RESUMO
Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.
Assuntos
L-Aminoácido Oxidase/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Adulto , Idoso , Animais , Linhagem Celular , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Glioma/imunologia , Glioma/metabolismo , Glioma/terapia , Células HEK293 , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Leucemia Linfocítica Crônica de Células B/imunologia , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , RatosRESUMO
T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Here, we explored the microenvironmental signals regulating T cell exhaustion using a model of chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset of PD-1hi, functionally impaired CD8+ T cells that accumulated in secondary lymphoid organs during disease progression and a functionally competent PD-1int subset. Frequencies of PD-1int TCF-1+ CD8+ T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1hi cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signaling altered chromatin accessibility and disrupted cooperativity between the transcription factors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequencies of exhausted CD8+ T cells and poor survival in CLL and in breast cancer patients. Thus, balance between PD-1hi, exhausted CD8+ T cells and functional PD-1int TCF-1+ CD8+ T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Leucemia Linfocítica Crônica de Células B/imunologia , Receptores de Interleucina-10/metabolismo , Subpopulações de Linfócitos T/imunologia , Animais , Linhagem Celular Tumoral , Células Cultivadas , Microambiente Celular , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Humanos , Imunidade , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição NFATC/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptores de Interleucina-10/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/metabolismoRESUMO
The gut microbiota play a critical role in maintaining a healthy human body and their dysregulation is associated with various diseases. In this study, we investigated the influence of the gut microbiome diversity on chronic lymphocytic leukemia (CLL) development. Stool sample analysis of 59 CLL patients revealed individual and heterogeneous microbiome compositions, but allowed for grouping of patients according to their microbiome diversity. Interestingly, CLL patients with a lower microbiome diversity and an enrichment of bacteria linked to poor health suffered from a more advanced or aggressive form of CLL. In the Eµ-TCL1 mouse model of CLL, we observed a faster course of disease when mice were housed in high hygiene conditions. Shotgun DNA sequencing of fecal samples showed that this was associated with a lower microbiome diversity which was dominated by Mucispirillum and Parabacteroides genera in comparison to mice kept under lower hygiene conditions. In conclusion, we applied taxonomic microbiome analyses to demonstrate a link between the gut microbiome diversity and the clinical course of CLL in humans, as well as the development of CLL in mice. Our novel data serve as a basis for further investigations to decipher the pathological and mechanistic role of intestinal microbiota in CLL development.
RESUMO
Clonal evolution is involved in the progression of chronic lymphocytic leukemia (CLL). In order to link evolutionary patterns to different disease courses, we performed a long-term longitudinal mutation profiling study of CLL patients. Tracking somatic mutations and their changes in allele frequency over time and assessing the underlying cancer cell fraction revealed highly distinct evolutionary patterns. Surprisingly, in long-term stable disease and in relapse after long-lasting clinical response to treatment, clonal shifts are minor. In contrast, in refractory disease major clonal shifts occur although there is little impact on leukemia cell counts. As this striking pattern in refractory cases is not linked to a strong contribution of known CLL driver genes, the evolution is mostly driven by treatment-induced selection of sub-clones, underlining the need for novel, non-genotoxic treatment regimens.
Assuntos
Leucemia Linfocítica Crônica de Células B , Evolução Clonal/genética , Células Clonais , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/genética , Estudos Longitudinais , MutaçãoRESUMO
This study aims to investigate the determinants of the quality MRI in the Turkish healthcare system. The analysis is done by analysing the referred cases to a major university radiology department in Turkey, and matching the hospital and MRI use characteristics of the source institutions, where the original MRI was taken. Quality of MRI was measured by specialist radiologists. The resulting quality was analysed by gender and imaging area characteristics, source institutional quality, MRI use statistics in source institution and MRI machine use inclination of the source institution. Chi-square and logistic regression were conducted, with regional fixed effects. In the largest dataset, the highest quality institutions have significantly higher average expected MRI quality compared to one level beneath them (0.74 vs. 0.63) (P = 0.02), there is also a significant MRI quality difference between the second highest level of institution, and the third and the fourth (0.63-0.54). Smaller (<0.1) but significant quality difference (P = 0.05) exists for institutions with the lowest two quality levels. In the smaller dataset, with data only from the lowest two institutional quality groups, with a finer institutional quality grading, differences in institutional quality is again found to be a significant driver of MRI quality (P = 0.035).
