ALBERT

Beschreibung: The efficacy and safety of biological molecules in cancer therapy, such as peptides and small interfering RNAs (siRNAs), could be markedly increased if high concentrations could be achieved and amplified selectively in tumour tissues versus normal tissues after intravenous administration. This has not been achievable so far in humans. We hypothesized that a poxvirus, which evolved for blood-borne systemic spread in mammals, could be engineered for cancer-selective replication and used as a vehicle for the intravenous delivery and expression of transgenes in tumours. JX-594 is an oncolytic poxvirus engineered for replication, transgene expression and amplification in cancer cells harbouring activation of the epidermal growth factor receptor (EGFR)/Ras pathway, followed by cell lysis and anticancer immunity. Here we show in a clinical trial that JX-594 selectively infects, replicates and expresses transgene products in cancer tissue after intravenous infusion, in a dose-related fashion. Normal tissues were not affected clinically. This platform technology opens up the possibility of multifunctional products that selectively express high concentrations of several complementary therapeutic and imaging molecules in metastatic solid tumours in humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Breitbach, Caroline J -- Burke, James -- Jonker, Derek -- Stephenson, Joe -- Haas, Andrew R -- Chow, Laura Q M -- Nieva, Jorge -- Hwang, Tae-Ho -- Moon, Anne -- Patt, Richard -- Pelusio, Adina -- Le Boeuf, Fabrice -- Burns, Joe -- Evgin, Laura -- De Silva, Naomi -- Cvancic, Sara -- Robertson, Terri -- Je, Ji-Eun -- Lee, Yeon-Sook -- Parato, Kelley -- Diallo, Jean-Simon -- Fenster, Aaron -- Daneshmand, Manijeh -- Bell, John C -- Kirn, David H -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Aug 31;477(7362):99-102. doi: 10.1038/nature10358.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jennerex Inc., 450 Sansome Street, 16th floor, San Francisco, California 94111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21886163" target="_blank"〉PubMed〈/a〉

Beschreibung: Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that alpha-ketoglutarate (alpha-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit beta is identified as a novel binding protein of alpha-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that alpha-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by alpha-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by alpha-KG requires ATP synthase subunit beta and is dependent on target of rapamycin (TOR) downstream. Endogenous alpha-KG levels are increased on starvation and alpha-KG does not extend the lifespan of dietary-restricted animals, indicating that alpha-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263271/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263271/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chin, Randall M -- Fu, Xudong -- Pai, Melody Y -- Vergnes, Laurent -- Hwang, Heejun -- Deng, Gang -- Diep, Simon -- Lomenick, Brett -- Meli, Vijaykumar S -- Monsalve, Gabriela C -- Hu, Eileen -- Whelan, Stephen A -- Wang, Jennifer X -- Jung, Gwanghyun -- Solis, Gregory M -- Fazlollahi, Farbod -- Kaweeteerawat, Chitrada -- Quach, Austin -- Nili, Mahta -- Krall, Abby S -- Godwin, Hilary A -- Chang, Helena R -- Faull, Kym F -- Guo, Feng -- Jiang, Meisheng -- Trauger, Sunia A -- Saghatelian, Alan -- Braas, Daniel -- Christofk, Heather R -- Clarke, Catherine F -- Teitell, Michael A -- Petrascheck, Michael -- Reue, Karen -- Jung, Michael E -- Frand, Alison R -- Huang, Jing -- DP2 OD008398/OD/NIH HHS/ -- P01 HL028481/HL/NHLBI NIH HHS/ -- P40 OD010440/OD/NIH HHS/ -- T32 CA009120/CA/NCI NIH HHS/ -- T32 GM007104/GM/NIGMS NIH HHS/ -- T32 GM007185/GM/NIGMS NIH HHS/ -- T32 GM008496/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 19;510(7505):397-401. doi: 10.1038/nature13264. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; 1] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2]. ; Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Surgery, University of California Los Angeles, Los Angeles, California 90095, USA. ; Small Molecule Mass Spectrometry Facility, FAS Division of Science, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA. ; Pasarow Mass Spectrometry Laboratory, Department of Psychiatry and Biobehavioral Sciences and Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Environmental Health Sciences, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA [2] UCLA Metabolomics Center, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Human Genetics, University of California Los Angeles, Los Angeles, California 90095, USA. ; 1] Molecular Biology Institute, University of California Los Angeles, Los Angeles, California 90095, USA [2] Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828042" target="_blank"〉PubMed〈/a〉

