Elevated creatine kinase activity in primary hepatocellular carcinoma

BACKGROUND: Inconsistent findings have been reported on the occurrence and relevance of creatine kinase (CK) isoenzymes in mammalian liver cells. Part of this confusion might be due to induction of CK expression during metabolic and energetic stress. METHODS: The specific activities and isoenzyme patterns of CK and adenylate kinase (AdK) were analysed in pathological liver tissue of patients undergoing orthotopic liver transplantation. RESULTS: The brain-type, cytosolic BB-CK isoenzyme was detected in all liver specimens analysed. Conversely, CK activity was strongly increased and a mitochondrial CK (Mi-CK) isoenzyme was detected only in tissue samples of two primary hepatocellular carcinomas (HCCs). CONCLUSION: The findings do not support significant expression of CK in normal liver and most liver pathologies. Instead, many of the previous misconceptions in this field can be explained by interference from AdK isoenzymes. Moreover, the data suggest a possible interplay between p53 mutations, HCC, CK expression, and the growth-inhibitory effects of cyclocreatine in HCC. These results, if confirmed, could provide important hints at improved therapies and cures for HCC

Human Tumor Cell Proliferation Evaluated Using Manganese-Enhanced MRI

Tumor cell proliferation can depend on calcium entry across the cell membrane. As a first step toward the development of a non-invasive test of the extent of tumor cell proliferation in vivo, we tested the hypothesis that tumor cell uptake of a calcium surrogate, Mn(2+) [measured with manganese-enhanced MRI (MEMRI)], is linked to proliferation rate in vitro.Proliferation rates were determined in vitro in three different human tumor cell lines: C918 and OCM-1 human uveal melanomas and PC-3 prostate carcinoma. Cells growing at different average proliferation rates were exposed to 1 mM MnCl(2) for one hour and then thoroughly washed. MEMRI R(1) values (longitudinal relaxation rates), which have a positive linear relationship with Mn(2+) concentration, were then determined from cell pellets. Cell cycle distributions were determined using propidium iodide staining and flow cytometry. All three lines showed Mn(2+)-induced increases in R(1) compared to cells not exposed to Mn(2+). C918 and PC-3 cells each showed a significant, positive correlation between MEMRI R(1) values and proliferation rate (p≤0.005), while OCM-1 cells showed no significant correlation. Preliminary, general modeling of these positive relationships suggested that pellet R(1) for the PC-3 cells, but not for the C918 cells, could be adequately described by simply accounting for changes in the distribution of the cell cycle-dependent subpopulations in the pellet.These data clearly demonstrate the tumor-cell dependent nature of the relationship between proliferation and calcium influx, and underscore the usefulness of MEMRI as a non-invasive method for investigating this link. MEMRI is applicable to study tumors in vivo, and the present results raise the possibility of evaluating proliferation parameters of some tumor types in vivo using MEMRI

Cytoarchitectural and metabolic adaptations in muscles with mitochondrial and cytosolic creatine kinase deficiencies

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Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

\ua9 2023, Springer Nature Limited. The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Multi-ancestry genome-wide association meta-analysis of Parkinson’s disease

\ua9 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. Although over 90 independent risk variants have been identified for Parkinson’s disease using genome-wide association studies, most studies have been performed in just one population at a time. Here we performed a large-scale multi-ancestry meta-analysis of Parkinson’s disease with 49,049 cases, 18,785 proxy cases and 2,458,063 controls including individuals of European, East Asian, Latin American and African ancestry. In a meta-analysis, we identified 78 independent genome-wide significant loci, including 12 potentially novel loci (MTF2, PIK3CA, ADD1, SYBU, IRS2, USP8, PIGL, FASN, MYLK2, USP25, EP300 and PPP6R2) and fine-mapped 6 putative causal variants at 6 known PD loci. By combining our results with publicly available eQTL data, we identified 25 putative risk genes in these novel loci whose expression is associated with PD risk. This work lays the groundwork for future efforts aimed at identifying PD loci in non-European populations

Defining the causes of sporadic Parkinson’s disease in the global Parkinson’s genetics program (GP2)

The Global Parkinson’s Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia

Author Correction: Elucidating causative gene variants in hereditary Parkinson’s disease in the Global Parkinson’s Genetics Program (GP2)

Correction to: s41531-023-00526-9 npj Parkinson’s Disease, published online 27 June 2023 In this article the Global Parkinson’s Genetics Program (GP2) members names and affiliations were missing in the main author list of the Original article which are listed in the below

Effects of glutamine and hyperoxia on pulmonary oxygen uptake and muscle deoxygenation kinetics.

The aim of the present study was to determine whether glutamine ingestion, which has been shown to enhance the exercise-induced increase in the tricarboxylic acid intermediate (TCAi) pool size, resulted in augmentation of the rate of increase in oxidative metabolism at the onset of exercise. In addition, the potential interaction with oxygen availability was investigated by completing exercise in both normoxic and hyperoxic conditions. Eight male cyclists cycled for 6 min at 70% VO2max following consumption of a drink (5 ml kg body mass(-1)) containing a placebo or 0.125 g kg body mass(-1) of glutamine in normoxic (CON and GLN respectively) and hyperoxic (HYP and HPG respectively) conditions. Breath-by-breath pulmonary oxygen uptake and continuous, non-invasive muscle deoxygenation (via near infrared spectroscopy: NIRS) data were collected throughout exercise. The time constant of the phase II component of pulmonary oxygen uptake kinetics was unchanged between trials (CON: 21.5 +/- 3.0 vs. GLN: 18.2 +/- 1.3 vs. HYP: 18.9 +/- 2.0 vs. HPG: 18.6 +/- 1.2 s). There was also no alteration of the kinetics of relative muscle deoxygenation as measured via NIRS (CON: 5.9 +/- 0.7 vs. GLN: 7.3 +/- 0.8 vs. HYP: 6.5 +/- 0.9 vs. HPG: 5.2 +/- 0.4 s). Conversely, the mean response time of pulmonary oxygen uptake kinetics was faster (CON: 33.4 +/- 1.2 vs. GLN: 29.8 +/- 2.3 vs. HYP: 33.2 +/- 2.6 vs. HPG: 31.6 +/- 2.6 s) and the time at which muscle deoxygenation increased above pre-exercise values was earlier (CON: 9.6 +/- 0.9 vs. GLN: 8.7 +/- 1.1 vs. HYP: 8.5 +/- 0.8 vs. HPG: 8.4 +/- 0.7 s) following glutamine ingestion. In normoxic conditions, plasma lactate concentration was lower following glutamine ingestion compared to placebo. Whilst the results of the present study provide some support for the present hypothesis, the lack of any alteration in the time constant of pulmonary oxygen uptake and muscle deoxygenation kinetics suggest that the normal exercise induced expansion of the TCAi pool size is not limiting to oxidative metabolism at the onset of cycle exercise at 70% VO2max