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2.
Mol Cell ; 81(6): 1170-1186.e10, 2021 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-33571422

RESUMO

The complex architecture of transmembrane proteins requires quality control (QC) of folding, membrane positioning, and trafficking as prerequisites for cellular homeostasis and intercellular communication. However, it has remained unclear whether transmembrane protein-specific QC hubs exist. Here we identify cereblon (CRBN), the target of immunomodulatory drugs (IMiDs), as a co-chaperone that specifically determines chaperone activity of HSP90 toward transmembrane proteins by means of counteracting AHA1. This function is abrogated by IMiDs, which disrupt the interaction of CRBN with HSP90. Among the multiple transmembrane protein clients of CRBN-AHA1-HSP90 revealed by cell surface proteomics, we identify the amino acid transporter LAT1/CD98hc as a determinant of IMiD activity in multiple myeloma (MM) and present an Anticalin-based CD98hc radiopharmaceutical for MM radio-theranostics. These data establish the CRBN-AHA1-HSP90 axis in the biogenesis of transmembrane proteins, link IMiD activity to tumor metabolism, and nominate CD98hc and LAT1 as attractive diagnostic and therapeutic targets in MM.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cadeia Pesada da Proteína-1 Reguladora de Fusão/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Fatores Imunológicos/farmacologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Chaperonas Moleculares/metabolismo , Mieloma Múltiplo/metabolismo , Proteínas de Neoplasias/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Células Tumorais Cultivadas
3.
BMC Infect Dis ; 21(1): 121, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509115

RESUMO

BACKGROUND: Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications. CASE PRESENTATION: We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/µl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis. CONCLUSIONS: This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest.


Assuntos
Anemia Aplástica/etiologia , Antígenos CD19/uso terapêutico , Aspergillus fumigatus/isolamento & purificação , Candida glabrata/isolamento & purificação , Imunoterapia Adotiva/efeitos adversos , Infecções Fúngicas Invasivas/etiologia , Anemia Aplástica/terapia , Antígenos CD19/efeitos adversos , Evolução Fatal , Humanos , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/terapia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade
4.
Arch Gynecol Obstet ; 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277683

RESUMO

PURPOSE: Comprehensive genomic profiling identifying actionable molecular alterations aims to enable personalized treatment for cancer patients. The purpose of this analysis was to retrospectively assess the impact of personalized recommendations made by a multidisciplinary tumor board (MTB) on the outcome of patients with breast or gynecological cancers, who had progressed under standard treatment. Here, first experiences of our Comprehensive Cancer Center Molecular Tumor Board are reported. METHODS: All patients were part of a prospective local registry. 95 patients diagnosed with metastatic breast cancer or gynecological malignancies underwent extended molecular profiling. From May 2017 through March 2019, the MTB reviewed all clinical cases considering tumor profile and evaluated molecular alterations regarding further diagnostic and therapeutic recommendations. RESULTS: 95 patients with metastatic breast or gynecological cancers were discussed in the MTB (68% breast cancer, 20% ovarian cancer, 5% cervical cancer, 3% endometrial cancer and 4% others). Genes with highest mutation rate were PIK3CA and ERBB2. Overall, 34 patients (36%) received a biomarker-based targeted therapy recommendation. Therapeutic recommendations were implemented in nine cases; four patients experienced clinical benefit with a partial response or disease stabilization lasting over 4 months. CONCLUSION: In the setting of a multidisciplinary molecular tumor board, a small but clinically meaningful group of breast and gynecological cancer patients benefits from comprehensive genomic profiling. Broad and successful implementation of precision medicine is complicated by patient referral at late stage disease and limited access to targeted agents and early clinical trials. TRIAL REGISTRATION NUMBER: 284-10 (03.05.2018).

