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1.
Blood ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31697802

RESUMO

The genetic background of follicular lymphomas (FL) diagnosed in advanced clinical stages III/IV, frequently characterized by the t(14;18), has been substantially unraveled. Molecular features as exemplified in the m7FLIPI are important tools in risk stratification. In contrast, little information is available concerning localized-stage FL (clinical stages I/II), comprising approximately 20% of newly diagnosed FL in which the t(14;18) detection rate is only ~50%. To investigate the genetic background of localized-stage FL, patient cohorts of both advanced-stage and localized-stage FL, uniformly treated within phase III trials of the German Low-Grade Lymphoma Study Group (GLSG), were comparatively analyzed. Targeted gene expression (GE) profiling of 184 genes using the nCounter technology was performed in 110 localized-stage and 556 advanced-stage FL. By penalized Cox regression, a prognostic GE signature could not be identified in patients with advanced-stage FL, consistent with results from global tests and univariate regression. In contrast, it was possible to define robust GE signatures discriminating localized-stage and advanced-stage FL (AUC: 0.98) by penalized logistic regression. Of note, 3% of samples harboring an 'advanced-stage signature' in the localized-stage cohort demonstrated inferior failure-free survival (hazard ratio, HR, 7.1, p=0.0003). Likewise, in the advanced-stage cohort, 7% of samples with a 'localized-stage signature' had prolonged failure-free (HR 2.3, p=0.017) and overall survival (HR 3.4, p=0.072). These data support the concept of a biological difference between localized-stage and advanced-stage FL that might contribute to the superior outcome of localized FL.

2.
Int J Mol Sci ; 20(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640116

RESUMO

The growth of adipose tissue and its vasculature are tightly associated. Angiogenic factors have been linked to obesity, yet little is known about their expression during early childhood. To identify associations of angiogenic factors with characteristics on individual and tissue level, subcutaneous white adipose tissue samples were taken from 45 children aged 0-9 years undergoing elective surgery. We measured the expression of vascular endothelial growth factor A (VEFGA), fibroblast growth factor 1 and 2 (FGF1, FGF2), angiopoietin 1 and 2 (ANGPT1, ANGPT2), TEK receptor tyrosine kinase (TEK), and von Willebrand factor (VWF). In addition, we determined the mean adipocyte size in histologic tissue sections. We found positive correlations of age with FGF1 and FGF2 and a negative correlation with ANGPT2, with pronounced differences in the first two years of life. FGF1, FGF2, and ANGPT1 correlated positively with adipocyte size. Furthermore, we identified a correlation of ANGPT1 and TEK with body mass index-standard deviation score (BMI-SDS), a measure to define childhood obesity. Except for ANGPT2, all angiogenic factors correlated positively with the endothelial marker VWF. In sum, our findings suggest that differences related to BMI-SDS begin early in childhood, and the analyzed angiogenic factors possess distinct roles in adipose tissue biology.

3.
Leukemia ; 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530861

RESUMO

Diffuse large B-cell lymphoma (DLBCL) is a disease with heterogeneous outcome. Stromal signatures have been correlated to survival in DLBCL. Their use, however, is hampered by the lack of assays for formalin-fixed paraffin-embedded material (FFPE). We constructed a lymphoma-associated macrophage interaction signature (LAMIS) interrogating features of the microenvironment using a NanoString assay applicable to FFPE. The clinical impact of the signature could be validated in a cohort of 466 patients enrolled in prospective clinical trials of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Patients with high expression of the signature (LAMIShigh) had shorter EFS, PFS, and OS. Multivariate analyses revealed independence from IPI factors in EFS (HR 1.7, 95% CI 1.2-2.4, p-value = 0.001), PFS (HR 1.8, 95% CI 1.2-2.5, p-value = 0.001) and OS (HR 1.8, 95% CI 1.3-2.7, p-value = 0.001). Multivariate analyses adjusted for the IPI factors showed the signature to be independent from COO, MYC rearrangements and double expresser status (DE). LAMIShigh and simultaneous DE status characterized a patient subgroup with dismal prognosis and early relapse. Our data underline the importance of the microenvironment in prognosis. Combined analysis of stromal features, the IPI and DE may provide a new rationale for targeted therapy.

