© 2018 American Association for Cancer Research Benign secretory epithelial cell Serous tubal intraepithelial carcinoma cell Ovary Ovarian cancer cell migration & clonogenic growth NOTE: Key to table: a vs. b , P ¼ 0.0014; a vs. c , P < 0.0001; b vs. c , P ¼ 0.0995; d vs. e , P ¼ 0.0007; d vs. f , P < 0.0001; e vs. f , P ¼ 0.0323. P values determined by Mann-Whitney test.Hooda et al.
Increasing evidence indicates that sirtuin 3 (Sirt3) has neuroprotective effects in regulating oxidative stress and energy metabolism, both of which are involved in the pathogenesis of Alzheimer's disease (AD). However, it is unclear whether Sirt3 is associated with cognitive performance and pathological changes in AD. We conducted a case-control study of the postmortem brains of AD (n = 16), mild cognitive impairment (n = 13), and age- and education-matched cognitively normal (CN, n = 11) subjects. We measured the mRNA and protein levels of Sirt3 and assessed their association with cognitive performance and AD pathology. In an ex vivo model of cortical neurons from transgenic mice that carry human tau protein, we modified Sirt3 expression by genetic knockdown and knock-in to investigate the cause-effect relationship between Sirt3 and tau. Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN. This reduction was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology. Further study with genetic manipulation of Sirt3 revealed that amyloid-β increased levels of total tau acetylated tau through its modulation of Sirt3. These data suggest that reduction of Sirt3 is critically involved in pathogenesis of AD.
Pituitary adenylate cyclase activating polypeptide (PACAP) is associated with Alzheimer’s disease (AD), but its age-related effects are unknown. We chose the rhesus macaque due to its closeness to human anatomy and physiology. We examined four variables: aging, cognitive performance, amyloid plaques and PACAP. Delayed nonmatching-to-sample recognition memory scores declined with age and correlated with PACAP levels in the striatum, parietal and temporal lobes. Because amyloid plaques were the only AD pathology in the old rhesus macaque, we further studied human amyloid precursor protein (hAPP) transgenic mice. Aging was associated with decreased performance in the Morris Water Maze (MWM). In wild type (WT) C57BL/6 mice, the performance was decreased at age 24–26 month whereas in hAPP transgenic mice, it was decreased as early as 9–12 month. Neuritic plaques in adult hAPP mice clustered in hippocampus and adjacent cortical regions, but did not propagate further into the frontal cortex. Cerebral PACAP protein levels were reduced in hAPP mice compared to age-matched WT mice, but the genetic predisposition dominated cognitive decline. Taken together, these data suggest an association among PACAP levels, aging, cognitive function and amyloid load in nonhuman primates, with both similarities and differences from human AD brains. Our results suggest caution in choosing animal models and in extrapolating data to human AD studies.
Object We characterize idiopathic normal pressure hydrocephalus (NPH) following treatment with lumbar puncture (LP) and shunt placement through clinical evaluation and quantitative ProtoKinetics Zeno walkway assessments. We evaluate the symptomology by determining gait characteristics altered by treatment. Methods Patients at Barrow Neurological Institute (BNI) who underwent a LP, removing 30‐32 mL cerebrospinal fluid) followed by ventriculoperitoneal shunt placement in February 2015 to February 2017 were analyzed for gait impairments. Inclusion in the study required a diagnosis of NPH, no conflicting comorbidities, and pre‐LP, post‐LP, and 6‐month post‐shunt assessments. Analyses of gait and balance data recorded by physical therapists and the ProtoKinetics Zeno Walkway at pre‐LP, post‐LP, and post‐shunt were performed. Results A total of 28 patients were included and one‐way analysis of variance and Tukey‐Kramer HSD was performed. Among the 15 clinical assessments, nine were significantly altered. Using the ProtoKinetics Zeno Walkway, 7 out of 10 characteristics recorded were considered significantly different among the three data sets. Furthermore, there were more significant differences between pre‐LP assessments and post‐shunt assessments in comparison to differences between pre‐LP assessments and post‐LP assessments. Conclusions Our results indicate that certain gait characteristics better fit NPH than others. By focusing on the features that are caused by NPH and alleviated by LP and/or shunt placement, a more definitive NPH diagnosis can be attained. Additionally, our findings confirm a cumulative effect of continuous drainage via shunt placement may lead to increased improvement in NPH symptoms over LP results.
