Intravoxel incoherent motion model-based liver lesion characterisation from three b-value diffusion-weighted MRI.

OBJECTIVE: To evaluate intravoxel incoherent motion (IVIM) model-based liver lesion characterisation from three b-value diffusion-weighted imaging (DWI). METHODS: The 1.5-T DWI data from a respiratory gated spin-echo echo-planar magnetic resonance imaging sequence (b = 0, 50, 800 s/mm(2)) were retrospectively analysed in 38 patients with different liver lesions. Conventional apparent diffusion coefficient ADC = ADC(0,800) as well as IVIM-based parameters D' = ADC(50,800), ADC_low = ADC(0,50), and f' were calculated voxel-wise. Sixty-one regions of interest in hepatocellular carcinomas (HCCs, n = 24), haemangiomas (HEMs, n = 11), focal nodular hyperplasias (FNHs, n = 11), and healthy liver tissue (REFs, n = 15) were analysed. Group differences were investigated using Student's t-test and receiver-operating characteristic (ROC) analysis. RESULTS: Mean values ± standard deviations of ADC, D', ADC_low (in 10(-5) mm(2)/s), and f' (in %) for REFs/FNHs/HEMs/HCCs were 130 ± 11/143 ± 27/168 ± 16/113 ± 25, 104 ± 12/123 ± 25/162 ± 18/102 ± 23, 518 ± 66/437 ± 97/268 ± 69/283 ± 120, and 18 ± 3/14 ± 4/6 ± 3/9 ± 5, respectively. Differences between lesions and REFs were more significant for IVIM-based parameters than for conventional ADC. ROC analysis showed the best discriminability between HCCs and FNHs for ADC_low and f' and between HEMs and FNHs or HCCs for D'. CONCLUSION: Three instead of two b-value DWI enables a numerically stable and voxel-wise IVIM-based analysis for improved liver lesion characterisation with tolerable acquisition time. KEY POINTS: • Quantitative analysis of diffusion-weighted MRI helps liver lesion characterisation. • Analysis of intravoxel incoherent motion is superior to apparent diffusion coefficient determination. • Only three b-values enable separation of diffusion and microcirculation effects. • The method presented is numerically stable, with voxel-wise results and short acquisition times.

Early biochemical signals arise from low affinity TCR-ligand reactions at the cell-cell interface.

The kinetics of acid release by a mixture of T cells and antigen presenting cells were measured with a microphysiometer during a brief exposure to antigenic peptides. We find that some of the early biochemical events that lead to cellular proliferation cause a specific increase in the rate of acid release. The duration of this increase in acid release reflects the life-time of the peptide-MHC complexes. Peptides that form long-lived complexes produce a response that is stable for more than an hour. Serial TCR engagement is suggested by the observation that the amplitude of this stable response can be rapidly shifted up or down with additional agonist peptide or with antibodies that block T cell receptor binding. Cells briefly exposed to a peptide that forms short-lived peptide-MHC complexes produce a response that decays rapidly as peptide is washed away. A quantitative analysis of the kinetics of this decay in acidification demonstrates that intercellular TCR-ligand reactions are rapid, reversible, and of low apparent affinity with < 20% of peptide-MHC ligand bound to a TCR at any one time. These results demonstrate that the fraction of peptide-MHC ligands bound to TCRs at the cell-cell interface is no higher than anticipated from the affinities observed in solution for isolated TCRs and ligands.

A population of murine gammadelta T cells that recognize an inducible MHC class Ib molecule.

Although gammadelta T cells are implicated in regulating immune responses, gammadelta T cell-ligand pairs that could mediate such regulatory functions have not been identified. Here, the expression of the major histocompatibility complex (MHC) class Ib T22 and the closely related T10 molecules is shown to be activation-induced, and they confer specificity to about 0.4% of the gammadelta T cells in normal mice. Thus, the increased expression of T22 and/or T10 might trigger immunoregulatory gammadelta T cells during immune responses. Furthermore, the fast on-rates and slow off-rates that characterize this receptor/ligand interaction would compensate for the low ligand stability and suggest a high threshold for gammadelta T cell activation.

