Refine
Has Fulltext
- yes (37)
Is part of the Bibliography
- yes (37)
Year of publication
- 2016 (37) (remove)
Document Type
- Journal article (35)
- Doctoral Thesis (2)
Language
- English (37) (remove)
Keywords
- Aspergillus fumigatus (2)
- Bone-marrow-transplantation (2)
- chemotherapy (2)
- multiple myeloma (2)
- 177Lu (1)
- AIDS (1)
- Acute lymphocytic leukaemia (1)
- Akute myeloische Leukämie (1)
- Alpha therapy (1)
- Autoimmune diseases (1)
- Bacteria (1)
- Bone marrow transplantantation (1)
- Breath tests (1)
- CA19-9 (1)
- CD11b+ myeloid cells (1)
- Cancer genetics (1)
- Candida albicans (1)
- Central nervous system (1)
- Central nervous system infection (1)
- Clinical practice guidelines (1)
- Clinical remission (1)
- Cytokine receptors (1)
- Diagnosis (1)
- Drug development (1)
- Drug metabolism (1)
- Drug-free remission (1)
- Duchenne muscular dystrophy (1)
- Expression (1)
- FOLFIRI (1)
- FOLFOX (1)
- Factor receptor (1)
- Fungal (1)
- Genetics research (1)
- Glucose metabolism (1)
- Graft versus Tumor (1)
- Graft-versus-leukemia (1)
- Guideline (1)
- Guinea pig model (1)
- HIV (1)
- HIV infections (1)
- Hepatitis B virus (1)
- Hepatitis C (1)
- Herpes simplex encephalitis (1)
- Herpes simplex virus (1)
- Hsp90 (1)
- Human immunodefiency virus (1)
- IL-12 family (1)
- Imatinib (1)
- Immunocompromised patient (1)
- Immunsuppression (1)
- Immuntherapie (1)
- Infections (1)
- Inflammation (1)
- Influenzae type B (1)
- Intracellular domain (1)
- Invasive Aspergillosis (1)
- Invasive fungal-infections (1)
- Jak kinases (1)
- Lipid metabolism (1)
- Liposomal amphotericin-B (1)
- Liver cirrhosis (1)
- Low-dose acyclovir (1)
- MAG3 (1)
- MDSC (1)
- MPACT (1)
- Malignant melanoma (1)
- Molekularbiologie (1)
- NFkB-relatedgenes (1)
- NK (1)
- Natürliche Killerzelle (1)
- Neutrophil granulocytes interaction (1)
- Neutrophiler Granulozyt (1)
- PRRT (1)
- Pneumocystis-carinii-pneumonia (1)
- Polymerase chain raction (1)
- Progressive multifocal leukoencephalopathy (1)
- Real-time PCR (1)
- Regulatory-cells (1)
- Respiratory syncytial virus (1)
- Responses (1)
- Rheumatoid arthritis (1)
- STAT3 activation (1)
- Signal transduction (1)
- Skin cancer screening (1)
- Stage distribution (1)
- Suppression (1)
- Survival analysis (1)
- Synovitis (1)
- T-cells (1)
- TNM staging (1)
- Th17 (1)
- Transport (1)
- Treatment (1)
- Tregs (1)
- Tumor-necrosis-factor (1)
- Tyrosine phosphorylation (1)
- Validation (1)
- Varicella-Zoster-Virus (1)
- Varicella-zoster-virus (1)
- Viral (1)
- Wilms tumor protein 1 (1)
- acute Graft versus Host Disease (1)
- adenocarcinoma of the ampulla of Vater (1)
- adjuvant (1)
- allogeneic stem cell transplantation (1)
- alternative to animal testing (1)
- amphotericin B (1)
- amplicon sequencing (1)
- anaplastic medulloblastoma (1)
- anastomotic leakage (1)
- anemia (1)
- animal model (1)
- anti-hDEC205-WT1 antibody fusion protein (1)
- antileukemia vaccine (1)
- antiviral treatment (1)
- aspergillus fumigatus (1)
- beta-D-glucan (1)
- biliary-tract cancer (1)
- biomarkers Myelomas (1)
- blood flow (1)
- bone imaging (1)
- brain tumor (1)
- cancer stem cells (1)
- care (1)
- children (1)
- chronic myelogenous leukemia (1)
- clinical-practice (1)
- collagens (1)
- complication (1)
- corticosteroids and cyclophosphamide (1)
- daratumumab monotherapy (1)
- dendritic cell-targeting (1)
- discordance (1)
- disease-activity score (1)
- drug adherence (1)
- endosponge (1)
- epithelial-mesenchymal transition (1)
- european leukemia net (1)
- fatigue (1)
- fatty liver (1)
- fine-needle-aspiration (1)
- fluorescence microscopy (1)
- fluorescent dyes (1)
- fungal disease (1)
- fungal host response (1)
- fungal infection (1)
- galactomannan (1)
- gastric cancer (1)
- gastrointestinal dysfunction (1)
- gemcitabine (1)
- gene expression data (1)
- gene regulation in immune cells (1)
- genetic polymorphisms (1)
- group 3 (1)
- growth-factor-receptor (1)