Assuntos
Imageamento por Ressonância Magnética , Humanos , TurquiaRESUMO
Chronic lymphocytic leukaemia (CLL) is associated with alterations in T cell number, subset distribution and function. Among these changes, an increase in CD4+ T cells was reported. CD4+ T cells are a heterogeneous population and distinct subsets have been described to exert pro- and anti-tumour functions. In CLL, controversial reports describing the dominance of IFNγ-expressing Th1 T cells or of IL-4-producing Th2 T cells exist. Our study shows that blood of CLL patients is enriched in Th1 T cells producing high amounts of IFNγ. Moreover, we observed that their frequency remains relatively stable in CLL patients over a time course of five years. Furthermore, we provide evidence for an accumulation of Th1 T cells in the Eµ-TCL1 mouse model of CLL. As TBET (encoded by Tbx21) is a crucial transcription factor for Th1 polarization, we generated Tbx21-/- bone marrow chimaeric mice which showed a lower number of IFNγ-producing Th1 T cells, and used them for adoptive transfer of Eµ-TCL1 leukaemia. Disease development in these mice was, however, comparable to that in wild-type controls, excluding a major role for TBET-expressing Th1 cells in Eµ-TCL1 leukaemia. Collectively, our data highlight that Th1 T cells accumulate in CLL but reducing their number has no impact on disease development.
Assuntos
Regulação Leucêmica da Expressão Gênica/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Proteínas de Neoplasias/imunologia , Neoplasias Experimentais/imunologia , Proteínas com Domínio T/imunologia , Células Th1/imunologia , Animais , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/genética , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Proteínas com Domínio T/genética , Células Th1/patologiaRESUMO
The CD95 (Fas/APO-1) death-inducing signaling complex (DISC) is essential for the initiation of CD95-mediated apoptotic and nonapoptotic responses. The CD95 DISC comprises CD95, FADD, procaspase-8, procaspase-10, and c-FLIP proteins. Procaspase-8 and procaspase-10 are activated at the DISC, leading to the formation of active caspases and apoptosis initiation. In this study we analyzed the stoichiometry of the CD95 DISC. Using quantitative western blots, mass spectrometry, and mathematical modeling, we reveal that the amount of DED proteins procaspase-8/procaspase-10 and c-FLIP at the DISC exceeds that of FADD by several-fold. Furthermore, our findings imply that procaspase-8, procaspase-10, and c-FLIP could form DED chains at the DISC, enabling the formation of dimers and efficient activation of caspase-8. Taken together, our findings provide an enhanced understanding of caspase-8 activation and initiation of apoptosis at the DISC.
Assuntos
Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Transdução de Sinais , Receptor fas/química , Apoptose , Caspase 10/metabolismo , Caspase 8/metabolismo , Dimerização , Proteína de Domínio de Morte Associada a Fas/metabolismo , Células HeLa , Humanos , Espectrometria de Massas/métodos , Microscopia de Fluorescência/métodos , Modelos Biológicos , Modelos Teóricos , Receptor fas/metabolismoRESUMO
Chronic lymphocytic leukemia is a malignancy of mature B cells that strongly depend on microenvironmental factors, and their deprivation has been identified as a promising treatment approach for this incurable disease. Cytokine array screening of 247 chronic lymphocytic leukemia serum samples revealed elevated levels of tumor necrosis factor (TNF) receptor-1 which were associated with poor clinical outcome. We detected a microenvironment-induced expression of TNF receptor-1 in chronic lymphocytic leukemia cells in vitro, and an aberrantly high expression of this receptor in the proliferation centers of patients' lymph nodes. Stimulation of TNF receptor-1 with TNF-α enhanced nuclear factor κ-light-chain-enhancer of activated B cells (NFκB) activity and viability of chronic lymphocytic leukemia cells, which was inhibited by wogonin. The therapeutic effects of wogonin were analyzed in mice after adoptive transfer of Eµ-T-cell leukemia 1 (TCL1) leukemic cells. Wogonin treatment prevented leukemia development when given early after transplantation. The treatment of full-blown leukemia resulted in the loss of the TNF receptor-1 on chronic lymphocytic leukemia cells and their mobilization to blood. Targeting TNF receptor-1 signaling is therefore proposed for the treatment of chronic lymphocytic leukemia.