5.
J Thromb Haemost ; 2020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33217134

RESUMO

OBJECTIVE: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can lead to severe pneumonia, but also thrombotic complications and non-pulmonary organ failure. Recent studies suggest intravascular neutrophil activation and subsequent immune cell triggered immunothrombosis as a central pathomechanism linking the heterogenous clinical picture of Coronavirus Disease 2019 (COVID-19). We sought to study whether immunothrombosis is a pathognomonic factor in COVID-19 or a general feature of (viral) pneumonia, as well as to better understand its upstream regulation. APPROACH AND RESULTS: By comparing histopathological specimens of SARS-CoV-2 with influenza affected lungs, we show that vascular neutrophil recruitment, NETosis, and subsequent immunothrombosis are typical features of severe COVID-19, but less prominent in influenza pneumonia. Activated neutrophils were typically found in physical association with monocytes. To explore this further, we combined clinical data of COVID-19 cases with comprehensive immune cell phenotyping and bronchoalveolar lavage fluid scRNA-seq data. We show that a HLADRlow CD9low monocyte population expands in severe COVID-19, which releases neutrophil chemokines in the lung, and might in turn explain neutrophil expansion and pulmonary recruitment in the late stages of severe COVID-19. CONCLUSIONS: In summary, our data underline an innate immune cell axis causing vascular inflammation and immunothrombosis in severe SARS-CoV-2 infection.

7.
Circulation ; 142(12): 1176-1189, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32755393

RESUMO

BACKGROUND: Severe acute respiratory syndrome corona virus 2 infection causes severe pneumonia (coronavirus disease 2019 [COVID-19]), but the mechanisms of subsequent respiratory failure and complicating renal and myocardial involvement are poorly understood. In addition, a systemic prothrombotic phenotype has been reported in patients with COVID-19. METHODS: A total of 62 subjects were included in our study (n=38 patients with reverse transcriptase polymerase chain reaction-confirmed COVID-19 and n=24 non-COVID-19 controls). We performed histopathologic assessment of autopsy cases, surface marker-based phenotyping of neutrophils and platelets, and functional assays for platelet, neutrophil functions, and coagulation tests, as well. RESULTS: We provide evidence that organ involvement and prothrombotic features in COVID-19 are linked by immunothrombosis. We show that, in COVID-19, inflammatory microvascular thrombi are present in the lung, kidney, and heart, containing neutrophil extracellular traps associated with platelets and fibrin. Patients with COVID-19 also present with neutrophil-platelet aggregates and a distinct neutrophil and platelet activation pattern in blood, which changes with disease severity. Whereas cases of intermediate severity show an exhausted platelet and hyporeactive neutrophil phenotype, patients severely affected with COVID-19 are characterized by excessive platelet and neutrophil activation in comparison with healthy controls and non-COVID-19 pneumonia. Dysregulated immunothrombosis in severe acute respiratory syndrome corona virus 2 pneumonia is linked to both acute respiratory distress syndrome and systemic hypercoagulability. CONCLUSIONS: Taken together, our data point to immunothrombotic dysregulation as a key marker of disease severity in COVID-19. Further work is necessary to determine the role of immunothrombosis in COVID-19.


Assuntos
Infecções por Coronavirus/diagnóstico , Pneumonia Viral/diagnóstico , Insuficiência Respiratória/etiologia , Betacoronavirus/genética , Betacoronavirus/isolamento & purificação , Transtornos da Coagulação Sanguínea/diagnóstico , Transtornos da Coagulação Sanguínea/etiologia , Plaquetas/citologia , Plaquetas/metabolismo , Plaquetas/patologia , Estudos de Casos e Controles , Infecções por Coronavirus/complicações , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/metabolismo , Humanos , Rim/patologia , Pulmão/patologia , Neutrófilos/citologia , Neutrófilos/metabolismo , Neutrófilos/patologia , Pandemias , Fenótipo , Ativação Plaquetária , Pneumonia Viral/complicações , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Insuficiência Respiratória/diagnóstico , Índice de Gravidade de Doença , Trombose/complicações , Trombose/diagnóstico
8.
Eur J Endocrinol ; 183(4): 453-462, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32567556

RESUMO

Purpose: We sought to refine the clinical picture of primary adrenal lymphoma (PAL), a rare lymphoid malignancy with predominant adrenal manifestation and risk of adrenal insufficiency. Methods: Ninety-seven patients from 14 centers in Europe, Canada and the United States were included in this retrospective analysis between 1994 and 2017. Results: Of the 81 patients with imaging data, 19 (23%) had isolated adrenal involvement (iPAL), while 62 (77%) had additional extra-adrenal involvement (PAL+). Among patients who had both CT and PET scans, 18FDG-PET revealed extra-adrenal involvement not detected by CT scan in 9/18 cases (50%). The most common clinical manifestations were B symptoms (55%), fatigue (45%), and abdominal pain (35%). Endocrinological assessment was often inadequate. With a median follow-up of 41.6 months, 3-year progression-free (PFS) and overall (OS) survival rates in the entire cohort were 35.5% and 39.4%, respectively. The hazard ratios of iPAL for PFS and OS were 40.1 (95% CI: 2.63-613.7, P = 0.008) and 2.69 (95% CI: 0.61-11.89, P = 0.191), respectively. PFS was much shorter in iPAL vs PAL+ (median 4 months vs not reached, P = 0.006), and OS also appeared to be shorter (median 16 months vs not reached), but the difference did not reach statistical significance (P = 0.16). Isolated PAL was more frequent in females (OR = 3.81; P = 0.01) and less frequently associated with B symptoms (OR = 0.159; P = 0.004). Conclusion: We found unexpected heterogeneity in the clinical spectrum of PAL. Further studies are needed to clarify whether clinical distinction between iPAL and PAL+ is corroborated by differences in molecular biology.


