48-Year-Old Woman With Dyspnea and Chest Pain

Immune-Related Adverse Events and Outcomes in Patients with Advanced Non–Small Cell Lung Cancer: A Predictive Marker of Efficacy?

Commentary: Another win for immunotherapy

Liver toxicity as a limiting factor to the increasing use of immune checkpoint inhibitors.

Durvalumab Consolidation Should Be the Standard Therapy in Stage III EGFR-Mutant NSCLC After Chemoradiation

Hyperprogression in hepatocellular carcinoma: Illusion or reality?

Molecular Biologic Staging of Lung Cancer

Cytoreduction and the Optimization Of Immune Checkpoint Inhibition with Radiation Therapy

Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.

Systematic Review of Neoadjuvant Immunotherapy for Patients With Non–Small Cell Lung Cancer

EUS staging of primary lung carcinoma: are we ready for it?

Preoperative Evaluation of Patients With Interstitial Lung Disease

Is Video-Assisted Thoracic Surgery Lobectomy Better? Quality of Life Considerations

Understanding mechanisms of primary resistance to checkpoint inhibitors will lead to precision immunotherapy of advanced gastric cancer

PD-L1 promotes myofibroblastic activation of hepatic stellate cells by distinct mechanisms selective for TGF-β receptor I versus II.

Pleiotrophin (PTN) is a secreted growth factor that induces neurite outgrowth and is mitogenic for fibroblasts, epithelial, and endothelial cells. During tumor growth PTN can serve as an angiogenic factor and drive tumor invasion and metastasis. To identify a receptor for PTN, we panned a phage display human cDNA library against immobilized PTN protein as a bait. From this we isolated a phage insert that was homologous to an amino acid sequence stretch in the extracellular domain (ECD) of the orphan receptor tyrosine kinase anaplastic lymphoma kinase (ALK). In parallel with PTN, ALK is highly expressed during perinatal development of the nervous system and down-modulated in the adult. Here we show in cell-free assays as well as in radioligand receptor binding studies in intact cells that PTN binds to the ALK ECD with an apparent Kd of 32 +/- 9 pm. This receptor binding is inhibited by an excess of PTN, by the ALK ECD, and by anti-PTN and anti-ECD antibodies. PTN added to ALK-expressing cells induces phosphorylation of both ALK and of the downstream effector molecules IRS-1, Shc, phospholipase C-gamma, and phosphatidylinositol 3-kinase. Furthermore, the growth stimulatory effect of PTN on different cell lines in culture coincides with the endogenous expression of ALK mRNA, and the effect of PTN is enhanced by ALK overexpression. From this we conclude that ALK is a receptor that transduces PTN-mediated signals and propose that the PTN-ALK axis can play a significant role during development and during disease processes.