4.
Int J Cancer ; 145(12): 3436-3444, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31407331

RESUMO

There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue-saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV-positive and HPV-negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens and 8 oncogenes) and 29 HPV-antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV-positive and 209 HPV-negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c-myc, LAGE-1, MAGE-A1, -A3, -A4, NY-ESO-1, SpanX-a1 and p53. AR to MAGE-A3, MAGE-A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with ≤10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue-sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV-positive and HPV-negative HNSCC.

5.
Am J Hematol ; 94(11): 1208-1213, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31396979

RESUMO

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can present with different histopathological growth patterns. The impact of these histopathological growth patterns on relapse characteristics is unknown. We therefore analyzed paired biopsies obtained at initial diagnosis and relapse from 33 NLPHL patients who had received first-line treatment within German Hodgkin Study Group (GHSG) trial protocols, and from a second cohort of 41 relapsed NLPHL patients who had been treated outside GHSG studies. Among the 33 GHSG patients, 21 patients presented with a typical growth pattern at initial diagnosis, whereas 12 patients had a variant histology. The histopathological growth patterns at initial diagnosis and at relapse were consistent in 67% of cases. A variant histology at initial diagnosis was associated with a shorter median time to lymphoma recurrence (2.8 vs 5.2 years; P = .0219). A similar tendency towards a shorter median time to lymphoma recurrence was observed for patients presenting with a variant histology at relapse, irrespective of the growth pattern at initial diagnosis. Results obtained from the 41 NLPHL patients who had been treated outside GHSG studies were comparable (median time to lymphoma recurrence for variant histology vs typical growth pattern at initial diagnosis: 1.5 vs 7.0 years). In conclusion, the histopathological growth pattern remains consistent at relapse in the majority of NLPHL cases, and has major impact on the time of relapse.

6.
Immunotherapy ; 11(14): 1193-1203, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31462115

RESUMO

Aim: In a prospective clinical initiative, we selected heavily pretreated head and neck carcinoma patients and assessed the clinical utility of a protein-based oncopanel for identification of potential targetable markers. Patients & methods: Tumor samples of 45 patients were evaluated using a 12-marker immunohistochemistry panel. The primary end point was the prevalence of potentially actionable markers. Results: At least one expressed marker in each case could be identified. We noted a high prevalence of EGFR (80%, 39/45) and MET (57.4%, 28/45). Three patients received oncopanel-based therapy with variable results. Conclusion: Despite the limited number of treated subjects, oncopanel analysis in end-stage head and neck cancer is operationally and technically feasible. Combination with targeted next generation sequencing might provide additional therapy options.

8.
Mutat Res ; 781: 71-87, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31416580

RESUMO

The comet assay offers the opportunity to measure both DNA damage and repair. Various comet assay based methods are available to measure DNA repair activity, but some requirements should be met for their effective use in human biomonitoring studies. These conditions include i) robustness of the assay, ii) sources of inter- and intra-individual variability must be known, iii) DNA repair kinetics should be assessed to optimize sampling timing; and iv) DNA repair in accessible surrogate tissues should reflect repair activity in target tissues prone to carcinogenic effects. DNA repair phenotyping can be performed on frozen and fresh samples, and is a more direct measurement than genomic or transcriptomic approaches. There are mixed reports concerning the regulation of DNA repair by environmental and dietary factors. In general, exposure to genotoxic agents did not change base excision repair (BER) activity, whereas some studies reported that dietary interventions affected BER activity. On the other hand, in vitro and in vivo studies indicated that nucleotide excision repair (NER) can be altered by exposure to genotoxic agents, but studies on other life style related factors, such as diet, are rare. Thus, crucial questions concerning the factors regulating DNA repair and inter-individual variation remain unanswered. Intra-individual variation over a period of days to weeks seems limited, which is favourable for DNA repair phenotyping in biomonitoring studies. Despite this reported low intra-individual variation, timing of sampling remains an issue that needs further investigation. A correlation was reported between the repair activity in easily accessible peripheral blood mononuclear cells (PBMCs) and internal organs for both NER and BER. However, no correlation was found between tumour tissue and blood cells. In conclusion, although comet assay based approaches to measure BER/NER phenotypes are feasible and promising, more work is needed to further optimize their application in human biomonitoring and intervention studies.