[Castleman's disease in ear, nose, and throat practice]. / Morbus Castleman. Eine Erkrankung für den HNO-Arzt?

Castleman's disease, also called angiofollicular lymph node hyperplasia or benign giant lymphoma, is a rare lymphoproliferative disorder of unknown etiology. Three histologic subtypes are described--hyaline vascular (80-90%), plasma cell (10-20%), and mixed (rare). In the clinical setting, localized and multicentric entities are distinguished. Due to the lack of tumor-specific clinical, biochemical, and radiological features, final diagnosis of Castleman's disease depends on histopathology. Surgical tumor resection is the treatment of choice for localized disease. Prognosis is good, and adjuvant therapy is not required. Therefore, early invasive removal and histopathological differentiation from neoplasia is mandatory. In contrast, the prognosis for multicentric Castleman's disease remains poor even if multimodal treatment regimens are employed. Major clinical symptoms, histology, and therapy are summarized, and the disease characteristics are highlighted presenting the case of an 11-year-old girl. On admission, the patient complained of a painless pharyngeal tumor mass and ipsilateral lymph node swelling. Magnetic resonance imaging revealed a parapharyngeal contrast-enhancing lesion extending from the hypopharynx to the skull base without signs of infiltration and accompanied by ipsilateral lymph node hyperplasia of the neck. Laboratory test results were within normal limits. After tumor resection, histopathological examination, and clinical staging, localized Castleman's disease was diagnosed (hyaline vascular subtype).

CD56 expression aids in the differential diagnosis of cholangiocarcinomas and benign cholangiocellular lesions.

CD56 (neuronal cell adhesion molecule, N-CAM) has been reported in neuroendocrine tumours and as a marker of reactive biliary epithelial cells. However, up to date, it is not used to distinguish malignant from non-malignant biliary lesions. In this study, we systematically examined CD56 expression on 98 tumours arising from the biliary tree as well as intrahepatic conditions with reactive neoductules. When neuroendocrine carcinomas are excluded, only 4 of 32 (12.5%) cholangiocarcinomas expressed CD56, 2 of which showed clear cell morphology. Reactive bile ductules adjacent to cirrhotic nodules as well as in focal nodular hyperplasia were CD56 positive. Twelve of 17 (70.5%) bile duct adenomas were CD56 positive, whereas von Meyenburg complexes expressed CD56 only very focally in less than 5% of lesional cells. Bile duct cysts were negative for CD56 with the exception of focally interspersed neuroendocrine cells, similar to that seen in segmental bile ducts. Thus, if van Meyenburg complexes are excluded, CD56 can be used to differentiate intrahepatic non-neoplastic from neoplastic proliferations, which is a helpful diagnostic tool in small liver biopsies.

Kit transduced signals counteract erythroid maturation by MAPK-dependent modulation of erythropoietin signaling and apoptosis induction in mouse fetal liver.

Signaling by the stem cell factor receptor Kit in hematopoietic stem and progenitor cells is functionally associated with the regulation of cellular proliferation, differentiation and survival. Expression of the receptor is downregulated upon terminal differentiation in most lineages, including red blood cell terminal maturation, suggesting that omission of Kit transduced signals is a prerequisite for the differentiation process to occur. However, the molecular mechanisms by which Kit signaling preserves the undifferentiated state of progenitor cells are not yet characterized in detail. In this study, we generated a mouse model for inducible expression of a Kit receptor carrying an activating mutation and studied its effects on fetal liver hematopoiesis. We found that sustained Kit signaling leads to expansion of erythroid precursors and interferes with terminal maturation beyond the erythroblast stage. Primary KIT(D816V) erythroblasts stimulated to differentiate fail to exit cell cycle and show elevated rates of apoptosis because of insufficient induction of survival factors. They further retain expression of progenitor cell associated factors c-Myc, c-Myb and GATA-2 and inefficiently upregulate erythroid transcription factors GATA-1, Klf1 and Tal1. In KIT(D816V) erythroblasts we found constitutive activation of the mitogen-activated protein kinase (MAPK) pathway, elevated expression of the src kinase family member Lyn and impaired Akt activation in response to erythropoietin. We demonstrate that the block in differentiation is partially rescued by MAPK inhibition, and completely rescued by the multikinase inhibitor Dasatinib. These results show that a crosstalk between Kit and erythropoietin receptor signaling cascades exists and that continuous Kit signaling, partly mediated by the MAPK pathway, interferes with this crosstalk.

