Aberrant \u3ci\u3eAZIN2\u3c/i\u3e and Polyamine Metabolism Precipitates Tau Neuropathology

Tauopathies display a spectrum of phenotypes from cognitive to affective behavioral impairments; however, mechanisms promoting tau pathology and how tau elicits behavioral impairment remain unclear. We report a unique interaction between polyamine metabolism, behavioral impairment, and tau fate. Polyamines are ubiquitous aliphatic molecules that support neuronal function, axonal integrity, and cognitive processing. Transient increases in polyamine metabolism hallmark the cell’s response to various insults, known as the polyamine stress response (PSR). Dysregulation of gene transcripts associated with polyamine metabolism in Alzheimer’s disease (AD) brains were observed, and we found that ornithine decarboxylase antizyme inhibitor 2 (AZIN2) increased to the greatest extent. We showed that sustained AZIN2 overexpression elicited a maladaptive PSR in mice with underlying tauopathy (MAPT P301S; PS19). AZIN2 also increased acetylpolyamines, augmented tau deposition, and promoted cognitive and affective behavioral impairments. Higher-order polyamines displaced microtubule-associated tau to facilitate polymerization but also decreased tau seeding and oligomerization. Conversely, acetylpolyamines promoted tau seeding and oligomers. These data suggest that tauopathies launch an altered enzymatic signature that endorses a feed-forward cycle of disease progression. Taken together, the tau-induced PSR affects behavior and disease continuance, but may also position the polyamine pathway as a potential entry point for plausible targets and treatments of tauopathy, including AD

Animal Studies in Spinal Cord Injury: A Systematic Review of Methylprednisolone

The objective of this study was to examine whether animal studies can reliably be used to determine the usefulness of methylprednisolone (MP) and other treatments for acute spinal cord injury (SCI) in humans. This was achieved by performing a systematic review of animal studies on the effects of MP administration on the functional outcome of acute SCI. Data were extracted from the published articles relating to: outcome; MP dosing regimen; species/strain; number of animals; methodological quality; type of injury induction; use of anaesthesia; functional scale used; and duration of follow-up. Subgroup analyses were performed, based on species or strain, injury method, MP dosing regimen, functional outcome measured, and methodological quality. Sixty-two studies were included, which involved a wide variety of animal species and strains. Overall, beneficial effects of MP administration were obtained in 34% of the studies, no effects in 58%, and mixed results in 8%. The results were inconsistent both among and within species, even when attempts were made to detect any patterns in the results through subgroup analyses. The results of this study demonstrate the barriers to the accurate prediction from animal studies of the effectiveness of MP in the treatment of acute SCI in humans. This underscores the need for the development and implementation of validated testing methods

Laboratory Routines Cause Animal Stress

Eighty published studies were appraised to document the potential stress associated with three routine laboratory procedures commonly performed on animals: handling, blood collection, and orogastric gavage. We defined handling as any non-invasive manipulation occurring as part of routine husbandry, including lifting an animal and cleaning or moving an animal\u27s cage. Significant changes in physiologic parameters correlated with stress (e.g., serum or plasma concentrations of corticosterone, glucose, growth hormone or prolactin, heart rate, blood pressure, and behavior) were associated with all three procedures in multiple species in the studies we examined. The results of these studies demonstrated that animals responded with rapid, pronounced, and statistically significant elevations in stress-related responses for each of the procedures, although handling elicited variable alterations in immune system responses. Changes from baseline or control measures typically ranged from 20% to 100% or more and lasted at least 30 min or longer. We interpret these findings to indicate that laboratory routines are associated with stress, and that animals do not readily habituate to them. The data suggest that significant fear, stress, and possibly distress are predictable consequences of routine laboratory procedures, and that these phenomena have substantial scientific and humane implications for the use of animals in laboratory research

