Increased Adenine Nucleotide Degradation in Skeletal Muscle Atrophy

Adenine nucleotides (AdNs: ATP, ADP, AMP) are essential biological compounds that facilitate many necessary cellular processes by providing chemical energy, mediating intracellular signaling, and regulating protein metabolism and solubilization. A dramatic reduction in total AdNs is observed in atrophic skeletal muscle across numerous disease states and conditions, such as cancer, diabetes, chronic kidney disease, heart failure, COPD, sepsis, muscular dystrophy, denervation, disuse, and sarcopenia. The reduced AdNs in atrophic skeletal muscle are accompanied by increased expression/activities of AdN degrading enzymes and the accumulation of degradation products (IMP, hypoxanthine, xanthine, uric acid), suggesting that the lower AdN content is largely the result of increased nucleotide degradation. Furthermore, this characteristic decrease of AdNs suggests that increased nucleotide degradation contributes to the general pathophysiology of skeletal muscle atrophy. In view of the numerous energetic, and non-energetic, roles of AdNs in skeletal muscle, investigations into the physiological consequences of AdN degradation may provide valuable insight into the mechanisms of muscle atrophy

Break the Monopoly of Lawyers on the Supreme Court

The questions these cases pose are: Do lawyers alone have the wisdom to make such sociological and moral decisions as Plessy, Brown, and Roe? Should only lawyers deal with political theory in the way the Supreme Court has in the Legislative Reapportionment Cases? Can only lawyers deal in a definitive way with the troublesome questions concerning the relationship of church and state presented by the Prayer Cases? Although the list of cases may be extended to cover the full range of socioeconomic questions that remain of fundamental importance to this country, the answer to these questions remains the same. No one can argue validly that lawyers have better consciences or better insight into the great governmental affairs than do nonlawyers. The work of the Supreme Court is different from that of any other court. It is, as Justice Frankfurter once remarked, a very special kind of court. The cases that come before the Supreme Court require the Justices to answer questions for which neither law school, legal practice,nor the usual prejudicial career provides the necessary skills. Lawyers do not have a monopoly on governmental wisdom

Phosphatidylinositol 3-kinase pathway genomic alterations in 60,991 diverse solid tumors informs targeted therapy opportunities.

BackgroundThe phosphatidylinositol 3-kinase (PI3K) pathway is frequently altered in cancer. This report describes the landscape of PI3K alterations in solid tumors as well as co-alterations serving as potential resistance/attenuation mechanisms.MethodsConsecutive samples were analyzed in a commercial Clinical Laboratory Improvement Amendment-certified laboratory using comprehensive genomic profiling performed by next-generation sequencing (315 genes). The co-alterations evaluated included the Erb-B2 receptor tyrosine kinase 2 (ERBB2), ERBB3, ERBB4, RAS, MET proto-oncogene tyrosine kinase (MET), and mitogen-activated protein kinase kinase (MAP2K) genes as well as tumor protein 53 (TP53), estrogen receptor 1 (ESR1), and androgen receptor (AR).ResultsAlterations in any of 18 PI3K-pathway associated genes were identified in 44% of 60,991 tumors. Although single base and insertions/deletions (indels) were the most frequent alterations, copy number changes and rearrangements were identified in 11% and 0.9% of patients, respectively. Overall, the most frequently altered genes were PIK3 catalytic subunit α (PIK3CA) (13%), phosphatase and tensin homolog (PTEN) (9%), and serine/threonine kinase 11 (STK11) (5%). Tumor types that frequently harbored at least 1 PI3K alteration were uterine (77%), cervical (62%), anal (59%), and breast (58%) cancers. Alterations also were discerned frequently in tumors with carcinosarcoma (89%) and squamous cell carcinoma (62%) histologies. Tumors with a greater likelihood of co-occurring PI3K pathway and MAPK pathway alterations included colorectal cancers (odds ratio [OR], 1.64; P < .001), mesotheliomas (OR, 2.67; P = .024), anal cancers (OR, 1.98; P = .03), and nonsquamous head and neck cancers (OR, 2.03; P = .019). The co-occurrence of ESR1 and/or AR alterations with PI3K alterations was statistically significant in bladder, colorectal, uterine, prostate, and unknown primary cancers.ConclusionsComprehensive genomic profiling reveals altered PI3K-related genes in 44% of solid malignancies, including rare disease and histology types. The frequency of alterations and the co-occurrence of resistance pathways vary by tumor type, directly affecting opportunities for targeted therapy

Hyaluronan Modulated Expression of MMPs 2, 9, and 12 in Macrophages

Hyaluronan (HA) is a ubiquitously expressed Glycosaminoglycan (GAG) found as a main component of the extracellular matrix (ECM). Matrix metalloproteases (MMPs) are class of enzyme responsible for the degradation of multiple ECM components, including HA. Following a myocardial infarction (MI), ECM remodeling occurs in the infarct tissue and involves an accumulation of HA. Remodeling is facilitated by multiple cell types, including macrophages. During post-MI ECM remodeling, macrophages degrade and ingulf dead cells and ECM components, a process which requires the expression of MMPs. MMPs 2, 9, and 12 are known to be elevated post-MI; MMPs 9 and 12 are known to have HA as a substrate. These factors make MMPs 2, 9, and 12 especially relevant to the post-MI ECM remodeling process. The effect of increased HA present post-MI on levels of MMP expression in macrophages has yet to be investigated