disorders such as MGUS. The objective of the study was to assess the immune response to the 13-valent pneumococcal conjugate vaccine (PCV13) in treatment-naive MGUS patients versus healthy subjects. All study groups were evaluated for the levels of specific pneumococcal antibodies, the levels of IgG and IgG subclasses, and selected peripheral blood lymphocyte subpopulations, including the proportion of plasmablasts before and after immunization. PATIENTS AND METHODS: A total of 22 previously untreated patients with MGUS and 15 healthy age- and sex-matched volunteers were included in the study. All participants were immunized with PCV13 Prevenar13 (Pfizer). The following parameters were assessed: 1) serum-specific pneumococcal antibody titers before and 30 days after vaccination, 2) percentage of plasmablasts, defined as CD19+/IgD-/CD27++, before and 7 days after vaccination, 3) serum total IgG and IgG1, IgG2, IgG3, IgG4 levels before and 30 days after vaccination. RESULTS AND CONCLUSION: PCV13 vaccination in MGUS patients is safe and effectively protects against S. pneumoniae infection. In unvaccinated individuals, vaccination should be carried out as soon as possible after diagnosis. It can protect patients against serious infectious complications, which can contribute to extending the time to progression and transformation into more aggressive diseases. PCV13 vaccination is more effective in MGUS patients with a lower concentration of M protein. Serum M protein concentration in patients diagnosed with MGUS may be a useful predictor of the effectiveness of vaccination.
Assuntos
Gamopatia Monoclonal de Significância Indeterminada/tratamento farmacológico , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/administração & dosagem , Vacinas Conjugadas/administração & dosagem , Adulto , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/sangue , Proteínas do Mieloma/análiseRESUMO
PURPOSE: Infection with Epstein-Bar virus (EBV) is associated with an unfavourable prognosis in chronic lymphocytic leukaemia (CLL), but the underlying mechanisms remain unknown. We aimed to establish whether EBV worsens the course of CLL by up-regulating the programmed cell death 1 expression. PATIENTS AND METHODS: Using polymerase chain reaction, we measured EBV DNA in the blood of 110 newly diagnosed, treatment-naïve patients with CLL. We used flow cytometry to measure the expression of programmed cell death protein 1 (PD-1) and programmed cell death protein 1 ligand (PD-L1) on CD4+, CD8+, and CD19+ cells. Additionally, PD-1 and PD-L1 serum concentrations were measured using enzyme-linked immunosorbent assays. We related the expressions of PD-1 and PD-L1 to EBV DNA load and clinical outcomes. RESULTS: Fifty-nine (54%) patients had detectable EBV DNA [EBV(+)], and these patients had more advanced disease at baseline than the rest. PD-1 and PD-L1 serum concentrations and their expressions on all cell populations were higher in EBV(+) than EBV(-) patients. EBV load correlated positively with unfavourable clinical markers of CLL and the expression of PD-1 and PD-L1 on CD4+ and CD8+ cells (rho =0.42-0.75; p<0.001). EBV(+) patients had increased risks of treatment initiation and lymphocyte doubling during a median follow-up period of 32 months (p<0.001). Among EBV(+), but not EBV(-), patients, higher expressions of PD-1 and PD-L1 on CD4+ and CD8+ cells were associated with higher risks of treatment initiation and lymphocyte doubling (p≤0.020). CONCLUSION: EBV-induced up-regulation of PD-1-PD-L1 expression is associated with worse outcomes in CLL.