Animal Studies in Spinal Cord Injury: A Systematic Review of Methylprednisolone

The objective of this study was to examine whether animal studies can reliably be used to determine the usefulness of methylprednisolone (MP) and other treatments for acute spinal cord injury (SCI) in humans. This was achieved by performing a systematic review of animal studies on the effects of MP administration on the functional outcome of acute SCI. Data were extracted from the published articles relating to: outcome; MP dosing regimen; species/strain; number of animals; methodological quality; type of injury induction; use of anaesthesia; functional scale used; and duration of follow-up. Subgroup analyses were performed, based on species or strain, injury method, MP dosing regimen, functional outcome measured, and methodological quality. Sixty-two studies were included, which involved a wide variety of animal species and strains. Overall, beneficial effects of MP administration were obtained in 34% of the studies, no effects in 58%, and mixed results in 8%. The results were inconsistent both among and within species, even when attempts were made to detect any patterns in the results through subgroup analyses. The results of this study demonstrate the barriers to the accurate prediction from animal studies of the effectiveness of MP in the treatment of acute SCI in humans. This underscores the need for the development and implementation of validated testing methods

Animal Studies in Spinal Cord Injury: A Systematic Review of Methylprednisolone

The objective of this study was to examine whether animal studies can reliably be used to determine the usefulness of methylprednisolone (MP) and other treatments for acute spinal cord injury (SCI) in humans. This was achieved by performing a systematic review of animal studies on the effects of MP administration on the functional outcome of acute SCI. Data were extracted from the published articles relating to: outcome; MP dosing regimen; species/strain; number of animals; methodological quality; type of injury induction; use of anaesthesia; functional scale used; and duration of follow-up. Subgroup analyses were performed, based on species or strain, injury method, MP dosing regimen, functional outcome measured, and methodological quality. Sixty-two studies were included, which involved a wide variety of animal species and strains. Overall, beneficial effects of MP administration were obtained in 34% of the studies, no effects in 58%, and mixed results in 8%. The results were inconsistent both among and within species, even when attempts were made to detect any patterns in the results through subgroup analyses. The results of this study demonstrate the barriers to the accurate prediction from animal studies of the effectiveness of MP in the treatment of acute SCI in humans. This underscores the need for the development and implementation of validated testing methods

Animal Studies in Spinal Cord Injury: A Systematic Review of Methylprednisolone

The objective of this study was to examine whether animal studies can reliably be used to determine the usefulness of methylprednisolone (MP) and other treatments for acute spinal cord injury (SCI) in humans. This was achieved by performing a systematic review of animal studies on the effects of MP administration on the functional outcome of acute SCI. Data were extracted from the published articles relating to: outcome; MP dosing regimen; species/strain; number of animals; methodological quality; type of injury induction; use of anaesthesia; functional scale used; and duration of follow-up. Subgroup analyses were performed, based on species or strain, injury method, MP dosing regimen, functional outcome measured, and methodological quality. Sixty-two studies were included, which involved a wide variety of animal species and strains. Overall, beneficial effects of MP administration were obtained in 34% of the studies, no effects in 58%, and mixed results in 8%. The results were inconsistent both among and within species, even when attempts were made to detect any patterns in the results through subgroup analyses. The results of this study demonstrate the barriers to the accurate prediction from animal studies of the effectiveness of MP in the treatment of acute SCI in humans. This underscores the need for the development and implementation of validated testing methods

Animal Models in Spinal Cord Injury: A Review

Multiple neuroprotective agents have shown benefit for the treatment of acute spinal cord injury (SCI) in animal studies. However, clinical trials have, thus far, been uniformly dis ·appointing. This review explores reasons for discrepancies between promising animal studies and disappointing clinical trials and potential barriers to extrapolation of research results from animals to humans. The three major barriers disclosed are: differences in injury type between laboratory-induced SCI and clinical SCI, difficulties in interpreting functional outcome in animals, and inter-species and interstrain differences in pathophysiology of SCI. These barriers can impair the effectiveness of animal models of SCI to predict human outcomes. While some of these barriers can be overcome, others are inherent to the animal models

Comprehensive molecular profiling of lung adenocarcinoma

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen(mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis

Comprehensive molecular characterization of urothelial bladder carcinoma

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomasto provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalitiesclose27