Astrocyte-specific knockout of YKL-40/Chi3l1 reduces Aß burden and restores memory functions in 5xFAD mice.

Glial cell-mediated neuroinflammation and neuronal attrition are highly correlated with cognitive impairment in Alzheimer's disease. YKL-40 is a secreted astrocytic glycoprotein that serves as a diagnostic biomarker of Alzheimer's disease. High levels of YKL-40 are associated with either advanced Alzheimer's disease or the normal aging process. However, the functional role of YKL-40 in Alzheimer's disease development has not been firmly established. In a 5xFAD mouse model of Alzheimer's disease, we observed increased YKL-40 expression in the cerebrospinal fluid of 7-month-old mice and was correlated with activated astrocytes. In primary astrocytes, Aß1-42 upregulated YKL-40 in a dose-dependent manner and was correlated with PI3-K signaling pathway activation. Furthermore, primary neurons treated with YKL-40 and/or Aß1-42 resulted in significant synaptic degeneration, reduced dendritic complexity, and impaired electrical parameters. More importantly, astrocyte-specific knockout of YKL-40 over a period of 7 days in symptomatic 5xFAD mice could effectively reduce amyloid plaque deposition in multiple brain regions. This was also associated with attenuated glial activation, reduced neuronal attrition, and restored memory function. These biological phenotypes could be explained by enhanced uptake of Aß1-42 peptides, increased rate of Aß1-42 degradation and acidification of lysosomal compartment in YKL-40 knockout astrocytes. Our results provide new insights into the role of YKL-40 in Alzheimer's disease pathogenesis and demonstrate the potential of targeting this soluble biomarker to alleviate cognitive defects in symptomatic Alzheimer's disease patients.

Investigation of high gamma-glutamyltransferase syndrome in California Thoroughbred racehorses.

BACKGROUND: Increases in serum gamma-glutamyltransferase (GGT) activity have been reported in Thoroughbred (TB) racehorses and associated with maladaptation to training but the underlying etiology remains unknown. HYPOTHESIS/OBJECTIVES: Classify the etiology of high GGT syndrome in racing TBs by assessment of pancreatic enzymes, vitamin E concentrations, and both a candidate gene and whole genome association study. We hypothesized that a genetic variant resulting in antioxidant insufficiency or pancreatic dysfunction would be responsible for high GGT syndrome in TBs. ANIMALS: A total of 138 California racing TBs. Amylase: n = 31 affected (serum GGT activity ≥60 IU/L), n = 52 control (serum GGT activity <40 IU/L). Lipase: n = 19 affected, n = 35 control. Serum α-tocopherol concentrations: n = 32 affected, n = 46 control. Genome-wide association study (GWAS): 36 affected, 58 control. Whole genome sequencing: n = 5 affected, n = 5 control. METHODS: Biochemical and vitamin analytes were compared among cohorts. A GWAS was performed and a subset of TBs underwent whole genome sequencing to interrogate candidate genes and positional genetic regions. RESULTS: Serum lipase and amylase activity and α-tocopherol concentrations did not differ between groups. No genetic variants were identified in 2 candidate genes (UGT1A1 and GGT1) that associated with the phenotype. Four single nucleotide polymorphisms (SNPs) approached a suggestive association with the phenotype (P = 2.15 × 10-5 ), defining a 100 kb region on chromosome 5 surrounding cluster of differentiation 1a (CD1A1), a transmembrane gene related to the major histocompatibility complex. CONCLUSIONS AND CLINICAL IMPORTANCE: An underlying genetic etiology may exist for high GGT syndrome in racing TBs, similar to genetic disorders in humans.

The mitotic regulator RCC2 promotes glucose metabolism through BACH1-dependent transcriptional upregulation of hexokinase II in glioma.

Weighted gene co-expression network analysis (WGCNA) identified a cell-cycle module that is associated with poor prognosis and aggressiveness of glioma. One of the core members, Regulator of chromatin condensation 2 (RCC2) is a component of the chromosome passenger complex. Accumulating evidence suggests that RCC2 plays a vital role in the mitotic process and that abnormal RCC2 expression is involved in cancer development. Gene silencing experiments show that RCC2 is required for glioma cell proliferation and migration. RNA-Sequencing analysis reveals a dual role of RCC2 in both the cell cycle and metabolism. Specifically, RCC2 regulates G2/M progression via CDC2 phosphorylation at Tyrosine 15. Metabolomic analysis identifies a role for RCC2 in promoting the glycolysis and pentose phosphate pathway. RCC2 exerts effects on metabolism by stabilizing the transcription factor BACH1 at its C-terminus leading to the transcriptional upregulation of hexokinase 2 (HK2). These findings elucidate a novel PTEN/RCC2/BACH1/HK2 signaling axis that drives glioma progression through the dual regulation of mitotic cell cycle and glycolytic events.

