Márta Jäckel

The role of TTF-1 in differentiating primary and metastatic lung adenocarcinomas.

Thyroid transcription factor-1 (TTF-1) is a sensitive marker for pulmonary and thyroid adenocarcinomas. The aim of this work was to determine its usefulness in distinction between primary and metastatic lung adenocarcinomas. We have examined the expression of TTF-1 in 100 solitary pulmonary nodules. They included 50 stage I peripheral primary bronchial adenocarcinomas (30 men, 20 women, mean age: 60 years) and 50 metastatic pulmonary adenocarcinomas (21 men, 29 women, mean age: 57 years) of different origins, such as breast (13), colon (13), rectum (13), kidney (7), stomach (2), and thyroid gland (2). TTF-1 immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissues. In primary bronchial adenocarcinomas we found immunopositivity in 46/50 cases, among them 30 cases showed strong nuclear immunostaining. In four primary adenocarcinoma cases the observed immunopositivity was localized to the cytoplasm. Out of the metastatic adenocarcinomas all but the 2 thyroid cancers were negative. Both thyroid tumors showed strong immunopositivity. Our results confirm that TTF-1 immunohistochemistry is a very sensitive and highly specific method in the differential diagnosis of primary and metastatic lung adenocarcinomas and should be used in the everyday clinical practice.

STUDY OF INFLAMMATORY RESPONSES TO CROCIDOLITE AND BASALT WOOL IN THE RAT LUNG

The subacute effects of crocidolite and basalt wool dusts were studied by means of biochemical, morphological, and histological methods 1 and 3 mo after intrabronchial instillation. The cell count, protein and phospholipid contents, and lactate dehydrogenase (LDH) activity were determined in the bronchoalveolar lavage (BAL). Both types of fibers induced a prolonged inflammatory reaction in the lung. All the parameters studied in the experimental groups were more markedly elevated after 3 mo. Relative to the control, the protein and LDH values were increased three- to fivefold, the phospholipid content twofold, and the number of free cells in the BAL exceeded the control level up to ninefold. The inflammatory responses to crocidolite and basalt wool in the lung did not differ significantly. In spite of this, basalt wool is recommended as an asbestos substitute, as the use of this man-made fiber may result in a significantly lower release of dust than that from crocidolite.

Domain interactions direct misfolding and amyloid formation of yeast phosphoglycerate kinase

There are proteins that are built of two structural domains and are deposited full‐length in amyloid plaques formed in various diseases. In spite of the known differences in the mechanisms of folding of single‐ and multidomain proteins, no published studies can be found that address the role of the domain–domain interactions during misfolding and amyloid formation. By the discovery of the role of domain–domain interactions, here we provide important insight in the submolecular mechanism of amyloid formation. A model system based on yeast phosphoglycerate kinase was designed. This system includes the wild‐type yeast phosphoglycerate kinase and single‐tryptophan mutants of the individual N and C terminal domains and the complete protein. Electron microscopic measurements proved that amyloid fibrils grow from all mutants under identical conditions as for the wild‐type protein. Misfolding and amyloid formation was followed in stopped‐flow and manual mixing experiments on the 1 ms to 4 days timescale. Tryptophan fluorescence was used for selective detection of conformational changes accompanying the formation of the amyloidogenic intermediates and the growth of amyloid fibrils. The interactions between the polypeptide chains of the two domains direct the misfolding process from the early steps to the amyloid formation, and influence the final structure. The kinetics of misfolding is different for the individual domains, pointing to the significance of the amino acid sequence. Misfolding of the domains within the complete protein is synchronized indicating that domain–domain interactions direct the misfolding and amyloid formation mechanism. Proteins 2006.

Significance of Primary Tumor Location and Histology for Brain Metastasis Development and Peritumoral Brain Edema in Lung Cancer.

Background: Brain metastasis of lung cancer adversely affects overall survival (OS) and quality of life, while peritumoral brain edema is responsible for life-threatening complications. Methods: We retrospectively analyzed the clinicopathological and cerebral radiological data of 575 consecutive lung cancer patients with brain metastases. Results: In adenocarcinoma and squamous cell carcinoma, peritumoral brain edema was more pronounced than in small-cell lung cancer (p < 0.001 and p < 0.001, respectively). There was a positive correlation between the size of metastasis and the thickness of peritumoral brain edema (p < 0.001). It was thicker in supratentorial tumors (p = 0.019), in younger patients (≤50 years) (p = 0.042), and in females (p = 0.016). The time to development of brain metastasis was shorter in central than in peripheral lung cancer (5.3 vs. 9.0 months, p = 0.035). Early brain metastasis was characteristic for adenocarcinomas. A total of 135 patients had brain only metastases (N0 disease) characterized by peripheral lung cancer predominance (p < 0.001) and a longer time to development of brain metastasis (9.2 vs. 4.4 months, p < 0.001). OS was longer in the brain only subgroup than in patients with N1-3 diseases (p < 0.001). Conclusions: The clinicopathological characteristics of lung cancer are related to the development and radiographic features of brain metastases. Our results might be helpful in selecting patients who might benefit from prophylactic cranial irradiation.