9.
Br J Haematol ; 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31407320

RESUMO

Mutations in SOCS1 are frequent in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma. In the latter, SOCS1 mutations affect the length of the encoded protein (major mutations) and are associated with shorter patient survival. Two independent studies examined the prognostic impact of SOCS1 mutations in diffuse large B-cell lymphoma (DLBCL) and showed differing results. This may be due to the small number of included patients, the heterogeneity of patients' demographics and the distinct treatment schemes in these studies. To overcome the size limitations of these previous studies, we assessed SOCS1 mutations in the RICOVER-60 cohort. The cohort uniformly consists of elderly patients (aged 61-80 years) treated with the CHOP-14 scheme (cyclophosphamide, hydroxydaunorubicin, vincristine, prednisolone at 14-day intervals) with or without an additional rituximab treatment. Patient outcomes were analysed with regard to overall SOCS1 mutation frequency, major and minor mutations and a novel impact-based classifier - against the treatment modalities. Patients harbouring putative pathogenic SOCS1 mutations showed significant reduced overall survival within the CHOP plus rituximab group. Hence, putative pathogenic SOCS1 mutations seem to efface the beneficial effect of the therapeutic CD20 antibody. Comparing published data of whole exome and transcriptome sequencing of a large DLBCL cohort confirmed that predicted deleterious SOCS1 mutations forecast pre-eminent survival in early onset DLBCL.

10.
Mutat Res ; 843: 24-32, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31421734

RESUMO

The comet assay (single cell gel electrophoresis) is widely used as a biomonitoring tool to assess DNA damage - strand breaks, as well as oxidised bases; it can also be adapted to measure DNA repair. It is based on the ability of breaks in the DNA to relax supercoiling, allowing DNA loops to extend from the nuclear core (nucleoid) under an electric field to form a comet-like tail. Most commonly, it is applied to white blood cells. The range of detection is between a few hundred breaks per cell and a few thousand, encompassing levels of damage that can be repaired and tolerated by human cells. Its applications include monitoring various diseases, studying the influence of nutrition on DNA stability, and investigating effects of environmental and occupational mutagens. Here we address the issue of inter-laboratory variation in comet assay results. This variation is largely due to differences in methods. Imposing a standard protocol is not practical, but users should be aware of the crucial parameters that affect performance of the assay. These include the concentration of agarose in which the cells are embedded; the duration of cell lysis, and of enzyme incubation when oxidised bases are being measured; the duration of alkaline unwinding; the duration of electrophoresis and the voltage gradient applied; and the method used to score the comets. Including reference standards in each experiment allows experimental variability to be monitored - and if variation is not extreme, results can be normalised using reference standard values. Reference standards are also essential for inter-laboratory comparison. Finally, we offer recommendations which, we believe, will limit variability and increase the usefulness of this assay in molecular epidemiology.

11.
Mutat Res ; 843: 66-72, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31421741

RESUMO

This study investigated associations between levels of oxidatively damaged DNA, measured by the formamidopyrimidine DNA glycosylase (Fpg)-modified comet assay and intake of fish, salad, fruits, vegetables, wholegrain items, and potatoes in a cross-sectional study of 382 men and 591 women between 18 and 93 years. Intake of dietary items was obtained from questionnaires, and stratified into less than once per week, weekly or daily consumption. Intake of fish as main course was inversely associated with levels of Fpg-sensitive sites in peripheral blood mononuclear cells (PBMCs) in especially women (P < 0.001 multivariate linear regression). Intake of fish was also inversely associated with lower levels of Fpg-sensitive sites in men (P < 0.05, univariate analysis), although it was not statistically significant in analysis adjusted for lifestyle and other dietary factors. Intake of salad was inversely associated with levels of Fpg-sensitive sites in men (P < 0.001, multivariate linear regression). Statistically significant associations were also observed for intake of vegetables and potatoes in men, although these were weak and not robust in all statistical models. The sum the six individual dietary items was inversely associated with levels of Fpg-sensitive sites in the strata of men (P < 0.001, multivariate linear regression). Finally, levels of DNA repair incision activity were not associated with individual food categories or the total dietary food score. In summary, consumption of health-promoting foods is associated with lower levels of Fpg-sensitive sites in human PBMCs and strongest effects in the present population were ingestions of fish and salad.