- health-assessment questionnaire (1)
- hematopoietic SCT (1)
- hepatic stellate cells (1)
- high-risk hematology (1)
- highly-active antiretroviral therapy (1)
- human biomarker (1)
- human cholangiocellular carcinoma (1)
- human intrahepatic cholangiocarcinoma (1)
- immune activation (1)
- immune cell recruitment (1)
- induce cyclooxygenase-2 expression (1)
- insulin (1)
- insulin signaling (1)
- integrins (1)
- interaction (1)
- interferon alpha (IFNα) (1)
- interferon alpha signalling (1)
- interferon-alpha (1)
- intestinal-type adenocarcinoma (1)
- invasive aspergillosis (1)
- invasive fungal infections (1)
- ischemic stroke (1)
- leukemia (1)
- mammalian genomics (1)
- melanoma therapy (1)
- methylation (1)
- micronuclei (1)
- minimally important difference (1)
- molecular response in cml (1)
- mouse models DNA damage (1)
- multimodal (1)
- multiple myeloma Lesions (1)
- myeloma cells (1)
- nab-paclitaxel (1)
- nanoparticle albumin-bound paclitaxel (1)
- neoadjuvant (1)
- neuroendocrine tumor (1)
- nucleoside transporter (1)
- oncology (1)
- orthotopic xenograft (1)
- oxidative stress (1)
- pancreatic cancer (1)
- pancreatobiliary type (1)
- panobinostat (1)
- physicians (1)
- platelet activation (1)
- platelet aggregation (1)
- platelets (1)
- primary sclerosing cholangitis (1)
- pulmonary aspergillosis (1)
- rare SNP (1)
- real-time PCR (1)
- receptor tyrosine kinases (1)
- relapsed (1)
- relapsed and refractory (1)
- renal scintigraphy (1)
- reported outcomes (1)
- ribavirin serum levels (1)
- risk factor (1)
- serotonin (1)
- skin equivalents (1)
- suppression (1)
- survival (1)
- susceptibility (1)
- systemic sclerosis (1)
- tissue engineering (1)
- transporter protein associated with antigen processing-1 (TAP1) (1)
- validation (1)
- vascularization (1)
- viral load (1)
- viral replication (1)
Institute
- Medizinische Klinik und Poliklinik II (37) (remove)
Tissue-engineered skin equivalents mimic key aspects of the human skin, and can thus be employed as wound coverage for large skin defects or as in vitro test systems as an alternative to animal models. However, current skin equivalents lack a functional vasculature limiting clinical and research applications. This study demonstrates the generation of a vascularized skin equivalent with a perfused vascular network by combining a biological vascularized scaffold (BioVaSc) based on a decellularized segment of a porcine jejunum and a tailored bioreactor system. Briefly, the BioVaSc was seeded with human fibroblasts, keratinocytes, and human microvascular endothelial cells. After 14 days at the air-liquid interface, hematoxylin & eosin and immunohistological staining revealed a specific histological architecture representative of the human dermis and epidermis including a papillary-like architecture at the dermal-epidermal-junction. The formation of the skin barrier was measured non-destructively using impedance spectroscopy. Additionally, endothelial cells lined the walls of the formed vessels that could be perfused with a physiological volume flow. Due to the presence of a complex in-vivo-like vasculature, the here shown skin equivalent has the potential for skin grafting and represents a sophisticated in vitro model for dermatological research.
Objective
To use statistical methods to establish a threshold for individual response in patient-reported outcomes (PROs) in patients with rheumatoid arthritis.
Methods
We used an analysis of variance model in patients on stable therapy (discovery cohort) to establish critical differences (d(crit)) for the minimum change associated with a significant individual patient response (beyond normal variation) in the PRO measures of pain (0-10), fatigue (0-10), and function (Funktionsfragebogen Hannover questionnaire; 0-100). We then evaluated PRO responses in patients initiating adalimumab in a noninterventional study (treatment cohort).