Podocalyxin-like protein 1 expression in primary hepatic tumours and tumour-like lesions.

AIMS: The differential diagnosis of benign hepatic lesions and well-differentiated hepatocellular carcinomas can be a challenge, especially in small biopsy specimens. Recently, novel proteins expressed by the neovasculature in hepatocellular carcinoma (HCC) have been identified. The aim of this study was to compare the expression of podocalyxin-like protein 1 (PODXL1), a CD34-related sialomucin, in HCC and benign liver tumours or tumour-like lesions. METHODS AND RESULTS: Vascular marker expression was examined using tissue microarrays as well as standard paraffin sections from formalin fixed paraffin-embedded liver tissue samples. Expression of PODXL1 was compared with anti-CD34, CD31 and von Willebrand factor VIII staining by immunohistochemistry. PODXL1 is expressed in tumour-associated microvasculature endothelial cells in HCC, as well as in capillarized sinusoidal endothelium of focal nodular hyperplasia (FNH) and hepatic adenoma. Expression in cirrhotic nodules correlates with CD34 and highlights endothelium in the inflow area. In dysplastic nodules CD34 and PODXL1 are not or only focally expressed. CONCLUSIONS: Expression patterns of CD34 and PODXL1 are almost identical in primary hepatic tumours and tumour-like lesions. The presence of CD34+ and PODXL1+ sinusoidal endothelial cells aids in the diagnosis of HCC. Sinusoidal expression of PODXL1 is also seen in a less diffuse pattern in FNH and adenoma.

Induction of rapid T cell activation and tolerance by systemic presentation of an orally administered antigen.

To understand how orally introduced antigen regulates peripheral immune responses, we fed cytochrome c protein to mice transgenic for the beta chain of a cytochrome c-specific TCR and followed the antigen-specific T cell responses with a cyt c/I-Ek tetramer staining reagent. We find that within 6 hr of cytochrome c administration, antigen-specific systemic T cell activation is induced, and spleen cells gain the ability to stimulate cytochrome c-specific T cell responses. Feeding multiple low doses of cytochrome c down-regulates the systemic immune response, which can be correlated with a reduction of antigen-specific T cells and not with immune deviation. These results suggest that systemic distribution of antigen contributes significantly to oral tolerance induction.

Transforming growth factor beta 1 regulates tissue inhibitor of metalloproteinases-1 expression in differentiated human articular chondrocytes.

OBJECTIVE: To investigate the role of interleukin-6 (IL-6) and transforming growth factor beta 1 (TGF beta 1) in the regulation of tissue inhibitor of metalloproteinases-1 (TIMP-1) synthesis in human articular chondrocytes. METHODS: Articular cartilage was obtained from human knee joints 24 hours after death. Chondrocytes were isolated by collagenase digestion and embedded in low-gelling-temperature agarose. After stimulation by cytokines, total RNA was isolated and analyzed by Northern blotting. TIMP-1 protein levels were determined using a competitive enzyme-linked immunosorbent assay. RESULTS: Human chondrocytes in agarose culture expressed messenger RNA (mRNA) for the IL-6 receptor (gp80) and its signal-transducing subunit gp130. In contrast to the findings in a previous study, IL-6 did not stimulate TIMP-1 expression in these cells, whereas TGF beta 1 was an important inducer of TIMP-1 mRNA and protein synthesis. CONCLUSION: Our findings suggest that TGF beta 1 has a protective effect on the extracellular matrix of human articular chondrocytes.