12.
Clin Cancer Res ; 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31444248

RESUMO

PURPOSE: The identification of high-risk patients within Human Papillomavirus (HPV) positive and negative head and neck squamous cell carcinoma patients is needed for improved treatment and surveillance strategies. In this study, we set out to discover Antibody responses (AR) with prognostic impact in head and neck squamous cell carcinoma (HNSCC) stratified by HPV-status. EXPERIMENTAL DESIGN: A fluorescent bead-based multiplex serology assay to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens, 8 oncogenes) and 29 HPV-antigens was performed in samples of 362 HNSCC patients from five independent cohorts (153 HPV-positive, 209 HPV-negative). A multivariable cox proportional hazard model with bootstrapping (M=1000) was used for validation of prognostic antibody responses. RESULTS: AR to any of the cancer antigens were found in 257/362 patients (71%). In HPV-negative patients, antibody responses to to c-myc, MAGE-A1, -A4 and Rhodopsin E2 (combined as ARhigh risk) were significantly associated with shorter overall survival. In HPV-positive patients antibody responses to IMP-1 were discovered as a negative prognostic factor. ARhigh risk (HR=1.76) and antibody responses to IMP-1 (HR=3.28) were confirmed as independent markers for a poor prognosis in a multivariable Cox proportional hazard model with bootstrapping (M=1000). CONCLUSION: We identified AR to cancer antigens that associate with a dismal prognosis in HNSCC patients beyond HPV-positive-status. ARhigh risk may be used to detect HPV-negative patients with an extraordinarily bad prognosis. Most importantly, AR to IMP-1 may serve as a marker for a subgroup of HPV-positive patients that present with a poor prognosis similar to that in HPV-negative patients.

13.
Toxicol In Vitro ; 61: 104594, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31279906

RESUMO

The rapid expansion of the incorporation of nano-sized materials in consumer products overlaps with the necessity for high-throughput reliable screening tools for the identification of the potential hazardous properties of the nanomaterials. The ToxTracker assay (mechanism-based reporter assay based on embryonic stem cells that uses GFP-tagged biomarkers for detection of DNA damage, oxidative stress and general cellular stress) is one such tool, which could prove useful in the field of particle toxicology allowing for high throughput screening. Here, ToxTracker was utilised to evaluate the potential hazardous properties of two particulates currently used in the food industry (vegetable carbon (E153) and food-grade TiO2 (E171)). Due to the fact that ToxTracker is based on a stem cell format, it is crucial that the data generated is assessed for its suitability and comparability to more conventionally used relevant source of cells - in this case cells from the gastrointestinal tract and the liver. Therefore, the cell reporter findings were compared to data from traditional assays (cytotoxicity, anti-oxidant depletion and DNA damage) and tissue relevant cell types. The data showed E171 to be the most cytotoxic, decreased intracellular glutathione and the most significant with regards to genotoxic effects. The ToxTracker data showed comparability to conventional toxicity and oxidative stress assays; however, some discrepancies were evident between the findings from ToxTracker and the comet assay.

14.
Mutagenesis ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31294794

RESUMO

The comet assay is widely used in studies on genotoxicity testing, human biomonitoring and clinical studies. The simple version of the assay detects a mixture of DNA strand breaks and alkali-labile sites; these lesions are typically described as DNA strand breaks to distinguish them from oxidatively damaged DNA that are measured with the enzyme-modified comet assay. This review assesses the association between high-prevalence diseases in high-income countries and DNA damage measured with the comet assay in humans. The majority of case-control studies have assessed genotoxicity in white blood cells. Patients with coronary artery disease, diabetes, kidney disease, chronic obstructive pulmonary disease and Alzheimer's disease have on average 2-fold higher levels of DNA strand breaks compared with healthy controls. Patients with coronary artery disease, diabetes, kidney disease and chronic obstructive pulmonary disease also have 2- to 3-fold higher levels of oxidatively damaged DNA in white blood cells than controls, although there is not a clear difference in DNA damage levels between the different diseases. Case-control studies have shown elevated levels of DNA strand breaks in patients with breast cancer, whereas there are only few studies on colorectal and lung cancers. At present, it is not possible to assess if these neoplastic diseases are associated with a different level of DNA damage compared with non-neoplastic diseases.

