A Cellular Automaton Framework for Infectious Disease Spread Simulation

In this paper, a cellular automaton framework for processing the spatiotemporal spread of infectious diseases is presented. The developed environment simulates and visualizes how infectious diseases might spread, and hence provides a powerful instrument for health care organizations to generate disease prevention and contingency plans. In this study, the outbreak of an avian flu like virus was modeled in the state of Tyrol, and various scenarios such as quarantine, effect of different medications on viral spread and changes of social behavior were simulated

Identification of Metabolites in the Normal Ovary and Their Transformation in Primary and Metastatic Ovarian Cancer

In this study, we characterized the metabolome of the human ovary and identified metabolic alternations that coincide with primary epithelial ovarian cancer (EOC) and metastatic tumors resulting from primary ovarian cancer (MOC) using three analytical platforms: gas chromatography mass spectrometry (GC/MS) and liquid chromatography tandem mass spectrometry (LC/MS/MS) using buffer systems and instrument settings to catalog positive or negative ions. The human ovarian metabolome was found to contain 364 biochemicals and upon transformation of the ovary caused changes in energy utilization, altering metabolites associated with glycolysis and β-oxidation of fatty acids—such as carnitine (1.79 fold in EOC, p<0.001; 1.88 fold in MOC, p<0.001), acetylcarnitine (1.75 fold in EOC, p<0.001; 2.39 fold in MOC, p<0.001), and butyrylcarnitine (3.62 fold, p<0.0094 in EOC; 7.88 fold, p<0.001 in MOC). There were also significant changes in phenylalanine catabolism marked by increases in phenylpyruvate (4.21 fold; p = 0.0098) and phenyllactate (195.45 fold; p<0.0023) in EOC. Ovarian cancer also displayed an enhanced oxidative stress response as indicated by increases in 2-aminobutyrate in EOC (1.46 fold, p = 0.0316) and in MOC (2.25 fold, p<0.001) and several isoforms of tocopherols. We have also identified novel metabolites in the ovary, specifically N-acetylasparate and N-acetyl-aspartyl-glutamate, whose role in ovarian physiology has yet to be determined. These data enhance our understanding of the diverse biochemistry of the human ovary and demonstrate metabolic alterations upon transformation. Furthermore, metabolites with significant changes between groups provide insight into biochemical consequences of transformation and are candidate biomarkers of ovarian oncogenesis. Validation studies are warranted to determine whether these compounds have clinical utility in the diagnosis or clinical management of ovarian cancer patients

Epidemiology of neurodegenerative diseases in sub-Saharan Africa: a systematic review

BACKGROUND:Sub-Saharan African (SSA) countries are experiencing rapid transitions with increased life expectancy. As a result the burden of age-related conditions such as neurodegenerative diseases might be increasing. We conducted a systematic review of published studies on common neurodegenerative diseases, and HIV-related neurocognitive impairment in SSA, in order to identify research gaps and inform prevention and control solutions. METHODS: We searched MEDLINE via PubMed, 'Banque de Donnees de Sante Publique' and the database of the 'Institut d'Epidemiologie Neurologique et de Neurologie Tropicale' from inception to February 2013 for published original studies from SSA on neurodegenerative diseases and HIV-related neurocognitive impairment. Screening and data extraction were conducted by two investigators. Bibliographies and citations of eligible studies were investigated. RESULTS: In all 144 publications reporting on dementia (n=49 publications, mainly Alzheimer disease), Parkinsonism (PD, n=20), HIV-related neurocognitive impairment (n=47), Huntington disease (HD, n=19), amyotrophic lateral sclerosis (ALS, n=15), cerebellar degeneration (n=4) and Lewy body dementia (n=1). Of these studies, largely based on prevalent cases from retrospective data on urban populations, half originated from Nigeria and South Africa. The prevalence of dementia (Alzheimer disease) varied between <1% and 10.1% (0.7% and 5.6%) in population-based studies and from <1% to 47.8% in hospital-based studies. Incidence of dementia (Alzheimer disease) ranged from 8.7 to 21.8/1000/year (9.5 to 11.1), and major risk factors were advanced age and female sex. HIV-related neurocognitive impairment's prevalence (all from hospital-based studies) ranged from <1% to 80%. Population-based prevalence of PD and ALS varied from 10 to 235/100,000, and from 5 to 15/100,000 respectively while that for Huntington disease was 3.5/100,000. Equivalent figures for hospital based studies were the following: PD (0.41 to 7.2%), ALS (0.2 to 8.0/1000), and HD (0.2/100,000 to 46.0/100,000). CONCLUSIONS: The body of literature on neurodegenerative disorders in SSA is large with regard to dementia and HIV-related neurocognitive disorders but limited for other neurodegenerative disorders. Shortcomings include few population-based studies, heterogeneous diagnostic criteria and uneven representation of countries on the continent. There are important knowledge gaps that need urgent action, in order to prepare the sub-continent for the anticipated local surge in neurodegenerative diseases

A new class of PentixaFor- and PentixaTher-based theranostic agents with enhanced CXCR4-targeting efficiency.