Assuntos
Neoplasias das Glândulas Suprarrenais/diagnóstico , Neoplasias das Glândulas Suprarrenais/epidemiologia , Linfoma/diagnóstico , Linfoma/epidemiologia , Neoplasias das Glândulas Suprarrenais/complicações , Insuficiência Adrenal/diagnóstico , Insuficiência Adrenal/epidemiologia , Insuficiência Adrenal/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Canadá/epidemiologia , Estudos de Coortes , Diagnóstico Diferencial , Europa (Continente)/epidemiologia , Feminino , Fluordesoxiglucose F18/farmacocinética , Humanos , Linfoma/complicações , Masculino , Pessoa de Meia-Idade , Imagem Multimodal , Fenótipo , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X , Estados Unidos/epidemiologia
9.
Br J Haematol ; 190(3): 361-370, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32350858

RESUMO

Hypomethylating agents (HMAs) are widely used in patients with higher-risk myelodysplastic syndromes (MDS) not eligible for stem cell transplantation; however, the response rate is <50%. Reliable predictors of response are still missing, and it is a major challenge to develop new treatment strategies. One current approach is the combination of azacytidine (AZA) with checkpoint inhibitors; however, the potential benefit of targeting the immunomodulator indoleamine-2,3-dioxygenase (IDO-1) has not yet been evaluated. We observed moderate to strong IDO-1 expression in 37% of patients with high-risk MDS. IDO-1 positivity was predictive of treatment failure and shorter overall survival. Moreover, IDO-1 positivity correlated inversely with the number of infiltrating CD8+ T cells, and IDO-1+ patients failed to show an increase in CD8+ T cells under AZA treatment. In vitro experiments confirmed tryptophan catabolism and depletion of CD8+ T cells in IDO-1+ MDS, suggesting that IDO-1 expression induces an immunosuppressive microenvironment in MDS, thereby leading to treatment failure under AZA treatment. In conclusion, IDO-1 is expressed in more than one-third of patients with higher-risk MDS, and is predictive of treatment failure and shorter overall survival. Therefore, IDO-1 is emerging as a promising predictor and therapeutic target, especially for combination therapies with HMAs or checkpoint inhibitors.

10.
Cell Rep ; 31(5): 107522, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32330423

RESUMO

Tumor cells orchestrate their microenvironment. Here, we provide biochemical, structural, functional, and clinical evidence that Cathepsin S (CTSS) alterations induce a tumor-promoting immune microenvironment in follicular lymphoma (FL). We found CTSS mutations at Y132 in 6% of FL (19/305). Another 13% (37/286) had CTSS amplification, which was associated with higher CTSS expression. CTSS Y132 mutations lead to accelerated autocatalytic conversion from an enzymatically inactive profrom to active CTSS and increased substrate cleavage, including CD74, which regulates major histocompatibility complex class II (MHC class II)-restricted antigen presentation. Lymphoma cells with hyperactive CTSS more efficiently activated antigen-specific CD4+ T cells in vitro. Tumors with hyperactive CTSS showed increased CD4+ T cell infiltration and proinflammatory cytokine perturbation in a mouse model and in human FLs. In mice, this CTSS-induced immune microenvironment promoted tumor growth. Clinically, patients with CTSS-hyperactive FL had better treatment outcomes with standard immunochemotherapies, indicating that these immunosuppressive regimens target both the lymphoma cells and the tumor-promoting immune microenvironment.