Assuntos
Flavanonas/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Transferência Adotiva , Animais , Técnicas de Cocultura , Humanos , Leucemia/patologia , Leucemia/prevenção & controle , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfonodos/metabolismo , Camundongos , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacosRESUMO
c-FLIP proteins (isoforms: c-FLIP(L), c-FLIP(S), and c-FLIP(R)) play an essential role in the regulation of death receptor (DR)-induced apoptosis and NF-κB activation. Here, we discuss multiple mechanisms by which c-FLIPs control NF-κB activation and the life/death decision made in cancer and immune cells. We focus on the role of c-FLIP in cellular signaling. We concentrate on c-FLIP protein modifications as well as on the regulation of c-FLIP expression levels. Furthermore, we discuss in detail how the exact quantity and dynamics of different c-FLIP isoforms in the cell influence the induction of pro- versus anti-apoptotic pathways.
Assuntos
Apoptose , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/fisiologia , NF-kappa B/metabolismo , Proteína Reguladora de Apoptosis Semelhante a CASP8 e FADD/metabolismo , Humanos , Isoformas de Proteínas , Transdução de SinaisRESUMO
Chronic lymphocytic leukemia (CLL) is a B-cell malignancy mainly occurring at an advanced age with no single major genetic driver. Transgenic expression of TCL1 in B cells leads after a long latency to a CLL-like disease in aged Eµ-TCL1 mice suggesting that TCL1 overexpression is not sufficient for full leukemic transformation. In search for secondary genetic events and to elucidate the clonal evolution of CLL, we performed whole exome and B-cell receptor sequencing of longitudinal leukemia samples of Eµ-TCL1 mice. We observed a B-cell receptor stereotypy, as described in patients, confirming that CLL is an antigen-driven disease. Deep sequencing showed that leukemia in Eµ-TCL1 mice is mostly monoclonal. Rare oligoclonality was associated with inability of tumors to develop disease upon adoptive transfer in mice. In addition, we identified clonal changes and a sequential acquisition of mutations with known relevance in CLL, which highlights the genetic similarities and therefore, suitability of the Eµ-TCL1 mouse model for progressive CLL. Among them, a recurrent gain of chromosome 15, where Myc is located, was identified in almost all tumors in Eµ-TCL1 mice. Interestingly, amplification of 8q24, the chromosomal region containing MYC in humans, was associated with worse outcome of patients with CLL.
Assuntos
Evolução Clonal , Mutação com Ganho de Função , Leucemia Linfocítica Crônica de Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas/metabolismo , Animais , Cromossomos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas/genéticaRESUMO
This study aims to examine the prevalence and determinants of unmet health care needs in Turkey. The nationally representative "Health Survey" data for the latest available year, 2016, is used in the analysis. The reasons for unmet health care needs are divided into three categories which are waiting time, affordability (cost), and the distance to health facilities. The probit methodology is employed to investigate the factors affecting unmet health care needs. Approximately 25% of participants (4392 of 17242) reported an unmet need for health care. Overall, females, individuals in lower income groups, those with chronic illness, those with lower education levels and those in younger age groups are more likely to report unmet health care needs. Estimation results point out that age and having a chronic illness have more influence on the reporting of unmet health care needs as compared to other variables included in the model. Therefore, it seems necessary to reorganize the health care system in Turkey to target the needs of individuals with chronic diseases.
Assuntos
Acessibilidade aos Serviços de Saúde , Necessidades e Demandas de Serviços de Saúde , Feminino , Instalações de Saúde , Humanos , Prevalência , TurquiaRESUMO
Indoleamine-2,3-dioxygenase 1 (IDO1), a tryptophan (Trp)-catabolizing enzyme producing metabolites such as kynurenine (Kyn), is expressed by myeloid-derived suppressor cells (MDSCs) and associated with cancer immune escape. IDO1-expressing monocytic MDSCs were shown to accumulate in patients with chronic lymphocytic leukemia (CLL) and to suppress T cell activity and induce suppressive regulatory T cells (Tregs) in vitro. In the Eµ-TCL1 mouse model of CLL, we observed a strong upregulation of IDO1 in monocytic and granulocytic MDSCs, and a significantly increased Kyn to Trp serum ratio. To explore the potential of IDO1 as a therapeutic target for CLL, we treated mice after adoptive transfer of Eµ-TCL1 leukemia cells with the IDO1 modulator 1-methyl-D-tryptophan (1-MT) which resulted in a minor reduction in leukemia development which disappeared over time. 1-MT treatment further led to a partial rescue of the immune cell changes that are induced with CLL development. Similarly, treatment of leukemic mice with the clinically investigated IDO1 inhibitor epacadostat reduced the frequency of Tregs and initially delayed CLL development slightly, an effect that was, however, lost at later time points. In sum, despite the observed upregulation of IDO1 in CLL, its inhibition is not sufficient to control leukemia development in the Eµ-TCL1 adoptive transfer model.