Non-invasive PET imaging of CXCR4 expression in cancer and inflammation as well as CXCR4-targeted radioligand therapy (RLT) have recently found their way into clinical research by the development of the theranostic agents [ &lt;sup&gt;68&lt;/sup&gt; Ga]PentixaFor (cyclo(D-Tyr &lt;sup&gt;1&lt;/sup&gt; -D-[NMe]Orn &lt;sup&gt;2&lt;/sup&gt; (AMBS-[ &lt;sup&gt;68&lt;/sup&gt; Ga]DOTA)-Arg &lt;sup&gt;3&lt;/sup&gt; -Nal &lt;sup&gt;4&lt;/sup&gt; -Gly &lt;sup&gt;5&lt;/sup&gt; ) = [ &lt;sup&gt;68&lt;/sup&gt; Ga]DOTA-AMBS-CPCR4) and [ &lt;sup&gt;177&lt;/sup&gt; Lu/ &lt;sup&gt;90&lt;/sup&gt; Y]PentixaTher (cyclo(D-3-iodo-Tyr &lt;sup&gt;1&lt;/sup&gt; -D-[NMe]Orn &lt;sup&gt;2&lt;/sup&gt; (AMBS-[ &lt;sup&gt;177&lt;/sup&gt; Lu/ &lt;sup&gt;90&lt;/sup&gt; Y]DOTA)-Arg &lt;sup&gt;3&lt;/sup&gt; -Nal &lt;sup&gt;4&lt;/sup&gt; -Gly &lt;sup&gt;5&lt;/sup&gt; ) = [ &lt;sup&gt;177&lt;/sup&gt; Lu/ &lt;sup&gt;90&lt;/sup&gt; Y]DOTA-AMBS-iodoCPCR4). Although convincing clinical results have already been obtained with both agents, this study was designed to further investigate the required structural elements for improved ligand-receptor interaction for both peptide cores (CPCR4 and iodoCPCR4). To this aim, a series of DOTA-conjugated CPCR4- and iodoCPCR4-based ligands with new linker structures, replacing the AMBA-linker in PentixaFor and PentixaTher, were synthesized and evaluated. Methods: The in vitro investigation of the novel compounds alongside with the reference peptides PentixaFor and PentixaTher encompassed the determination of hCXCR4 and mCXCR4 affinity (IC &lt;sub&gt;50&lt;/sub&gt; ) of the respective &lt;sup&gt;nat&lt;/sup&gt; Ga-, &lt;sup&gt;nat&lt;/sup&gt; Lu-, &lt;sup&gt;nat&lt;/sup&gt; Y- and &lt;sup&gt;nat&lt;/sup&gt; Bi-complexes in Jurkat and Eμ-myc 1080 cells using [ &lt;sup&gt;125&lt;/sup&gt; I]FC-131 and [ &lt;sup&gt;125&lt;/sup&gt; I]CPCR4.3 as radioligands, respectively, as well as the evaluation of the internalization and externalization kinetics of selected &lt;sup&gt;68&lt;/sup&gt; Ga- and &lt;sup&gt;177&lt;/sup&gt; Lu-labeled compounds in hCXCR4-transfected Chem-1 cells. Comparative small animal PET imaging studies (1h p.i.) as well as in vivo biodistribution studies (1, 6 and 48h p.i.) were performed in Daudi (human B cell lymphoma) xenograft bearing CB17 SCID mice. Results: Based on the affinity data and cellular uptake studies, [ &lt;sup&gt;68&lt;/sup&gt; Ga/ &lt;sup&gt;177&lt;/sup&gt; Lu]DOTA-r-a-ABA-CPCR4 and [ &lt;sup&gt;68&lt;/sup&gt; Ga/ &lt;sup&gt;177&lt;/sup&gt; Lu]DOTA-r-a-ABA-iodoCPCR4 (with r-a-ABA = D-Arg-D-Ala-4-aminobenzoyl-) were selected for further evaluation. Both analogs show app. 10-fold enhanced hCXCR4 affinity compared to the respective references [ &lt;sup&gt;68&lt;/sup&gt; Ga]PentixaFor and [ &lt;sup&gt;177&lt;/sup&gt; Lu]PentixaTher, four times higher cellular uptake in hCXCR4 expressing cells and improved cellular retention. Unfortunately, the improved in vitro binding and uptake characteristics of [ &lt;sup&gt;68&lt;/sup&gt; Ga]DOTA-r-a-ABA-CPCR4 and -iodoCPCR4 could not be recapitulated in initial PET imaging studies; both compounds showed similar uptake in the Daudi xenografts as [ &lt;sup&gt;68&lt;/sup&gt; Ga]PentixaFor, alongside with higher background accumulation, especially in the kidneys. However, the subsequent biodistribution studies performed for the corresponding &lt;sup&gt;177&lt;/sup&gt; Lu-labeled analogs revealed a clear superiority of [ &lt;sup&gt;177&lt;/sup&gt; Lu]DOTA-r-a-ABA-CPCR4 and [ &lt;sup&gt;177&lt;/sup&gt; Lu]DOTA-r-a-ABA-iodoCPCR4 over [ &lt;sup&gt;177&lt;/sup&gt; Lu]PentixaTher with respect to tumor uptake (18.3±3.7 and 17.2±2.0 %iD/g, respectively, at 1h p.i. vs 12.4±3.7%iD/g for [ &lt;sup&gt;177&lt;/sup&gt; Lu]PentixaTher) as well as activity retention in tumor up to 48h. Especially for [ &lt;sup&gt;177&lt;/sup&gt; Lu]DOTA-r-a-ABA-CPCR4 with its low background accumulation, tumor/organ ratios at 48h were 2- to 4-fold higher than those obtained for [ &lt;sup&gt;177&lt;/sup&gt; Lu]PentixaTher (except for kidney). Conclusions: The in-depth evaluation of a series of novel CPCR4- and iodoCPCR4 analogs with modified linker structure has yielded reliable structure-activity relationships. It was generally observed that a) AMBA-by-ABA-substitution leads to enhanced ligand internalization, b) the extension of the ABA-linker by two additional amino acids (DOTA-Xaa &lt;sub&gt;2&lt;/sub&gt; -Xaa &lt;sub&gt;1&lt;/sub&gt; -ABA-) provides sufficient linker length to minimize the interaction of the [M &lt;sup&gt;3+&lt;/sup&gt; ]DOTA-chelate with the receptor, and that c) introduction of a cationic side chain (Xaa &lt;sub&gt;2&lt;/sub&gt; ) greatly enhances receptor affinity of the constructs, obliterating the necessity for Tyr &lt;sup&gt;1&lt;/sup&gt; -iodination of the pentapeptide core to maintain high receptor affinity (such as in [ &lt;sup&gt;177&lt;/sup&gt; Lu]PentixaTher). As a result, [ &lt;sup&gt;177&lt;/sup&gt; Lu]DOTA-r-a-ABA-CPCR4 has emerged from this study as a powerful second-generation therapeutic CXCR4 ligand with greatly improved targeting efficiency and tumor retention and will be further evaluated in preclinical and clinical CXCR4-targeted dosimetry and RLT studies