11.
J Clin Invest ; 130(6): 2827-2844, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32338640

RESUMO

Inherited bone marrow failure syndromes (IBMFSs) are a heterogeneous group of disorders characterized by defective hematopoiesis, impaired stem cell function, and cancer susceptibility. Diagnosis of IBMFS presents a major challenge due to the large variety of associated phenotypes, and novel, clinically relevant biomarkers are urgently needed. Our study identified nuclear interaction partner of ALK (NIPA) as an IBMFS gene, as it is significantly downregulated in a distinct subset of myelodysplastic syndrome-type (MDS-type) refractory cytopenia in children. Mechanistically, we showed that NIPA is major player in the Fanconi anemia (FA) pathway, which binds FANCD2 and regulates its nuclear abundance, making it essential for a functional DNA repair/FA/BRCA pathway. In a knockout mouse model, Nipa deficiency led to major cell-intrinsic defects, including a premature aging phenotype, with accumulation of DNA damage in hematopoietic stem cells (HSCs). Induction of replication stress triggered a reduction in and functional decline of murine HSCs, resulting in complete bone marrow failure and death of the knockout mice with 100% penetrance. Taken together, the results of our study add NIPA to the short list of FA-associated proteins, thereby highlighting its potential as a diagnostic marker and/or possible target in diseases characterized by hematopoietic failure.

12.
J Clin Invest ; 130(6): 3270-3286, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32191641

RESUMO

Single-nucleotide polymorphisms and locus amplification link the NF-κB transcription factor c-Rel to human autoimmune diseases and B cell lymphomas, respectively. However, the functional consequences of enhanced c-Rel levels remain enigmatic. Here, we overexpressed c-Rel specifically in mouse B cells from BAC-transgenic gene loci and demonstrate that c-Rel protein levels linearly dictated expansion of germinal center B (GCB) cells and isotype-switched plasma cells. c-Rel expression in B cells of otherwise c-Rel-deficient mice fully rescued terminal B cell differentiation, underscoring its critical B cell-intrinsic roles. Unexpectedly, in GCB cells transcription-independent regulation produced the highest c-Rel protein levels among B cell subsets. In c-Rel-overexpressing GCB cells this caused enhanced nuclear translocation, a profoundly altered transcriptional program, and increased proliferation. Finally, we provide a link between c-Rel gain and autoimmunity by showing that c-Rel overexpression in B cells caused autoantibody production and renal immune complex deposition.

13.
Mol Cancer Res ; 18(2): 278-286, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31704732

RESUMO

Mechanisms of intrinsic resistance of serous ovarian cancers to standard treatment with carboplatin and paclitaxel are poorly understood. Seventeen primary serous ovarian cancers classified as responders or nonresponders to standard treatment were screened with DigiWest protein array analysis for 279 analytes. Histone methyl transferase EZH2, an interaction partner of ataxia telangiectasia mutated (ATM), was found as one of the most significantly represented proteins in responsive tumors. Survival analysis of 616 patients confirmed a better outcome in patients with high EZH2 expression, but a worse outcome in patients with low EZH2 and high-ATM-expressing tumors compared with patients with low EZH2 and low-ATM-expressing tumors. A proximity ligation assay further confirmed an association between ATM and EZH2 in tumors of patients with an increased disease-free survival. Knockdown of EZH2 resulted in treatment-resistant cells, but suppression of both EZH2 and ATM, or ATM alone, had no effect. DigiWest protein analysis of EZH2-knockdown cells revealed a decrease in proteins involved in mitotic processes and checkpoint regulation, suggesting that deregulated ATM may induce treatment resistance. IMPLICATIONS: Ovarian cancer is a malignancy with high mortality rates, with to date, no successful molecular characterization strategies. Our study uncovers in a comprehensive approach the involvement of checkpoint regulation via ATM and EZH2, potentially providing a new therapeutic perspective for further investigations.

14.
Oncogene ; 39(9): 1904-1913, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31754210

RESUMO

Targeted expression of transgenes is essential for the accurate representation of human disease in in vivo models. Current approaches to generate conditional transgenic mouse models are cumbersome and not amenable to high-throughput analysis since they require de novo generation and characterization of genetically modified mice. Here we describe a new system for lineage-restricted expression of transgenes based on a retroviral vector incorporating a translational stop cassette flanked by loxP recombination sites. Conditional transgene expression in chimeric mice is achieved by retroviral infection and transplantation of hematopoietic stem cells (HSC) derived from transgenic mice expressing Cre-recombinase from a lineage-specific promoter. For validation, we directed expression of NPM-ALK, the fusion oncogene driving a subset of anaplastic large cell lymphoma (ALCL), to T-cells by infecting hematopoietic stem cells from Lck-Cre-transgenic mice with a retroviral construct containing the NPM-ALK cDNA preceded by a translational stop cassette. These mice developed T-cell lymphomas within 12-16 weeks, featuring increased expression of the ALCL hallmark antigen CD30 as well as other cytotoxic T-cell markers, similar to the human disease. The new model represents a versatile tool for the rapid analysis of gene function in a defined lineage or in a developmental stage in vivo.