Tumour-derived substrate-adherent cells promote neuroblastoma survival through secreted trophic factors.

Neuroblastoma (NB) is the most common extracranial solid tumour in children. NB is highly heterogeneous and is comprised of a mixture of neuroblastic cancer cells and stromal cells. We previously reported that N-type cells (neuroblastic cells) and S-type cells (substrate-adherent cells) in the SK-N-SH cell line shared almost identical genetic backgrounds. Sublines of N- and S-type cells were isolated from an early passage (P35) of SK-N-SH. Sequencing analysis revealed that all sublines harboured the anaplastic lymphoma kinase (ALK) F1174L mutation, indicating that they were tumour derived. Surprisingly, over 74% resembled S-type cells. In coculture experiments, S-type cells protected N-type cells from apoptosis induced by the oncogenic ALK inhibitor TAE684. Western blotting analyses showed that ALK, protein kinase A (AKT) and STAT3 signalling were stimulated in the cocultures. Furthermore, the conditioned medium from S-type cells activated these downstream signalling molecules in the N-type cells. The activation of STAT3 in the N-type cells was ALK-independent, while AKT was regulated by the ALK activation status. To identify the responsible soluble factors, we used a combination of transcriptomic and proteomic analysis and found that plasminogen activator inhibitor 1, secreted protein acidic and cysteine rich, periostin and galectin-1 were potential mediators of STAT3 signalling. The addition of recombinant proteins to the tumour cells treated with the ALK inhibitor partially enhanced cell viability. Overall, the tumour-derived S-type cells prevented apoptosis in the N-type cells via ALK-independent STAT3 activation triggered by secreted factors. The inhibition of these factors in combination with ALK inhibition could provide a new direction for targeted therapies to treat high-risk NB.

Controversies in ulcerative colitis: a survey comparing decision making of experts versus community gastroenterologists.

BACKGROUND & AIMS: Despite the development of consensus guidelines in ulcerative colitis (UC), there remain several areas of uncertainty in the everyday management of this incompletely understood disease. We performed a national vignette survey to measure variations in decision-making in areas of controversy. METHODS: We constructed a survey with 3 vignettes to measure decision-making in 4 areas of controversy in UC: (1) dysplasia management, (2) mesalamine dosing, (3) diagnostic testing for underlying Crohn's disease, and (4) treatment of steroid-refractory inpatient UC. We compared responses between a group of community gastroenterologists and UC experts. RESULTS: We received 192 responses (36% response). Compared with community gastroenterologists, UC experts were more likely to endorse colectomy for both unifocal and multifocal low-grade dysplasia, use narrow band imaging and chromoendoscopy for surveillance colonoscopy, use high-dose mesalamine for inducing remission, use long-term mesalamine for cancer chemoprevention, order computed tomography enterography to evaluate for Crohn's disease, and to have a lower threshold to call for surgery consultation in steroid-refractory UC. There was little agreement regarding the optimal frequency of surveillance colonoscopy, even among experts. Most respondents favored using infliximab over cyclosporine in steroid-refractory UC. CONCLUSIONS: Community gastroenterologists and UC experts vary dramatically in their approach to many areas of uncertainty in UC. The only area of consensus between groups is the use of infliximab over cyclosporine in steroid-refractory UC, itself a controversial decision. These data suggest that current practice patterns are highly disparate and focus attention on specific areas of disconnect that should be further investigated.

The relationship between obesity and functional gastrointestinal disorders: causation, association, or neither?

It is possible that functional gastrointestinal disorders (FGIDs) and obesity have more in common than merely sharing high population prevalence. Epidemiologic data indicate that obesity is associated with chronic gastrointestinal complaints, many of which overlap with FGIDs such as irritable bowel syndrome or dyspepsia. This raises the possibility that obesity and FGIDs may be mechanistically linked. In this paper, we review and summarize the literature linking obesity and FGIDs, comment on the clinical relevancy of existing data, and suggest next steps for future research in this field.