Evolutionary History of Tissue Kallikreins

The gene family of human kallikrein-related peptidases (KLKs) encodes proteins with diverse and pleiotropic functions in normal physiology as well as in disease states. Currently, the most widely known KLK is KLK3 or prostate-specific antigen (PSA) that has applications in clinical diagnosis and monitoring of prostate cancer. The KLK gene family encompasses the largest contiguous cluster of serine proteases in humans which is not interrupted by non-KLK genes. This exceptional and unique characteristic of KLKs makes them ideal for evolutionary studies aiming to infer the direction and timing of gene duplication events. Previous studies on the evolution of KLKs were restricted to mammals and the emergence of KLKs was suggested about 150 million years ago (mya). In order to elucidate the evolutionary history of KLKs, we performed comprehensive phylogenetic analyses of KLK homologous proteins in multiple genomes including those that have been completed recently. Interestingly, we were able to identify novel reptilian, avian and amphibian KLK members which allowed us to trace the emergence of KLKs 330 mya. We suggest that a series of duplication and mutation events gave rise to the KLK gene family. The prominent feature of the KLK family is that it consists of tandemly and uninterruptedly arrayed genes in all species under investigation. The chromosomal co-localization in a single cluster distinguishes KLKs from trypsin and other trypsin-like proteases which are spread in different genetic loci. All the defining features of the KLKs were further found to be conserved in the novel KLK protein sequences. The study of this unique family will further assist in selecting new model organisms for functional studies of proteolytic pathways involving KLKs

Sarcoidosis in a 65-year-old woman presenting with a lung mass and pericardial effusion: a case report

<p>Abstract</p> <p>Introduction</p> <p>Sarcoidosis is a multi-systemic disorder of unknown origin and most commonly affects the lungs. Diagnosis relies on the presence of non-caseating granulomas on histologic specimens. In high-resolution computed tomography, the most characteristic findings are peribronchovascular thickening, perilymphatic nodular distribution, and bilateral hilar adenopathy. Confluent nodular opacities or large masses are rare manifestations of the disease. It is well recognized that sarcoidosis can mimic infectious, malignant, and granulomatous conditions. Here, we report a case with a high initial index of suspicion for lung malignancy in terms of clinical, lung imaging, and endoscopic findings.</p> <p>Case presentation</p> <p>A 65-year-old Caucasian woman, lifelong non-smoker with an unremarkable medical history, presented with a 10-month history of progressive breathlessness, dry cough, fatigue, arthralgias, and mild weight loss. The only significant clinical finding was bilateral enlargement of auxiliary lymph nodes. High-resolution computed tomography revealed a soft tissue density mass at the right hilum which was surrounding and narrowing airways and vascular components, nodules with vascular distribution, enlarged mediastinal lymph nodes, and pericardial effusion. Our patient underwent a bronchoscopy, which revealed the presence of submucosal infiltration and narrowing of the right upper bronchus. Endobronchial biopsies showed non-caseating granulomas. As local sarcoid reactions with non-caseating granulomas can be observed near tumors, our patient underwent video-assisted thoracoscopy and surgical removal of an auxiliary lymph node, both of which confirmed the presence of non-caseating granulomas and the diagnosis of sarcoidosis. She was treated with steroids with improvement of clinical and imaging findings. However, while on a maintenance dose, she presented with a pleural effusion, which, after the diagnostic work-up, proved to be sarcoidosis-related. Treatment with initially high doses of steroids plus a steroid-sparing agent led to resolution of the effusion.</p> <p>Conclusions</p> <p>We report a case with a high initial index of suspicion for lung malignancy. Clinicians should always be aware that sarcoidosis enters the differential diagnosis of patients presenting with a lung mass that encases and narrows bronchial and vascular structures with associated pericardial effusion. Rarely, pleural effusion can be the presenting symptom of disease relapse despite maintenance treatment.</p