Molecular mechanism of SHP2 activation by PD-1 stimulation.

In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine-based inhibitory motif (ITIM) and immune receptor tyrosine-based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2-PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.

[Diagnostic thoracoscopy in mediastinal space-occupying lesions]. / Diagnostische Thorakoskopie bei mediastinalen Raumforderungen.

Thoracoscopy is a helpful and safe procedure for diagnosing a variety of mediastinal masses if adequate information cannot be obtained out due to biological risk or patient non-compliance. An explicit description of thoracoscopic technique is given along with case reports demonstrating the efficiency of the method.

[The history and development of thoracoscopy]. / Geschichte und Entwicklung der Thorakoskopie.

The development of thoracoscopy is closely connected with the history of the artificial pneumothorax, of pleural suction drainage and of endoscopy. After its introduction in 1910 by Jacobaeus thoracoscopy was at first used mainly for therapeutic purposes (thoracocausty). With the onset of drug treatment of tuberculosis and the end of the area of pneumothorax therapy thoracoscopy was increasingly used as a diagnostic method. Today it is second in importance only to fibre bronchoscopy in pneumology.

[Pulmonary biopsy under visual control (author's transl)]. / Biopsie pulmonaire sous contrôle visuel.

Out of more than 3 000 diagnostic thoracoscopies carried out in the Chest Hospital Heckeshorn since 1950, a pneumothorax was induced in 43% because of pulmonary lesions and in 16% because of disease of the mediastinum or of the thoracic wall. The pathologic changes can be differentiated more exactly by the use of telescopes than by the naked eye. Biopsies can be taken from several different points under visual control. We did not observe major bleedings in our cases with biopsy specimens as large as raisins. The post thoracoscopic suction drainage should be performed through tubes with a caliber of 8 mm and with multiple side holes. A negative pressure of 100 mbar and a pumping flow of more than 3, 51/min has to be applied. The mean time for drainage was 3.4 days, long-lasting fistulas were not seen. A protective antibiotic therapy can be discussed after five days of intrapleural suction. 87% of the lung biopsies revealed a specific morphological diagnosis. In only 13% of the cases additional open biopsy was indicated. This gave new informations in about one half, in the remaining cases the thoracoscopic findings were confirmed. We used the rigid 8 mm-thoracoscope (Storz) with a cold-light source. Only one trocar and one cannula are necessary because observation, photography biopsy, puncture, suction and diathermy are possible through the one-channel thoracoscope. In our opinion, flexible fiberoptics have more disadvantages than advantages.

[Propagation of error, sensitivity and specificity of the CO gas transfer in various breath holding and steady state methods (author's transl)]. / Fehlerfortpflanzung, Sensibilität und Spezifität des CO-Gastransfers in verschiedenen Breathholding- und Steady-State-Methoden.

For determining DL/VA or the Krogh factor use of the breath-holding CO method only is recommended because it is relatively free from errors, independent of distribution and is relatively specific regarding diffusion. The steady state methods tend to be unspecific despite calculation of DL/VA and to be rather sensitive to uneven distribution of ventilation.

[The mixing index in the argon breath holding test for the demonstration of pharmacologically induced airways reactions. A comparison with other methods (author's transl)]. / Der Mischungsindex in der Argon-Breath-Holding-Methode zur Objektivierung pharmakologisch ausgelöster Atemwegsreaktionen im Vergleich mit anderen Untersuchungsmethoden.

In 42 patients with obstructive airways diseases the behavior of the mixing index (delta argon %/1 during phase III of the argon-volume diagram) was studied after beta2 stimulation or after provocation by acetylcholine. Changes in airways resistance resp. conductance (GAW), FEV1.0 and residual volume (RV) were also determined for comparison. In an inhomogeneous subgroup with obstructive airways disease of various aetiology the mixing index (MI) and FEV1.0 indicated changes in the airways system with about equal frequency. Distinct discrepancies between the two tests, observed in a few cases, suggest that the two methods register different pathophysiological reactions. These differences could be confirmed statistically in a more homogeneous subgroup with extrinsic bronchial asthma. A correlation could be established between MI and RV on the one hand and between FEV1.0 or GAW and RV on the other hand. The results indicate that the mixing index as a test of distribution of ventilation reflects mainly the reactions of the small airways. Its use offers the possibility of a more differentiated pharmacodynamic evaluation.

[The importance of cytodiagnosis of perbronchial fine needle aspiration of mediastinal or hilar tumours (author's transl)]. / Die Bedeutung der Zytodiagnostik der perbronchialen Feinnadelpunktion von mediastinalen oder hilären Tumoren

In almost all bronchoscopy patients perbronchial puncture of hilar lymph nodes was performed routinely. There were 1883 punctures performed in 1841 patients. In histologically proven malignant processes tumour cells were demonstrated in the smear in 84% of the cases, whereas in 97 cases of sarcoidosis a cytological diagnosis could be made in 94%. On account of the high specificity, the harmlessness of the procedure and the minimal stress caused to the patient in comparison with mediastinoscopy or thoracoscopy perbronchial fine needle asperation is highly recommended in unclear mediastinal processes as well as to determine the operability of a bronchial carcinoma or stage of a tumour according to the TNM system.

[Cytological examination of bronchial secretions in lung tumours, correlated with the tumour stage (TNM system) (author's transl)]. / Ergebnisse zytologischer Untersuchungen des Bronchialsekrets bei Lungentumorenim Verhältnis zum Tumorstadium (TNM-System)

Brochial secretions were examined cytologically in 2114 patients (2322 secretion samples). Among the 1006 patients with confirmed malignant lung tumour bronchial secretions were positive in 56%. The result depended on the size, type, and site of the tumour and its stage according to the TNM system.