RESUMO
Genome-wide association studies identified a single-nucleotide polymorphism (SNP) affecting the transcription factor Eomesodermin (EOMES) associated with a significantly increased risk to develop chronic lymphocytic leukemia (CLL). Epigenetic analyses, RNA sequencing, and flow cytometry revealed that EOMES is not expressed in CLL cells, but in CD8+ T cells for which EOMES is a known master regulator. We thus hypothesized that the increased CLL risk associated with the EOMES SNP might be explained by its negative impact on CD8+ T-cell-mediated immune control of CLL. Flow cytometry analyses revealed a higher EOMES expression in CD8+ T cells of CLL patients compared to healthy individuals, and an accumulation of PD-1+ EOMES+ CD8+ T cells in lymph nodes rather than blood or bone marrow in CLL. This was in line with an observed expansion of EOMES+ CD8+ T cells in the spleen of leukemic Eµ-TCL1 mice. As EOMES expression was highest in CD8+ T cells that express inhibitory receptors, an involvement of EOMES in T-cell exhaustion and dysfunction seems likely. Interestingly, Eomes-deficiency in CD8+ T cells resulted in their impaired expansion associated with decreased CLL control in mice. Overall, these observations suggest that EOMES is essential for CD8+ T-cell expansion and/or maintenance, and therefore involved in adaptive immune control of CLL.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Linfonodos/imunologia , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/fisiologia , Animais , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas com Domínio T/genéticaRESUMO
BACKGROUND: Equity in healthcare services utilization is on the agenda for both research and policy makers, especially after the Millennium Development Goals. Despite the recognition of the importance of mental health services utilization, equity in terms of access has not been widely researched. OBJECTIVE: This study aims to investigate the degree and progress of equity in mental healthcare services utilization in Turkey from a gender perspective. METHODS: The Horizontal Inequity (HI) index is calculated using a nationally representative dataset from the Health Surveys (2014 and 2016) conducted by the Turkish Statistical Institute. The index is calculated for males, females, and all individuals separately to identify gender differences. RESULTS: The results from the HI index indicate pro-poor inequities in the utilization of mental healthcare services in Turkey for both 2014 and 2016. For all individuals, the standardized HI indices were found to be - 0.3320 and - 0.3374 for 2014 and 2016, respectively. In 2014, the standardized HI indices were calculated to be - 0.3504 and - 0.3173 for males and females, respectively. In 2016, the HI indices were found to be - 0.3241 and - 0.3541 for females and males, respectively. CONCLUSIONS: There is a great need for gender-focused policies to improve horizontal equity in mental healthcare services utilization.
Assuntos
Disparidades em Assistência à Saúde , Serviços de Saúde Mental , Aceitação pelo Paciente de Cuidados de Saúde , Adolescente , Adulto , Idoso , Feminino , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Turquia , Adulto JovemRESUMO
BACKGROUND: Equity in the use of health care services is an issue which has increasingly been on the health policy agenda over recent years in both middle- and low-income countries. AIMS: The purpose of this study was to investigate the degree and progress of equity in health care utilization in Turkey during 2008-2012. METHODS: Wed use data from health surveys (2008, 2010, 2012) conducted by the Turkish Statistical Institute. The concentration index (CI) and the horizontal equity index (HI) were calculated as a measure of equity, and a Blinder-Oaxaca decomposition analysis was applied. RESULTS: The general practitioner (GP), specialist and inpatient visits display a pro-poor orientation. Averages of the CI and HI indices for 2008-2012 were 0.74 and -0.17 for GP visits, 0.75 and -0.13 for specialist visits, 0.83 and -0.31 for inpatient visits. CONCLUSION: Our findings indicate that health care utilization in Turkey appears to have become equitable over the years; however, the sustainability of equity is an issue of concern.