15.
Part Fibre Toxicol ; 16(1): 21, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31182122

RESUMO

BACKGROUND: Short-term controlled exposure to diesel exhaust (DE) in chamber studies have shown mixed results on lung and systemic effects. There is a paucity of studies on well-characterized real-life DE exposure in humans. In the present study, 29 healthy volunteers were exposed to DE while sitting as passengers in diesel-powered trains. Exposure in electric trains was used as control scenario. Each train scenario consisted of three consecutive days (6 h/day) ending with biomarker samplings. RESULTS: Combustion-derived air pollutants were considerably higher in the passenger carriages of diesel trains compared with electric trains. The concentrations of black carbon and ultrafine particles were 8.5 µg/m3 and 1.2-1.8 × 105 particles/cm3 higher, respectively, in diesel as compared to electric trains. Net increases of NOx and NO2 concentrations were 317 µg/m3 and 36 µg/m3. Exposure to DE was associated with reduced lung function and increased levels of DNA strand breaks in peripheral blood mononuclear cells (PBMCs), whereas there were unaltered levels of oxidatively damaged DNA, soluble cell adhesion molecules, acute phase proteins in blood and urinary excretion of metabolites of polycyclic aromatic hydrocarbons. Also the microvascular function was unaltered. An increase in the low frequency of heart rate variability measures was observed, whereas time-domain measures were unaltered. CONCLUSION: Exposure to DE inside diesel-powered trains for 3 days was associated with reduced lung function and systemic effects in terms of altered heart rate variability and increased levels of DNA strand breaks in PBMCs compared with electric trains. TRIAL REGISTRATION: ClinicalTrials.Gov ( NCT03104387 ). Registered on March 23rd 2017.

16.
Genome Med ; 11(1): 27, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31039827

RESUMO

BACKGROUND: Germinal center-derived B cell lymphomas are tumors of the lymphoid tissues representing one of the most heterogeneous malignancies. Here we characterize the variety of transcriptomic phenotypes of this disease based on 873 biopsy specimens collected in the German Cancer Aid MMML (Molecular Mechanisms in Malignant Lymphoma) consortium. They include diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt's lymphoma, mixed FL/DLBCL lymphomas, primary mediastinal large B cell lymphoma, multiple myeloma, IRF4-rearranged large cell lymphoma, MYC-negative Burkitt-like lymphoma with chr. 11q aberration and mantle cell lymphoma. METHODS: We apply self-organizing map (SOM) machine learning to microarray-derived expression data to generate a holistic view on the transcriptome landscape of lymphomas, to describe the multidimensional nature of gene regulation and to pursue a modular view on co-expression. Expression data were complemented by pathological, genetic and clinical characteristics. RESULTS: We present a transcriptome map of B cell lymphomas that allows visual comparison between the SOM portraits of different lymphoma strata and individual cases. It decomposes into one dozen modules of co-expressed genes related to different functional categories, to genetic defects and to the pathogenesis of lymphomas. On a molecular level, this disease rather forms a continuum of expression states than clearly separated phenotypes. We introduced the concept of combinatorial pattern types (PATs) that stratifies the lymphomas into nine PAT groups and, on a coarser level, into five prominent cancer hallmark types with proliferation, inflammation and stroma signatures. Inflammation signatures in combination with healthy B cell and tonsil characteristics associate with better overall survival rates, while proliferation in combination with inflammation and plasma cell characteristics worsens it. A phenotypic similarity tree is presented that reveals possible progression paths along the transcriptional dimensions. Our analysis provided a novel look on the transition range between FL and DLBCL, on DLBCL with poor prognosis showing expression patterns resembling that of Burkitt's lymphoma and particularly on 'double-hit' MYC and BCL2 transformed lymphomas. CONCLUSIONS: The transcriptome map provides a tool that aggregates, refines and visualizes the data collected in the MMML study and interprets them in the light of previous knowledge to provide orientation and support in current and future studies on lymphomas and on other cancer entities.