Assuntos
Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Linfoma de Células T/patologia , Processamento de Proteína Pós-Traducional , Proteínas Tirosina Quinases/metabolismo , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma de Células T/genética , Linfoma de Células T/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Tirosina Quinases/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Proc Natl Acad Sci U S A ; 116(48): 24275-24284, 2019 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-31712432

RESUMO

T cells expressing anti-CD19 chimeric antigen receptors (CARs) demonstrate impressive efficacy in the treatment of systemic B cell malignancies, including B cell lymphoma. However, their effect on primary central nervous system lymphoma (PCNSL) is unknown. Additionally, the detailed cellular dynamics of CAR T cells during their antitumor reaction remain unclear, including their intratumoral infiltration depth, mobility, and persistence. Studying these processes in detail requires repeated intravital imaging of precisely defined tumor regions during weeks of tumor growth and regression. Here, we have combined a model of PCNSL with in vivo intracerebral 2-photon microscopy. Thereby, we were able to visualize intracranial PCNSL growth and therapeutic effects of CAR T cells longitudinally in the same animal over several weeks. Intravenous (i.v.) injection resulted in poor tumor infiltration of anti-CD19 CAR T cells and could not sufficiently control tumor growth. After intracerebral injection, however, anti-CD19 CAR T cells invaded deeply into the solid tumor, reduced tumor growth, and induced regression of PCNSL, which was associated with long-term survival. Intracerebral anti-CD19 CAR T cells entered the circulation and infiltrated distant, nondraining lymph nodes more efficiently than mock CAR T cells. After complete regression of tumors, anti-CD19 CAR T cells remained detectable intracranially and intravascularly for up to 159 d. Collectively, these results demonstrate the great potential of anti-CD19 CAR T cells for the treatment of PCNSL.


Assuntos
Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia Adotiva/métodos , Microscopia Intravital/métodos , Linfoma/terapia , Linfócitos T/transplante , Animais , Antígenos CD19/análise , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Contagem de Células , Movimento Celular , Neoplasias do Sistema Nervoso Central/diagnóstico por imagem , Neoplasias do Sistema Nervoso Central/patologia , Citotoxicidade Imunológica , Fatores de Transcrição Forkhead/genética , Humanos , Injeções Intravenosas , Injeções Intraventriculares , Linfoma/diagnóstico por imagem , Linfoma/patologia , Masculino , Camundongos Mutantes , Neoplasias Experimentais/patologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/imunologia , Análise Espaço-Temporal , Linfócitos T/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Blood Cancer J ; 9(8): 63, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399557

RESUMO

Lymphopenia is associated with an increased mortality in several medical conditions. Its prognostic impact in myelodysplastic syndromes (MDS) is less well studied. Hence, we analyzed 1023 patients from the Düsseldorf MDS-registry with regard to the absolute lymphocyte count (ALC) at diagnosis. An ALC below the median of the population (1.2 × 109/l) was associated with lower counts of neutrophils (median 1.35 vs. 1.92 × 109/l, p < 0.001) and platelets (median 100 vs. 138 × 109/l, p < 0.001) and with a significant lower overall survival in univariate analysis (whole cohort: median 36 vs. 46 months, p = 0.016; 721 patients without hematopoietic stem cell transplantation or induction chemotherapy: median 36 vs. 56 months, p = 0.001). For low-risk MDS according to IPSS-R, an ALC < 1.2 × 109/l was of additional prognostic value in a multivariate Cox regression model together with age (< or ≥65 years) and LDH (< or ≥normal value of 240 U/l; HR 1.46, 95% CI: 1.03-2.08, p = 0.033). These data support the hypothesis of subtle but clinical relevant changes of the adaptive immune system in MDS. Further studies are necessary to identify the ALC cut-off best suitable for prognostication and the mechanisms responsible for the impairment of lymphoid homeostasis in MDS.