Beschreibung: This is the first study of Asian dust storm (ADS) particles collected in Beijing, China and Incheon, Korea during the same spring ADS event. Using a seven-stage May impactor and a quantitative electron probe X-ray microanalysis (ED-EPMA, also known as low-Z particle EPMA), we examined the composition and morphology of 4200 aerosol particles at stages 1–6 (with a size cut-off of 16, 8, 4, 2, 1, and 0.5 μm in equivalent aerodynamic diameter, respectively) collected during an ADS event on 28–29 April 2005. The results showed that there were large differences in the chemical compositions between particles in sample S1 collected in Beijing immediately after the peak time of the ADS and in samples S2 and S3, which were collected in Incheon approximately 5 h and 24 h later, respectively. In sample S1, mineral dust particles accounted for more than 88% in relative number abundance at stages 1–5, and organic carbon (OC) and reacted NaCl-containing particles accounted for 24% and 32%, respectively, at stage 6. On the other hand, in samples S2 and S3, in addition to approximately 60% mineral dust, many sea salt particles reacted with airborne SO2 and NOx, often mixed with mineral dust, were encountered at stages 1–5, and (C, N, O, S)-rich particles (likely a mixture of water-soluble organic carbon with (NH4)2SO4 and NH4NO3) and K-containing particles were abundantly observed at stage 6. This suggests that the secondary aerosols and the internal mixture of mineral dust with sea spray aerosol increased when the ADS particles passed over the Yellow Sea. In the reacted or aged mineral dust and sea salt particles, nitrate-containing and both nitrate- and sulfate-containing species vastly outnumbered the sulfate-containing species, implying that ambient nitrogen oxides had a greater influence on the atmospheric particles during the ADS episode than SO2. In addition to partially- or totally-reacted CaCO3, reacted or aged Mg-containing aluminosilicates (likely including amesite, allophite, vermiculite, illite, and montmorillonite) were observed frequently in samples S2 and S3; and furthermore, both the atomic concentration ratios of [Mg]/[Al] and [Mg]/[Si] were elevated compared to that in sample S1. This shows that a great evolution or aging process must have occurred on the mineral dust. This indicates that the number abundance, reactivity with gaseous pollutants, and ratios of [Mg]/[Al] and [Mg]/[Si] of Mg-containing aluminosilicates are promising indices of the aging process of ADS particles during long-range transport.

Beschreibung: This is the first study of Asian dust storm (ADS) particles collected in Beijing, China, and Incheon, Korea, during a spring ADS event. Using a seven-stage May impactor and a quantitative electron probe X-ray microanalysis (ED-EPMA, also known as low-Z particle EPMA), we examined the composition and morphology of 4200 aerosol particles at stages 1–6 (with a size cut-off of 16, 8, 4, 2, 1, and 0.5 μm in equivalent aerodynamic diameter, respectively) collected during an ADS event on 28–29 April 2005. The results showed that there were large differences in the chemical compositions between particles in sample S1 collected in Beijing immediately after the peak time of the ADS and in samples S2 and S3, which were collected in Incheon approximately 5 h and 24 h later, respectively. In sample S1, mineral dust particles accounted for more than 88% in relative number abundance at stages 1–5; and organic carbon (OC) and reacted NaCl-containing particles accounted for 24% and 32%, respectively, at stage 6. On the other hand, in samples S2 and S3, in addition to approximately 60% mineral dust, many sea spray aerosol (SSA) particles reacted with airborne SO2 and NOx (accounting for 24% and 14% on average in samples S2 and S3, respectively), often mixed with mineral dust, were encountered at stages 1–5, and (C, N, O, S)-rich particles (likely a mixture of water-soluble organic carbon with (NH4)2SO4 and NH4NO3) were abundantly observed at stage 6 (accounting for 68% and 51% in samples S2 and S3, respectively). This suggests that an accumulation of sea-salt components on individual ADS particles larger than 1 μm in diameter occurred and many secondary aerosols smaller than 1 μm in diameter were formed when the ADS particles passed over the Yellow Sea. In the reacted or aged mineral dust and SSA particles, nitrate-containing and both nitrate- and sulfate-containing species vastly outnumbered the sulfate-containing species, implying that ambient NOx had a greater influence on the atmospheric particles than SO2 during this ADS episode. In addition to partially- or totally-reacted CaCO3, reacted or aged Mg-containing aluminosilicates were observed frequently in samples S2 and S3; furthermore, a student's t test showed that both their atomic concentration ratios of [Mg] / [Al] and [Mg] / [Si] were significantly elevated (P 〈 0.05) compared to those in samples S1 (for [Mg] / [Al], 0.34 ± 0.09 and 0.40 ± 0.03 in samples S2 and S3, respectively, vs. 0.24 ± 0.01 in sample S1; for [Mg] / [Si], 0.21 ± 0.05 and 0.22 ± 0.01 in samples S2 and S3, respectively, vs. 0.12 ± 0.02 in sample S1). The significant increase of [Mg] / [Al] and [Mg] / [Si] ratios in Mg-containing aluminosilicates indicates that a significant evolution or aging must have occurred on the ADS particles in the marine atmosphere during transport from China to Korea.