17.
Int J Cancer ; 145(11): 2996-3010, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31008532

RESUMO

Next-generation sequencing has become a cornerstone of therapy guidance in cancer precision medicine and an indispensable research tool in translational oncology. Its rapidly increasing use during the last decade has expanded the options for targeted tumor therapies, and molecular tumor boards have grown accordingly. However, with increasing detection of genetic alterations, their interpretation has become more complex and error-prone, potentially introducing biases and reducing benefits in clinical practice. To facilitate interdisciplinary discussions of genetic alterations for treatment stratification between pathologists, oncologists, bioinformaticians, genetic counselors and medical scientists in specialized molecular tumor boards, several systems for the classification of variants detected by large-scale sequencing have been proposed. We review three recent and commonly applied classifications and discuss their individual strengths and weaknesses. Comparison of the classifications underlines the need for a clinically useful and universally applicable variant reporting system, which will be instrumental for efficient decision making based on sequencing analysis in oncology. Integrating these data, we propose a generalizable classification concept featuring a conservative and a more progressive scheme, which can be readily applied in a clinical setting.

18.
Clin Immunol ; 203: 125-133, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31028919

RESUMO

Intestinal epithelial cells (IECs) form a fundamental mucosal barrier and actively participate in tolerance and immunity against intestinal contents. Major histocompatibility complex class II (MHC II) and invariant chain (Ii) molecules are essential for adaptive immune response. MHC II deficiency often presents with gastrointestinal disorders. Intestinal biopsy samples revealed an absence of HLA-DR, Ii, and local immunoglobulins in both hematopoietic immune cells and IECs accompanied by a lack of faecal sIgA. After successful hematopoietic stem cell transplantation (HSCT) absent HLA-DR and Ii expression persisted in IECs and faecal stool analysis indicated inflammation and high microbial activity. We describe multifaceted disturbance of adaptive mucosal immunity in MHC II deficient patients suffering from enteropathy. HLA-DR and Ii expression on enterocytes is not restored by HSCT. This may account for increased susceptibility to enteric infections and intestinal inflammation leading to prolonged enteropathy reported in MHC II deficient patients.

19.
Sci Rep ; 9(1): 6458, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31015476

RESUMO

The giant cell tumor of bone (GCTB) is a locally aggressive primary bone tumor that is composed of mononuclear stroma cells, scattered macrophages, and multinucleated osteoclast-like giant cells which cause pathologic osteolysis. The stroma cells represent the neoplastic population of the tumor and are characterized by the H3F3A mutation G34W. This point mutation is regarded as the driver mutation of GCTB. We have established three new stable H3F3A mutated GCTB cell lines: U-GCT1, U-GCT2, and U-GCT3M. MK-1775 is a Wee1-kinase inhibitor which has been used for blocking of sarcoma growth. In the cell lines we detected Wee1, Cdk1, Cyclin B1, H3K36me3, and Rrm2 as members of the Wee1 pathway. We analyzed the effect of MK-1775 and gemcitabine, alone and in combination, on the growth of the cell lines. The cell lines showed a significant reduction in cell proliferation when treated with MK-1775 or gemcitabine. The combination of both agents led to a further significant reduction in cell proliferation compared to the single agents. Immunohistochemical analysis of 13 GCTB samples revealed that Wee1 and downstream-relevant members are present in GCTB tissue samples. Overall, our work offers valuable new tools for GCTB studies and presents a description of novel biomarkers and molecular targeting strategies.

20.
Biol Lett ; 15(4): 20180835, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-30966898

RESUMO

It has been known for about a century that European eels have a unique life history that includes offshore spawning in the Sargasso Sea about 5000-7000 km away from their juvenile and adult habitats in Europe and northern Africa. Recently hatched eel larvae were historically collected during Danish, German and American surveys in specific areas in the southern Sargasso Sea. During a 31 day period of March and April 2014, Danish and German research ships sampled for European eel larvae along 15 alternating transects of stations across the Sargasso Sea. The collection of recently hatched eel larvae (≤12 mm) from 70° W and eastward to 50° W showed that the European eel had been spawning across a 2000 km wide region of the North Atlantic Ocean. Historical collections made from 1921 to 2007 showed that small larvae had also previously been collected in this wide longitudinal zone, showing that the spatial extent of spawning has not diminished in recent decades, irrespective of the dramatic decline in recruitment. The use of such a wide spawning area may be related to variations in the onset of the silver eel spawning migration, individual differences in their long-term swimming ability, or aspects of larval drift.

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