Background: Proteomic studies have identified many potential proteins associated with early diagnosis, differential diagnosis, prognosis and therapeutic response in diverse diseases. Recent proteomic analysis of Alzheimer's disease (AD) plaques has identified a novel amyloid associated protein, secernin-1, which is a 50 kDa cytosolic protein (Acta Neuropathol 133: 933-954, 2017). Secernin-1 is known to regulate exocytosis in mast cells and increases both the extent of secretion and the sensitivity of mast cells to stimulation with calcium. It has been identified as a novel immunotherapy target for gastric cancer and a novel marker for prognosis in colorectal cancer. It is highly expressed in brain tissue and has dipeptidase activity. However, secernin-1 had not been previously known to be associated with neurodegenerative disorders. Methods:The presence of neuritic amyloid plaques and intracellular neurofibrillary tangles are hallmarks of AD However the soluble oligomers of amyloid beta (Ab) and hyperphosphorylated tau are thought to be the major toxic species in AD. To determine the potential role of secernin-1 in AD neurodegeneration we initially performed in vitro binding experiments of human secernin-1 to the Ab peptide and to recombinant human Tau-His tag. These two AD proteins were polymerized by glutaraldehyde treatment to form stable oligomers. Binding was assessed by western blot analysis with mouse monoclonal antibodies to Ab (6E10, epitope residues 1-16; 4G8, epitope residues 17-24), Tau and rabbit polyclonal anti Human secernin-1. Results:Surprisingly, the anti-secernin-1 antibody immunolabeled oligomers of Ab and tau at approximately their original molecular weight. There were no discrete higher molecular weight positive bands detected by any antibody that would correspond to a complex of Ab or tau oligomer and intact secernin-1. Therefore only a small fragment of secernin-1 may be complexed with Ab and Tau oligomers. These complexes are being processed and analyzed by label-free quantitative LC-MS/MS analysis. Experiments with AD brain tissue extracts of Ab and tau oligomers are in progress. Conclusions: This secernin-1 peptide may be a novel marker for detection, prognosis and therapeutic evaluation in Alzheimer's disease.
<div>Abstract<p>Recent insights supporting the fallopian tube epithelium (FTE) and serous tubal intraepithelial carcinomas (STIC) as the tissue of origin and the precursor lesion, respectively, for the majority of high-grade serous ovarian carcinomas (HGSOC) provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Here, we investigate the role of the E3 ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis and report that heterozygous loss of RNF20 defines the majority of HGSOC tumors. At the protein level, H2Bub1 was lost or downregulated in a large proportion of STIC and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in the development of serous ovarian carcinoma. Knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to enhance cell migration and clonogenic growth of FTE cells. To investigate the mechanisms underlying these effects, we performed ATAC-seq and RNA-seq in RNF20 knockdown FTE cell lines. Loss of RNF20 and H2Bub1 was associated with a more open chromatin conformation, leading to upregulation of immune signaling pathways, including IL6. IL6 was one of the key cytokines significantly upregulated in RNF20- and H2Bub1-depleted FTE cells and imparted upon these cells an enhanced migratory phenotype. These studies provide mechanistic insight into the observed oncogenic phenotypes triggered by the early loss of H2Bub1.</p>Significance:<p>Loss of RNF20 and H2Bub1 contributes to transformation of the fallopian tube epithelium and plays a role in the initiation and progression of high-grade serous ovarian cancer.</p></div>
<p>Supplementary Figures and Tables - Figure S1. RNF40 somatic copy number alterations in a cohort of 579 HGSOC cases from The Cancer Genome Atlas (TCGA). Heterozygous loss of RNF40 is present in 36% of HGSOCs. Figure S2A. H2Bub1 stain intensity dot plot. Figure S2B. Distribution of H2Bub1 immunoreactivity (% positive cells). Figure S2C. Immunohistochemical analysis of Total H2B and H2Bub1 levels in invasive high-grade serious ovarian cancer. Figure S3. Stable RNF20 and H2Bub1 depletion escalates oncogenic behavior in FTSEC cell lines. Figure S4. Transient RNF20 and H2Bub1 depletion escalates oncogenic behavior in FTSECs. Figure S5. RNF20-depletion changes chromatin accessibility and redistributes open chromatin. Figure S6. RNF20-depletion changes chromatin accessibility and alters gene expression of immune signaling pathways in FTSEC cells. Figure S7. RNF20 and H2Bub1 deficiency alters the levels of cytokines. Figure S8. Representative images for RNA in situ hybridization of IL6 expression in FFPE tumor and normal tissue sections. Supplementary Table 1. Antibody information and staining conditions for immunohistochemistry (IHC).</p>
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