Assuntos
Linfopenia/sangue , Síndromes Mielodisplásicas/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Contagem de Linfócitos , Linfopenia/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Nomogramas , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Adulto Jovem
17.
Acta Haematol ; 141(4): 225-231, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30965326

RESUMO

BACKGROUND/AIMS: There is growing evidence supporting the role of innate immune deregulation and inflammation in the pathogenesis of myelodysplastic syndromes (MDS). Vitamin D (VD) is known to be involved in various immune and epigenetic processes. This analysis aimed to evaluate serum VD levels in patients with MDS and to analyze associations between serum VD levels and disease characteristics. METHODS: Serum levels of 25-hydroxyvitamin D3 (25(OH)-D3), the major form of VD in human serum, were measured by chemiluminescence immunoassay in 62 unselected patients with MDS. Associations between serum 25(OH)-D3 levels and disease characteristics were analyzed using Kendall's tau and two-sided p values. RESULTS: The median serum 25(OH)-D3 level was markedly reduced (17.5 ng/mL). Patients with lower-risk disease features had lower serum 25(OH)-D3 levels than patients with higher-risk disease features with regard to medullary blast counts (16 vs. 31 ng/mL, p < 0.001), the revised international prognostic scoring system (13 vs. 30.5 ng/mL, p = 0.001), and blood counts. CONCLUSIONS: We show that patients with lower-risk disease characteristics exhibit lower serum VD levels than patients with higher-risk disease characteristics. Whether these findings might reflect innate immune deregulation has to be investigated in further studies.


Assuntos
Crise Blástica/sangue , Calcifediol/sangue , Síndromes Mielodisplásicas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Crise Blástica/patologia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Estudos Retrospectivos
18.
Oncotarget ; 9(16): 12769-12780, 2018 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-29560108

RESUMO

Recently the Aurora-Kinases (Aurk) moved into the focus as novel disease related biomarkers and therapeutic targets. Elevated Aurora-Kinase expression has been found in a number of malignancies, amongst them HNSCC. For esophageal cancer, the AurkA Phe31-Ile polymorphism has previously been associated with tumor progression. Here we evaluated the treatment efficiency of HNSCC cell radiation as a function of Aurora-Kinases in HNSCC cell lines. Moreover, we investigated a potential sensitization to radiation by a cell treatment with the inhibitors Alisertib, Barasertib, Docetaxel and VX-680. In parallel the radiation dependent expression and regulation of AurkA/B, p-Akt Ser 473 and Survivin and the AurkA polymorphism were investigated in primary tumor samples. We identified a high-risk collective with elevated AurkA and Survivin or AurkA and p-Akt Ser 473 expression. High AurkA, AurkB, and p-Akt Ser 473 expression was exclusively found in the heterozygous cell line. We found a polymorphism dependent sensitivity to treatments with different Aurk inhibitors: The homozygous cell line UD-SCC-5 could be sensitized to radiation with Docetaxel in combination with any of the Aurora-Kinase inhibitors. In contrast, treatment with Docetaxel or radiation did not enhance the inhibitory effect of Barasertib or VX-680 in the heterozygous SAS cell line. These findings indicate that the Aurora-Kinase A Phe31-Ile-polymorphism is a possibly predictive factor for response to radiation in combination with Docetaxel and Aurora-Kinase inhibitor treatments.

19.
Cell Death Dis ; 9(2): 86, 2018 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-29367645

RESUMO

Drug resistance is a significant obstacle in cancer treatment and therefore a frequent subject of research. Developed or primary resistance limits the treatment success of inhibitors of the B cell receptor (BCR) pathway in mantle cell lymphoma (MCL) patients. Recent research has highlighted the role of the nuclear factor-kappa B (NFκB) pathway in the context of resistance to BCR inhibitors in MCL. In this study, we analyzed the dependency of MCL cell lines on NFκB signaling and illustrated the ability of CD40L to activate the alternative NFκB pathway in MCL. This activation leads to independency of classical NFκB signaling and results in resistance to BCR inhibitors. Therefore, ligands (such as CD40L) and their activation of the alternative NFκB pathway have a major impact on the drug response in MCL. Furthermore, this study indicates a protective role for cells expressing specific ligands as microenvironmental niches for MCL cells and underlines the significance of therapeutically targeting alternative NFκB signaling in MCL.


Assuntos
Ligante de CD40/metabolismo , Resistencia a Medicamentos Antineoplásicos , Linfoma de Célula do Manto/metabolismo , NF-kappa B/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais , Linhagem Celular Tumoral , Humanos , Quinase I-kappa B/metabolismo , Proteínas Recombinantes/farmacologia
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