Results
In the discovery cohort (n=700), PROs showed excellent long-term retest reliability. The minimum change that exceeded random fluctuation was conservatively determined to be 3 points for pain, 4 points for fatigue, and 16 points for function. In the treatment cohort (n=2,788), 1,483 patients (53.2%) achieved a significant individual therapeutic response as assessed by Disease Activity Score in 28 joints (DAS28)-d(crit) (1.8 points) after 12 months of adalimumab treatment; 68.5% of patients with a DAS28-d(crit) response achieved a significant improvement in pain, whereas approximately 40% achieved significant improvements in fatigue or function. Significant improvements in all 3 PROs occurred in 22.7% of patients; 22.8% did not have any significant PRO responses. In contrast, significant improvements in all 3 PROs occurred in only 4.4% of 1,305 patients who did not achieve a DAS28-d(crit) response at month 12, and 59.1% did not achieve any significant PRO responses.
Conclusion
The establishment of critical differences in PROs distinguishes true responses from random variation and provides insights into appropriate patient management.
We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial. The weighted analysis revealed a CR rate of 24% (95% CI: 20–27%) and a median OS of 3.3 months (95% CI: 2.8–3.6) in the historical cohort compared with a CR/CRh rate of 43% (95% CI: 36–50%) and a median OS of 6.1 months (95% CI: 4.2–7.5) in the blinatumomab trial. Propensity score analysis estimated increased odds of CR/CRh (OR=2.68, 95% CI: 1.67–4.31) and improved OS (HR=0.536, 95% CI: 0.394–0.730) with blinatumomab. The analysis demonstrates the application of different study designs and statistical methods to compare novel therapies for R/R ALL with historical data.
Background
A phase I/II study and subsequent phase III study (MPACT) reported significant correlations between CA19-9 decreases and prolonged overall survival (OS) with nab-paclitaxel plus gemcitabine (nab-P + Gem) treatment for metastatic pancreatic cancer (MPC). CA19-9 changes at week 8 and potential associations with efficacy were investigated as part of an exploratory analysis in the MPACT trial.
Patients and methods
Untreated patients with MPC (N = 861) received nab-P + Gem or Gem alone. CA19-9 was evaluated at baseline and every 8 weeks.
Results
Patients with baseline and week-8 CA19-9 measurements were analyzed (nab-P + Gem: 252; Gem: 202). In an analysis pooling the treatments, patients with any CA19-9 decline (80%) versus those without (20%) had improved OS (median 11.1 versus 8.0 months; P = 0.005). In the nab-P + Gem arm, patients with (n = 206) versus without (n = 46) any CA19-9 decrease at week 8 had a confirmed overall response rate (ORR) of 40% versus 13%, and a median OS of 13.2 versus 8.3 months (P = 0.001), respectively. In the Gem-alone arm, patients with (n = 159) versus without (n = 43) CA19-9 decrease at week 8 had a confirmed ORR of 15% versus 5%, and a median OS of 9.4 versus 7.1 months (P = 0.404), respectively. In the nab-P + Gem and Gem-alone arms, by week 8, 16% (40/252) and 6% (13/202) of patients, respectively, had an unconfirmed radiologic response (median OS 13.7 and 14.7 months, respectively), and 79% and 84% of patients, respectively, had stable disease (SD) (median OS 11.1 and 9 months, respectively). Patients with SD and any CA19-9 decrease (158/199 and 133/170) had a median OS of 13.2 and 9.4 months, respectively.
Conclusion
This analysis demonstrated that, in patients with MPC, any CA19-9 decrease at week 8 can be an early marker for chemotherapy efficacy, including in those patients with SD. CA19-9 decrease identified more patients with survival benefit than radiologic response by week 8.
Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.
Infections of the central nervous system (CNS) are infrequently diagnosed in immunocompetent patients, but they do occur in a significant proportion of patients with hematological disorders. In particular, patients undergoing allogeneic hematopoietic stem-cell transplantation carry a high risk for CNS infections of up to 15%. Fungi and Toxoplasma gondii are the predominant causative agents. The diagnosis of CNS infections is based on neuroimaging, cerebrospinal fluid examination and biopsy of suspicious lesions in selected patients. However, identification of CNS infections in immunocompromised patients could represent a major challenge since metabolic disturbances, side-effects of antineoplastic or immunosuppressive drugs and CNS involvement of the underlying hematological disorder may mimic symptoms of a CNS infection. The prognosis of CNS infections is generally poor in these patients, albeit the introduction of novel substances (e.g. voriconazole) has improved the outcome in distinct patient subgroups. This guideline has been developed by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) with the contribution of a panel of 14 experts certified in internal medicine, hematology/oncology, infectious diseases, intensive care, neurology and neuroradiology. Grades of recommendation and levels of evidence were categorized by using novel criteria, as recently published by the European Society of Clinical Microbiology and Infectious Diseases.
Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25–31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.
Comparison of nonculture blood-based tests for diagnosing invasive aspergillosis in an animal model
(2016)
The European Aspergillus PCR Initiative (EAPCRI) has provided recommendations for the PCR testing of whole blood (WB) and serum/plasma. It is important to test these recommended protocols on nonsimulated "in vivo" specimens before full clinical evaluation. The testing of an animal model of invasive aspergillosis (IA) overcomes the low incidence of disease and provides experimental design and control that is not possible in the clinical setting. Inadequate performance of the recommended protocols at this stage would require reassessment of methods before clinical trials are performed and utility assessed. The manuscript describes the performance of EAPCRI protocols in an animal model of invasive aspergillosis. Blood samples taken from a guinea pig model of IA were used for WB and serum PCR. Galactomannan and beta-D-glucan detection were evaluated, with particular focus on the timing of positivity and on the interpretation of combination testing. The overall sensitivities for WB PCR, serum PCR, galactomannan, and beta-D-glucan were 73%, 65%, 68%, and 46%, respectively. The corresponding specificities were 92%, 79%, 80%, and 100%, respectively. PCR provided the earliest indicator of IA, and increasing galactomannan and beta-D-glucan values were indicators of disease progression. The combination of WB PCR with galactomannan and beta-D-glucan proved optimal (area under the curve AUC], 0.95), and IA was confidently diagnosed or excluded. The EAPRCI-recommended PCR protocols provide performance comparable to commercial antigen tests, and clinical trials are warranted. By combining multiple tests, IA can be excluded or confirmed, highlighting the need for a combined diagnostic strategy. However, this approach must be balanced against the practicality and cost of using multiple tests.
The interleukin (IL)-12-type cytokines IL-12 and IL-23 are involved in T-helper (Th) 1 and Th17 immunity, respectively. They share the IL-12 receptor beta 1 (IL-12R beta 1) as one component of their receptor signaling complexes, with IL-12R beta 2 as second receptor for IL-12 and IL-23R for IL-23 signal transduction. Stimulation with IL-12 and IL-23 results in activation of receptor-associated Janus kinases (Jak) and phosphorylation of STAT proteins in target cells. The Janus kinase tyrosine kinase (Tyk) 2 associates with IL-12R beta 1, whereas Jak2 binds to IL-23R and also to IL-12R beta 2. Receptor association of Jak2 is mediated by Box1 and Box2 motifs located within the intracellular domain of the receptor chains. Here we define the Box1 and Box2 motifs in IL-12R beta 1 and an unusual Jak2-binding site in IL-23R by the use of deletion and site-directed mutagenesis. Our data show that nonfunctional box motifs abolish IL-12- and IL-23-induced STAT3 phosphorylation and cytokine-dependent proliferation of Ba/F3 cells. Coimmunoprecipitation of Tyk2 by IL-12R beta 1 and Jak2 by IL-23R supported these findings. In addition, our data demonstrate that association of Jak2 with IL-23R is mandatory for IL-12 and/or IL-23 signaling, whereas Tyk2 seems to be dispensable.
Background: There is much evidence that T cells are strongly involved in the pathogenesis of localized and systemic forms of scleroderma (SSc). A dysbalance between FoxP3+ regulatory CD4+ T cells (Tregs) and inflammatory T-helper (Th) 17 cells has been suggested. Methods: The study aimed (1) to investigate the phenotypical and functional characteristics of Th17 and Tregs in SSc patients depending on disease manifestation (limited vs. diffuse cutaneous SSc, dcSSc) and activity, and (2) the transcriptional level and methylation status of Th17- and Treg-specific transcription factors. Results: There was a concurrent accumulation of circulating peripheral IL-17-producing CCR6+ Th cells and FoxP3+ Tregs in patients with dcSSc. At the transcriptional level, Th17- and Treg-associated transcription factors were elevated in SSc. A strong association with high circulating Th17 and Tregs was seen with early, active, and severe disease presentation. However, a diminished suppressive function on autologous lymphocytes was found in SSc-derived Tregs. Significant relative hypermethylation was seen at the gene level for RORC1 and RORC2 in SSc, particularly in patients with high inflammatory activity. Conclusions: Besides the high transcriptional activity of T cells, attributed to Treg or Th17 phenotype, in active SSc disease, Tregs may be insufficient to produce high amounts of IL-10 or to control proliferative activity of effector T cells in SSc. Our results suggest a high plasticity of Tregs strongly associated with the Th17 phenotype. Future directions may focus on enhancing Treg functions and stabilization of the Treg phenotype.