Assuntos
Disparidades em Assistência à Saúde/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adolescente , Adulto , Idoso , Feminino , Medicina Geral/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Medicina/estatística & dados numéricos , Pessoa de Meia-Idade , Fatores Socioeconômicos , Inquéritos e Questionários , Turquia , Adulto JovemRESUMO
Chronic lymphocytic leukemia (CLL) is associated with an accumulation of oligoclonal CD8+ effector T-cells, which control leukemia progression in mice, but gradually acquire a dysfunctional phenotype along with disease progression. Exhaustion of CD8+ T-cells is characterized by increased expression of inhibitory receptors like PD-1, decreased proliferation, and reduced effector function such as cytokine production, which reduces anti-tumor control. Despite the accumulation of exhausted PD-1+ CD8+ T-cells in secondary lymphoid organs of CLL patients, immune checkpoint blockade as a means to reinvigorate anti-tumor T-cell activity has not shown the expected efficacy. This highlights the need for a better understanding of T-cell exhaustion in CLL. Here, we uncover the transcriptional program of T-cell exhaustion in CLL by comparing naïve with dysfunctional effector CD8+ T-cells with high PD-1 expression from mice after adoptive transfer of Eµ-TCL1 leukemic cells. Our data provide clear evidence for activation-induced dysfunction of CD8+ T-cells in the CLL microenvironment and assess the heterogeneity in the expression of functionally relevant proteins in specific clusters of CD8+ T-cells at a single-cell level.
Assuntos
Leucemia Linfocítica Crônica de Células B , Animais , Linfócitos T CD8-Positivos , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Ativação Linfocitária , Camundongos , Fenótipo , Microambiente TumoralRESUMO
Tumor-promoting inflammation and escape from immune-mediated tumor destruction have been recognized as hallmarks of cancer, and myeloid cells are key players in these processes. By exploiting the tremendous plasticity of myeloid cells, tumors induce a variety of tumor-supportive and immunosuppressive cell phenotypes like tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). The relevance of these cell types in hematopoietic malignancies has only recently gained a stronger attention. Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that expand in secondary lymphoid organs and the bone marrow, and accumulate in the blood of patients. A large body of evidence suggests that the interactions between CLL cells and non-malignant cells in the tumor microenvironment play a key role in the pathology of this disease. CLL is associated with an inflammatory milieu and defective immune responses. A severe skewing of myeloid and T cells toward leukemia-supportive and immunosuppressive phenotypes have been observed in patient samples and the Eµ-TCL1 mouse model of CLL. Myeloid cells were thereby shown to enhance survival of CLL cells and contribute to apoptosis-resistance, to suppress anti-tumoral immunity, and to be involved in immune deficiency of leukemia patients. In addition, treatment regimens that are currently used for CLL target not only directly the malignant cells, but have also an impact on non-malignant bystander cells, including myeloid cells. This review summarizes current literature on these aspects and gives a perspective on how our current knowledge might be used to design novel immunotherapeutic approaches that can be combined with CLL-targeting drugs to achieve better therapeutic responses in CLL patients.
Assuntos
Efeito Espectador/imunologia , Leucemia Linfocítica Crônica de Células B/imunologia , Células Mieloides/fisiologia , Microambiente Tumoral/imunologia , Animais , Linfócitos B/patologia , Linfócitos B/fisiologia , Efeito Espectador/fisiologia , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Macrófagos/patologia , Macrófagos/fisiologia , Camundongos , Células Supressoras Mieloides/fisiologia , Linfócitos T/patologia , Linfócitos T/fisiologiaRESUMO
BACKGROUND: Demographic and socio-economic factors determine pharmaceutical health care utilization for individuals. Prescription and non-prescription medicine use are expected to have different determinants. Even though prescription and non-prescription medicine use is being well researched for developed countries, there are only a few studies for developing countries. OBJECTIVES: This paper aims to analyze the socio-economic and individual characteristics that determine the use of prescription and non-prescription medicine. We examine the issue for the specific case of Turkey since Turkey's health system has undertaken significant changes in the last two decades and especially after 2003 with the "Health Transformation Programme". METHODS: Data from the nationally representative "Health Survey" are used in the analysis. The data set covers the 2008-2016 period with two-year intervals. Pooled multivariate logistic regression is employed to identify the underlying determinants of prescription and non-prescription medicine use. RESULTS: When compared to 2008, non-prescription medicine use decreases until 2012, however, an increasing trend appears after 2012. For prescription medicine use, a decreasing trend emerges after 2012. Findings from the marginal effects indicate that for non-prescription medicine use, the highest effect stems from the health status. For prescription medicine use, the highest marginal effects arise from age, health and employment status indicating the importance of the need and predisposing factors. CONCLUSION: Decreasing non-prescription medicine use largely depends on easier access to health care service utilization. Although having a health insurance has a positive relationship with prescription medicine use, there is still a problem for individuals living a rural area and heaving a lower income level since they are more likely to use non-prescription medicine.