Assuntos
Asma/sangue , Asma/complicações , Imunoglobulina G/sangue , Metotrexato/uso terapêutico , Xantogranuloma Necrobiótico/diagnóstico , Xantogranuloma Necrobiótico/tratamento farmacológico , Xantogranuloma Necrobiótico/etiologia , Idoso , Fármacos Dermatológicos/uso terapêutico , Oftalmopatias/diagnóstico por imagem , Humanos , Masculino , Xantogranuloma Necrobiótico/fisiopatologia , Polônia , Doenças Raras/sangue , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Resultado do TratamentoRESUMO
BACKGROUND Gelsolin (GSN) is an actin-binding and PIP2/Ca²âº-regulated protein found in the cytoplasm and blood plasma. Hypogelsolinemia occurs in a wide range of traumatic injuries and inflammatory reactions. We hypothesize that blood GSN levels will be altered in patients diagnosed with acute myeloid leukemia (AML) that develop sepsis, and assessment of GSN concentration will be a useful marker to determine their clinical outcome. To achieve this task, we evaluated the plasma gelsolin concentration in blood samples collected from patients diagnosed with acute myeloid leukemia (AML) at initial stages of sepsis. MATERIAL AND METHODS To assess if AML patients might be at risk of sepsis, a SOFA score was determined. Plasma gelsolin concentration was evaluated using an immunoblotting technique. RESULTS We found that GSN concentration in the blood of the AML group with developing sepsis was significantly lower (32±41 µg/ml; p<0.05) compared to the AML group (65±35 µg/ml) and control group (176±37 µg/ml; p<0.001). Additionally, low gelsolin concentration in the blood of AML patients developing sepsis was associated with a high SOFA score. A decrease of GSN concentration in the blood of AML subjects with developing sepsis suggests that GSN level in blood reflects not only chronic inflammation stage associated with leukemia, but that GSN depletion also manifests the inflammation associated with sepsis development. CONCLUSIONS The results presented here suggest the possible utility of GSN evaluation for diagnostic purposes. Overall, these data support the that reversing plasma GSN deficiency might be a possible new strategy in sepsis treatment.
Assuntos
Gelsolina/análise , Sepse/metabolismo , Adulto , Idoso , Biomarcadores/sangue , Feminino , Gelsolina/sangue , Gelsolina/metabolismo , Humanos , Inflamação/metabolismo , Leucemia Mieloide Aguda/complicações , Masculino , Pessoa de Meia-Idade , Sepse/diagnósticoRESUMO
Under normal conditions, the immune system responds effectively to both external and internal threats without damaging healthy tissues. Cells undergoing a neoplastic transformation are one such threat. An efficient activation of T cells is enabled by T-cell receptor (TCR) interactions with antigen-presenting class I and class II molecules of the major histocompatibility complex (MHC), co-stimulatory molecules, and cytokines. After threatening stimuli are removed from the body, the host's immune response ceases, which prevents tissue damage or chronic inflammation. The recognition of foreign antigens is highly selective, which requires multistep regulation to avoid reactions against the antigens of healthy cells. This multistep regulation includes central and peripheral tolerance toward the body's own antigens. Here, we discuss T-cell dysfunction, which leads to poor effector function against foreign antigens, including cancer. We describe selected cellular receptors implicated in T-cell dysfunction and discuss how immune-checkpoint inhibitors can help overcome T-cell dysfunction in cancer treatment.
RESUMO
BACKGROUND: Chronic lymphocytic leukemia (CLL) is a condition characterized by the accumulation of morphologically mature monoclonal lymphocytes B with the CD19+/CD5+/CD23+ phenotype in lymphoid tissue, peripheral blood and bone marrow. The clinical course of patients with CLL is heterogeneous, ranging from indolent to aggressive. The role of lymphocyte activation in the natural history of CLL is still a matter of discussion. OBJECTIVES: The aim of this study was to determine the percentages and absolute numbers of lymphocytes B and T in peripheral blood and bone marrow of CLL patients. Moreover, we analyzed the relationship between the number of CD25-positive and CD69-positive lymphocytes and the established prognostic factors in CLL. MATERIAL AND METHODS: The study included 80 untreated patients with CLL and 20 healthy subjects. The immunophenotype of peripheral blood mononuclear cells (in both groups) and bone marrow cells (solely in the CLL group) was determined by means of flow cytometry. RESULTS: Patients with CLL showed a higher absolute number of activated lymphocytes B with phenotypes CD19+CD25+ and CD19+CD69+, as well as a higher absolute number of CD3+CD25+ lymphocytes T than the controls. The enhanced activation of peripheral blood and bone marrow lymphocytes was associated with higher Rai stages, an increased concentration of lactate dehydrogenase and beta-2 microglobulin and the progression of the disease. The number of lymphocytes B CD19+ZAP-70+ correlated positively with the number of CD19+CD25+ B cells and CD3+CD69+ T cells. CONCLUSIONS: The study confirmed the association between an unfavorable prognosis and a high expression of activation markers in CLL patients. The determination of CD25+ and CD69+ lymphocytes T and B constitutes a valuable diagnostic tool, completing the cytometric evaluation of CLL.