Ex vivo generated natural killer cells acquire typical natural killer receptors and display a cytotoxic gene expression profile similar to peripheral blood natural killer cells

Ex vivo differentiation systems of natural killer (NK) cells from CD34+ hematopoietic stem cells are of potential importance for adjuvant immunotherapy of cancer. Here, we analyzed ex vivo differentiation of NK cells from cord blood-derived CD34+ stem cells by gene expression profiling, real-time RT-PCR, flow cytometry, and functional analysis. Additionally, we compared the identified characteristics to peripheral blood (PB) CD56(bright) and CD56(dim) NK cells. The data show sequential expression of CD56 and the CD94 and NKG2 receptor chains during ex vivo NK cell development, resulting finally in the expression of a range of genes with partial characteristics of CD56(bright) and CD56(dim) NK cells from PB. Expression of characteristic NK cell receptors and cytotoxic genes was mainly found within the predominant ex vivo generated population of NKG2A+ NK cells, indicating the importance of NKG2A expression during NK cell differentiation and maturation. Furthermore, despite distinct phenotypic characteristics, the detailed analysis of cytolytic genes expressed within the ex vivo differentiated NK cells revealed a pattern close to CD56(dim) NK cells. In line with this finding, ex vivo generated NK cells displayed potent cytotoxicity. This supports that the ex vivo differentiation system faithfully reproduces major steps of the differentiation of NK cells from their progenitors, constitutes an excellent model to study NK cell differentiation, and is valuable to generate large-scale NK cells appropriate for immunotherapy