Hedgehog-GLI mediated control of renal formation and malformation

CAKUT is the leading cause of end-stage kidney disease in children and comprises a broad spectrum of phenotypic abnormalities in kidney and ureter development. Molecular mechanisms underlying the pathogenesis of CAKUT have been elucidated in genetic models, predominantly in the mouse, a paradigm for human renal development. Hedgehog (Hh) signaling is critical to normal embryogenesis, including kidney development. Hh signaling mediates the physiological development of the ureter and stroma and has adverse pathophysiological effects on the metanephric mesenchyme, ureteric, and nephrogenic lineages. Further, disruption of Hh signaling is causative of numerous human developmental disorders associated with renal malformation; Pallister-Hall Syndrome (PHS) is characterized by a diverse spectrum of malformations including CAKUT and caused by truncating variants in the middle-third of the Hh signaling effector GLI3. Here, we outline the roles of Hh signaling in regulating murine kidney development, and review human variants in Hh signaling genes in patients with renal malformation

Model-Based Testing for the Cloud

Software in the cloud is characterised by the need to be highly adaptive and continuously available. Incremental changes are applied to the deployed system and need to be tested in the field. Different configurations need to be tested. Higher quality standards regarding both functional and non-functional properties are put on those systems, as they often face large and diverse customer bases and/or are used as services from different peer service implementations. The properties of interest include interoperability, privacy, security, reliability, performance, resource use, timing constraints, service dependencies, availability, and so on. This paper discusses the state of the art in model-based testing of cloud systems. It focuses on two central aspects of the problem domain: (a) dealing with the adaptive and dynamic character of cloud software when tested with model-based testing, by developing new online and offline test strategies, and (b) dealing with the variety of modeling concerns for functional and non-functional properties, by devising a unified framework for them where this is possible. Having discussed the state of the art we identify challenges and future directions

Phase II Trial of IL-12 Plasmid Transfection and PD-1 Blockade in Immunologically Quiescent Melanoma.

PurposeTumors with low frequencies of checkpoint positive tumor-infiltrating lymphocytes (cpTIL) have a low likelihood of response to PD-1 blockade. We conducted a prospective multicenter phase II trial of intratumoral plasmid IL-12 (tavokinogene telseplasmid; "tavo") electroporation combined with pembrolizumab in patients with advanced melanoma with low frequencies of checkpoint positive cytotoxic lymphocytes (cpCTL).Patients and methodsTavo was administered intratumorally days 1, 5, and 8 every 6 weeks while pembrolizumab (200 mg, i.v.) was administered every 3 weeks. The primary endpoint was objective response rate (ORR) by RECIST, secondary endpoints included duration of response, overall survival and progression-free survival. Toxicity was evaluated by the CTCAE v4. Extensive correlative analysis was done.ResultsThe combination of tavo and pembrolizumab was well tolerated with adverse events similar to those previously reported with pembrolizumab alone. Patients had a 41% ORR (n = 22, RECIST 1.1) with 36% complete responses. Correlative analysis showed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T cell receptor clones and, ultimately, systemic cellular immune responses.ConclusionsThe combination of tavo and pembrolizumab was associated with a higher than expected response rate in this poorly immunogenic population. No new or unexpected toxicities were observed. Correlative analysis showed T cell infiltration with enhanced immunity paralleling the clinical activity in low cpCTL tumors