The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors.

The erbB-2/HER2 oncogene is overexpressed in a significant fraction of human carcinomas of the breast, ovary, and lung in a manner that correlates with poor prognosis. Although the encoded protein resembles several receptors for growth factors, no high affinity ligand of ErbB-2 has so far been fully characterized. However, several lines of evidence have raised the possibility that ErbB-2 can augment signal transduction initiated by binding of certain growth factors to their direct receptors. Here, we contrasted these two models of ErbB-2 function: First, examination of a large series of epidermal growth factor (EGF)-like ligands and neuregulins, including virus-encoded ligands as well as related motifs derived from the precursor of EGF, failed to detect interactions with ErbB-2 when this protein was singly expressed. Second, by using antibodies that block inter-ErbB interactions and cells devoid of surface ErbB-2, we learned that signaling by all ligands examined, except those derived from the precursor of EGF, was enhanced by the oncoprotein. These results imply that ErbB-2 evolved as a shared receptor subunit of all ErbB-specific growth factors. Thus, oncogenicity of ErbB-2 in human epithelia may not rely on the existence of a specific ligand but rather on its ability to act as a coreceptor for multiple stroma-derived growth factors.

Transport and activation of the vacuolar aspartic proteinase phytepsin in barley (Hordeum vulgare L.).

The primary translation product of barley aspartic proteinase, phytepsin (EC 3.4.23.40), consists of a signal sequence, a propart, and mature enzyme forms. Here, we describe post-translational processing and activation of phytepsin during its transport to the vacuole in roots, as detected by using metabolic labeling and immunoprecipitation. After removal of the signal sequence, the glycosylated precursor of 53 kDa (P53) was produced and further processed to polypeptides of 31 and 15 kDa (P31 + P15) and, subsequently, to polypeptides of 26 and 9 kDa (P26 + P9), 45 min and 24 h after synthesis, respectively. The processing occurred in a late-Golgi compartment or post-Golgi compartment, because brefeldin A inhibited the processing, and P53 acquired partial endoglycosidase H resistance 30 min after synthesis, whereas P15 was completely resistant. The N-glycosylation inhibitor tunicamycin had no effect on transport, but the absence of glycans on P53 accelerated the proteolytic processing. Phytepsin was also expressed in baculovirus-infected insect cells. The recombinant prophytepsin underwent autoproteolytic activation in vitro and showed enzymatic properties similar to the enzyme purified from grains. However, a comparison of the in vitro/in vivo processing sites revealed slight differences, indicating that additional proteases are needed for the completion of the maturation in vivo.

Neu differentiation factor/neuregulin isoforms activate distinct receptor combinations.

The multiple isoforms of Neu differentiation factor (NDF/neuregulin) induce a pleiotropic cellular response that is isoform-specific and cell type-dependent. The molecular basis of this heterogeneity was addressed by comparing the two major groups of isoforms, alpha and beta. Both groups bind to the catalytically impaired receptor tyrosine kinase ErbB-3, whose mitogenic stimulation by NDF requires transactivation by other ErbB proteins, either ErbB-1 or ErbB-2. By expressing each pair of receptors in interleukin 3-dependent myeloid cells, we found that both isoforms induced mitogenic signals in cells co-expressing the combination of ErbB-3 with ErbB-2. However, only the beta isoform stimulated cells that expressed both ErbB-3 and ErbB-1, and neither isoform was active on cells expressing ErbB-3 alone. Both isoforms bind to all ErbB-3-expressing cells, albeit with different affinities, but the co-stimulatory mitogenic effect is correlated with the ability of each auxiliary receptor to transphosphorylate ErbB-3. These results imply that NDF isoforms differ in their ability to induce receptor heterodimers; whereas both types of isoforms signal through ErbB-3/ErbB-2 heterodimers, only beta isoforms are able to stabilize ErbB-3/ErbB-1 heterodimers.

[Localized 31P-NMR-spectroscopy using ISIS (image-selected in vivo spectroscopy) and surface coils: methodology and initial applications to studies of the liver, the transplanted kidney and the mediastinum]. / Lokalisierte 31P-NMR-Spektroskopie mit ISIS und Oberflächenspule: Methodik und erste Anwendungen bei der Untersuchung von Leber, Transplantatniere und Mediastinum.

A new method for image-guided localized phosphorus NMR spectroscopy of superficial tissues has been investigated using a 1.5 Tesla whole-body-MR-System. We used a surface coil combined with adiabatic excitation pulses and a modified ISIS sequence. This approach is related to imaging sequences and thus permits a flexible and accurate determination of the volume of interest from "conventional" proton images. The scope and advantages of the method are demonstrated by phantom studies. Clinical applications to the liver, renal transplants, and the mediastinum are described.

[Colonic contrast enema in digital luminescent radiography (DLR) and conventional x-ray technic]. / Kolonkontrasteinlauf in digitaler Lumineszenzradiographie (DLR) und konventioneller Röntgentechnik.