Assuntos
Linfócitos B/patologia , Leucemia Linfocítica Crônica de Células B/sangue , Subpopulações de Linfócitos/imunologia , Linfócitos T/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/biossíntese , Antígenos de Diferenciação de Linfócitos T/biossíntese , Linfócitos B/imunologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Lectinas Tipo C/biossíntese , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/patologia , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Prognóstico , Linfócitos T/imunologiaRESUMO
BACKGROUND: Impaired apoptotic pathways in leukemic cells enable them to grow in an uncontrolled way. Moreover, aberrations in the apoptotic pathways are the main factor of leukemic cells drug resistance. METHODS: To assess the presence of potential abnormalities that might promote dysfunction of leukemic cells growth, HPLC system was used to determine sphingosine (SFO), sphinganine (SFA), sphingosine-1-phosphate (S1P) and ceramide (CER) concentration in the blood collected from patients diagnose with acute myeloblastic leukemia (AML; n = 49) and compare to values of control (healthily) group (n = 51). Additionally, in AML group concentration of SFO, SFA, S1P and CER was determined in bone marrow plasma and compared to respective values in blood plasma. The concentration of S1P and CER binding protein - plasma gelsolin (GSN) was also assessed in collected samples using immunoblotting assay. RESULTS: We observed that in AML patients the average SFO, SFA and CER concentration in blood plasma was significantly higher (p < 0.001) compare to control group, when blood plasma S1P concentration was significantly lower (p < 0.001). At the same time the CER/S1P ratio in AML patient (44.5 ± 19.4) was about 54% higher compare to control group (20.9 ± 13.1). Interestingly the average concentration of S1P in blood plasma (196 ± 13 pmol/ml) was higher compare to its concentration in plasma collected from bone marrow (154 ± 21 pmol/ml). CONCLUSIONS: We hypothesize that changes in profile of sphingolipids concentration and some of their binding protein partners such as GSN in extracellular environment of blood and bone marrow cells in leukemic patients can be targeted to develop new AML treatment method(s).
Assuntos
Ceramidas/sangue , Gelsolina/sangue , Leucemia Mieloide Aguda/sangue , Lisofosfolipídeos/sangue , Esfingosina/análogos & derivados , Esfingosina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION Bortezomib was the first proteasome inhibitor approved for the therapy of multiple myeloma (MM). Currently, VMP (bortezomib, melphalan, prednisone) is one of the standard regimens recommended as the firstline therapy for patients with MM ineligible for highdose chemotherapy (HDT) with autologous stemcell transplantation (autoSCT). OBJECTIVES Participants of clinical trials are highly selected populations; therefore, the aim of this study was to present observations from real practice that might provide important information for practitioners. PATIENTS AND METHODS We retrospectively analyzed the data on the efficacy and safety of bortezomibbased regimens in 154 patients with newly diagnosed MM ineligible for HDT with autoSCT (median age, 73 years; range, 39-89 years) with particular attention to the effect of age, performance status, and concomitant diseases. RESULTS Patients aged 75 years or older constituted 53.2% of the study cohort. Performance status was impaired in 34.4% of the patients, according to the Eastern Cooperative Oncology Group scale. Comorbidities were reported in 83.8% of the patients (mainly arterial hypertension and atherosclerotic vascular disease). A total of 798 courses of bortezomibbased regimens (mainly VMP, 86%) were administered. The overall response rate was 81.7%, including 12.7% for complete response and 29.6% for very good partial response. The median progressionfree survival (PFS) and eventfree survival were 17.3 and 7.1 months, respectively. The impaired performance status and age of 75 or older were negative predictors of PFS. The most common severe adverse events were neuropathy (19.4%), infections (19.2%), and neutropenia (14.9%). CONCLUSIONS Bortezomibbased regimens are effective and well tolerated in the firstline therapy of elderly patients with MM and comorbidities, with advanced disease, and light chain MM. A more detailed assessment of patients' frailty is needed to increase the efficacy of treatment.
Assuntos
Bortezomib/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Bortezomib/efeitos adversos , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/epidemiologia , Polônia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer. Cancer Res; 77(10); 2735-45. ©2017 AACR.