No abstract

This study was designed to investigate the e ects of detraining that occurred during an 8 week period of muscular inactivity following a 12 week training program of arti®cial computerized functional electrical stimulation cycle ergometry (CFES LE) and arm ergometry. Six spinal cord injured male individuals were followed through an 8 week detraining period that was preceded by a 12 week exercise program including CFES LE and arm ergometry. Maximal graded exercise tests were completed and measurements of peak oxygen consumption (VO 2 ), heart rate (HR), ventilation (V E ) workload, and creatine kinase were taken. Testing occurred at initial training (0T), after 12 weeks of training (12T), and after 8 weeks of detraining (DT). After the training program, peak VO 2 increased signi®cantly from 0.562+0.126 (0T) to 1.021+0.247 l/min (12T, P50.05). After DT, peak VO 2 decreased to 0.791=0.216 l/min, which was lower than 12T (P50.05), yet higher than 0T (P50.05). After DT, peak workoad had decreased from 0.675+0.203 (12T) to 0.32+0.203 kp (P50.05), which was not di erent than 0T. Creatine kinase levels were signi®cantly lower both at 12T and DT compared to OT (P50.05). In addition, this training program induced linear increases in both VO 2 and HR with workload, which were retained after DT. These increases did not reach statistical signi®cance, however. No apparent relationship existed between these values at baseline. There were no signi®cant di erences in submaximal or peak HR of V E between the three testing periods. The results indicate that both peripheral muscular adaptations and central distribution adaptations in SCI individuals are partially maintained following 8 weeks of DT from CFES LE and arm ergometry.

A 13-year-old boy with a strong family history of hereditary pancreatitis was found to have a PRSS1 mutation after being tested at age 5 years during his first documented incident of pancreatitis. Since then, a multidisciplinary team has been treating him for the diagnosis of hereditary pancreatitis. His pain episodes increased in severity over the past several months such that the pain began to severely interfere with his daily life. After extensive discussion, a total pancreatectomy with auto islet cell transplant was performed. He is now pain free and does not require any insulin. This leads us to the questions of what is hereditary pancreatitis and how is it diagnosed? What are the management and follow-up strategies needed for these patients? This article addresses these questions and informs the reader about this diagnosis and the importance of having a high index of clinical suspicion.

No abstract

Drug resistant mutations that arise in therapeutic targets often limit clinical responses. However, the discovery of such mutations has historically been performed one gene or mutation at a time, often over decades of experimental and clinical testing, limiting our understanding of conserved mechanisms of drug resistance. We hypothesized that deep mutational scanning of canonical kinases may expedite this process and identify novel conserved elements that cause drug resistance when mutated (similar to the well-studied “Gatekeeper” residue). To test this, we generated cDNA-expression libraries containing all possible amino acid substitutions in CDK6, CDK4, ERK2, and EGFR. We screened each library against clinically utilized, ATP-competitive small molecule inhibitors. We then mapped the phenotypic data for over 40,000 missense mutations onto the aligned crystal structures of each protein and searched for shared structural attributes associated with drug resistance. This analysis revealed 4 equivalent amino acid sites whose mutation conferred drug resistance to ATP-competitive inhibitors in all of our screens: the Gatekeeper residue, as well as three uncharacterized residues. One of these sites, which we have termed the “Keymaster”, was additionally found to cause resistance in published data sets of sub-saturation BRAF, HER2, BCR-ABL, and MEK1 mutagenesis screens against their respective inhibitors. We confirmed that drug resistant phenotypes are caused by these alterations utilizing growth assays and protein target phosphorylation detection assays. Mechanistically, we show preliminary evidence that Keymaster-mutant proteins are competent for drug binding, but may display elevated basal activity. Consistent with our findings, we additionally identified mutations at Keymaster residues in reported patient tumors in a number of oncogene kinases, suggesting that Keymaster mutations could be drivers of tumorigenesis, as well as drug resistance. These efforts may prove useful for characterizing somatic kinase mutations of unknown function, designing next-generation therapeutics and deepening our understanding of kinase regulation. Citation Format: Nicole S. Persky, Desiree Hernandez, Jonathon Cordova, Amanda Walker, Lisa Brenan, Federica Piccioni, Sasha Pantel, Yenarae Lee, Amy Goodale, Xiaoping Yang, Yoichiro Mitsuishi, Mariana Do Carmo, Cong Zhu, Aleksandr Andreev, David E. Root, Cory M. Johannessen. Massively parallel identification of conserved drug resistant mutations in kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1815.