120 double-contrast barium enemas were obtained by both digital luminescent radiography (DLR) and conventional screen-film systems, the digital exposure dose being 50% of the conventional one. In DLR two differently post processed images were obtained from one x-ray exposure: a display with low spatial frequency enhancement was processed to look like a conventional radiograph and was complemented by a display with high spatial frequency enhancement. Analysing the results statistically DLR proved to be diagnostically equivalent to conventional radiography despite the reduction in exposure dose and a slightly diminished image quality. High spatial frequency enhancement did not provide further diagnostic information and is therefore superfluous in barium enemas.

[What does radiologic diagnosis of the thymus gland accomplish in myasthenia gravis?]. / Was leistet die radiologische Thymusdiagnostik bei der Myasthenia gravis?

Radiologic imaging in myasthenia gravis is used for the evaluation of pathologic changes of the thymus gland. Computed tomography can demonstrate tumors of the anterior mediastinum in nearly 90% and is therefore superior to conventional radiography. Because of the variety of size and shape of the normal thymus gland, differentiation between normal thymus, follicular hyperplasia and thymoma is rarely possible especially in younger patients. In elderly patients with myasthenia gravis and involution of the thymus gland tumors of the thymus are reliably detected by computed tomography, whereas the ability of computed tomography to predict the histological diagnosis is poor even with intravenous administration of contrast media.

[The importance of magnetic resonance tomography in the diagnosis of cerebral infections]. / Die Bedeutung der Kernspintomographie in der Diagnostik zerebraler Infektionen.

Amongst 1.345 MR examinations of the skull 49 patients were suspected of a cerebral infection. With a knowledge of the clinical situation, the abnormal findings were classified according to their localization, number, extent and distribution. The final diagnoses included meningitis, meningoencephalitis, and abscesses of varying etiology. CT was carried out in 29 patients; it was found that MRI was more sensitive and able to show the lesion at an earlier stage (sensitivity 90% compared with 66%). Observations of proton density and relaxation time combined with morphological criteria and clinical history reduced differential diagnoses. On the other hand, the changes due to intracranial infections lead to an inflammatory reaction that may be similar to the findings in degenerative or even tumorous cerebral lesions. This explains why twelve patients with abnormal MRI findings were erroneously diagnosed as having cerebral infections.

[Posture-related arrest of contrast medium in the myelogram]. / Lagerungsbedingter Kontrastmittelstop im Myelogramm.

An increase in intraabdominal pressure leads to the filling of the epidural vein plexus and thereby to an increased epidural pressure and consecutive compression of the dural sac. This has often been demonstrated in myelography as an ascending of the contrast medium. We observed a complete stop of the contrast medium in ascending myelography although neither computed tomography nor magnetic resonance tomography could demonstrate an intraspinal tumour. We suppose, therefore, that this phenomenon is of "functional origin".

[Late intramedullary metastases of a medulloblastoma with primary extramedullary seeded metastases--magnetic resonance tomographic detection using gadolinium-DTPA]. / Intramedulläre Spätmetastasierung bei einem Medulloblastom mit primär extramedullären Abtropfmetastasen--kernspintomographischer Nachweis mit Gadolinium-DTPA.

Dissemination of tumour cells via CSF occurs if there is close proximity of a malignant space-occupying growth to the CSF circulation system. According to the anatomic localisation of the metastases a distinction is made between intra- and extra medullary metastases. Magnetic resonance tomography is a highly sensitive method that can point not only to the pathological process, but also to its localisation and extent, especially if paramagnetic substances are used, to a much more accurate degree than had been possible so far with invasive myelography or computed tomography.

Combined 1H-MR imaging and localized 31P-spectroscopy of intracranial tumors in 43 patients.

Combined imaging and volume-selective spectroscopy of normal human brain tissue and tumors located anywhere in the brain could be obtained routinely in a clinical setting. Image-guided localized phosphorus MR spectra of healthy brain tissue have been reproducible, but further examinations seem necessary to determine individual physiologic variations. Compared with healthy brain tissue, spectra from meningiomas demonstrated the most obvious differences: the phosphocreatine peak decreased below the level of adenosine triphosphate, and the phosphodiester signal was reduced, whereas the phosphomonoester peak increased in some cases. Malignant gliomas showed less distinct changes: in particular, the phosphodiester peak was reduced and, in several cases, seemed to split. Often the phosphocreatine signal was diminished. In tumors with cystic components a poor signal-to-noise ratio was found. Four nonmalignant astrocytomas could not be differentiated from normal brain tissue spectroscopically. It has to be proved by an increased number of cases and quantification whether the observed spectral patterns can be correlated to histology. In three patients, follow-up studies during and after radiotherapy were performed. Metabolic changes were observed in one patient in a time frame in which imaging methods did not detect any change. Phosphorous spectroscopy has the potential to emerge as a useful tool in this field.