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Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Medicamentos sem Prescrição , Medicamentos sob Prescrição , Feminino , Inquéritos Epidemiológicos , Humanos , Modelos Logísticos , Masculino , Saúde da População Rural , Fatores Socioeconômicos , Turquia , Saúde da População UrbanaRESUMO
Targeting B-cell receptor signaling using the PI3Kδ inhibitor idelalisib is a highly effective treatment option for relapsed/refractory chronic lymphocytic leukemia (CLL) patients. In addition to its direct impact on tumor cells, PI3Kδ inhibition can modulate the activity of regulatory T-cells (Tregs) resulting in enhanced anti-tumoral immune functions which may contribute to the success of PI3Kδ inhibitors in cancer therapy. The role of Tregs in CLL and their modulation by PI3Kδ inhibitors was so far poorly understood. Using the Eµ-TCL1 adoptive transfer model of CLL, we show that disease development induces the accumulation of activated and highly immunosuppressive Tregs. Depletion of CD25+ Tregs using anti-CD25 antibodies resulted in enhanced CD8+ T-cell activation, effector differentiation, and functional capacity. We further show that pharmacological inhibition of PI3Kδ effectively controlled disease and significantly decreased both CD25+ and CD25- Treg numbers, proliferation and activation status in CLL-bearing mice. Nonetheless, this PI3Kδ-mediated decrease in Tregs did not translate into better CD8+ T-cell function, as PI3Kδ inhibition concomitantly abrogated T-cell receptor signaling in CD8+ T-cells leading to decreased activation, effector cell differentiation and proliferation. Collectively, these data highlight the strong immunomodulatory effects of PI3Kδ inhibitors in CLL and are of relevance for a rational design of idelalisib-based combination therapies in CLL.
Assuntos
Antineoplásicos/farmacologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Leucemia Linfocítica Crônica de Células B/imunologia , Purinas/farmacologia , Quinazolinonas/farmacologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais , Linfócitos T Reguladores/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Chronic lymphocytic leukemia (CLL) is known for its strong dependency on the tumor microenvironment. We found progranulin (GRN), a protein that has been linked to inflammation and cancer, to be upregulated in the serum of CLL patients compared to healthy controls, and increased GRN levels to be associated with an increased hazard for disease progression and death. This raised the question of whether GRN is a functional driver of CLL. We observed that recombinant GRN did not directly affect viability, activation, or proliferation of primary CLL cells in vitro. However, GRN secretion was induced in co-cultures of CLL cells with stromal cells that enhanced CLL cell survival. Gene expression profiling and protein analyses revealed that primary mesenchymal stromal cells (MSCs) in co-culture with CLL cells acquire a cancer-associated fibroblast-like phenotype. Despite its upregulation in the co-cultures, GRN treatment of MSCs did not mimic this effect. To test the relevance of GRN for CLL in vivo, we made use of the Eµ-TCL1 CLL mouse model. As we detected strong GRN expression in myeloid cells, we performed adoptive transfer of Eµ-TCL1 leukemia cells to bone marrow chimeric Grn-/- mice that lack GRN in hematopoietic cells. Thereby, we observed that CLL-like disease developed comparable in Grn-/- chimeras and respective control mice. In conclusion, serum GRN is found to be strongly upregulated in CLL, which indicates potential use as a prognostic marker, but there is no evidence that elevated GRN functionally drives the disease.