Abstract
TP53 is the most commonly mutated gene in human cancer for which no effective targeted anti-cancer drug exists. We identified NSC319726 (726) as a mutant p53 reactivating compound, and a ...lead compound for mutant p53 targeted drug development. Prior evidence indicated that the effects of 726 were allele-specific, by restoring wildtype structure and function to the third most common p53 mis-sense mutant (p53-R175H). This effect was dependent on the zinc-chelating and redox modulating properties of 726. The p53 protein binds a single zinc ion which is necessary for proper p53 structure and function. The p53-R175H mutation impairs the protein from binding zinc causing it to mis-fold and lose transcriptional function. We have investigated these properties of 726 in the mechanism of p53-R175H reactivation and provide evidence for a novel “dual” mechanism where 726 restores wild-type structure to the p53-R175H using a zinc-metallochaperone function to provide an optimal concentration of zinc to facilitate proper folding. We also demonstrate that the redox modulating properties of 726 function to transactivate the newly conformed p53-R175 and induce an apoptotic program. Lastly, we demonstrate that this zinc-metallochaperone function applies to other p53 mis-sense mutants with impaired zinc binding. This later finding extends the potential pool of patients that could be impacted by the clinical development of 726 as a mutant p53 targeted anti-cancer drug.
Citation Format: Xin Yu, David Lubin, Sumana Narayanan, Alexei Vazquez, Stewart Loh, Arnold J. Levine, Darren R. Carpizo. NSC319726 reactivates zinc-binding p53 mis-sense mutants using a novel dual mechanism. abstract. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2330. doi:10.1158/1538-7445.AM2013-2330
The significance of green public spaces is well documented in relation to social inclusiveness, human health, and biodiversity, yet how green public spaces achieve what Gough (2017) has termed ...‘sustainable wellbeing’ is less understood. This contribution presents preliminary results from a study of green public spaces in four mega-cities of South and Southeast Asia: Chennai (Republic of India), Metro Manila (Republic of the Philippines), Singapore, and Shanghai (People’s Republic of China), cities that have climates ranging from tropical, to subtropical and temperate. The conceptual framework brings together social practice theories with human development theories, methodological implications for the study of park usage, and Protected Needs. This study sets out to understand how parks satisfy human needs by uncovering practices in relation to activities and material arrangements. Central to the research design and sampling strategy is a desire to understand park-related practices in all of their diversity, and accounting for how different activities are carried out by diverse groups of people. The paper presents exemplary results showing that parks provide a space in which a multitude of needs are satisfied, and that parks cannot be substituted by other settings such as commercialized spaces. The paper will conclude by discussing tensions between types of park usage, and in relation to commercial encroachments on public space.
Vive la Difference NARAYANAN, SUMANA
Economic and political weekly,
05/2015, Letnik:
50, Številka:
20
Journal Article, Magazine Article
The wedding, a civil ceremony, was to be in Paris and apparently la mairie (Town Hall) requires the happy couple to provide "recent" birth certificates (less than six months old). Civil ceremonies in ...France-remember the French predilection for separation of Church and State-are supposed to be stripped of anything remotely religious but to us the whole affair sounded like a religion-neutered version of a church wedding. ...the French require recently attested birth certificates and so, before making the trek to Ripon Building (which houses the corporation), we decided to try our luck on their website, hoping to at least get the name and phone number of some kindly soul there.
The media reports had, as usual, a mishmash of information - that the survey recorded 246 butterfly species; spotting of the Baby Five Ring, a rare butterfly, whose presence had been recorded in the ...Reserve only thrice in the last 100 years; that the last survey was conducted 22 years ago in 1992, when 162 species were recorded; and that butterflies are indicator species, that is they indicate an ecosystem's health. ...this is a median number, and there is always a range and a margin of error. Since census by definition is an estimate, one cannot be sure that all individual animals have been counted. Within a given region, different kinds of habitats are picked - because of variation in flora assemblages - and surveyed. Since every square inch of the forest cannot be covered, some kind of transect is plotted. Considering the number of species of both flora and fauna and various ecosystems (forest, coral reefs, grasslands and so on) which need to be regularly surveyed, a fair amount of resources would be needed on a long-term basis.
Turkish Delight Narayanan, Sumana
Economic and political weekly,
04/2014
Journal Article, Magazine Article
Breakfast at the hotel was sumptuous - Greek-style yoghurt, fruits, olives, various preserves, honey, cheese, breads, juice, coffee, cake, and some strange greens mixed with cheese. After much ...gesticulation and an emphatic "NO MEAT!" entreaty, we got a huge bowl of salad - shredded vegetables, with hardly a dollop of spice, not even a sprinkling of salt. Istanbul's Grand Bazaar and Spice Bazaar are favourite tourist haunts, laden with spices, plasticware, utensils, and chunks of meat treated with a mix of spices and other ingredients for curing and preservation that gives it a very pungent flavour.
Oncologic resections of the second and third portions of the duodenum (D2 and D3) via partial duodenectomy can pose a challenging clinical problem. The duodenum must be repaired primarily or ...reconstructed. We have adopted a method of reconstruction using a Roux-en-Y duodenojejunostomy (D-J) in patients with extensive duodenal wall loss. We report our results in the first series of these cases. A retrospective review of patients who underwent post partial duodenectomy with reconstruction between June 2004 and March 2014 was performed. Five patients underwent partial duodenectomy with reconstruction. Two had resection for extrinsic tumors (colonic adenocarcinoma). Three had intrinsic duodenal tumors (one tubular adenoma, one adenocarcinoma and one gastrointestinal stromal tumor). All patients were reconstructed via retrocolic Roux-en-Y D-J. Mean estimated blood loss was 470 mL with median length of stay of 11 days. Post-operative complications included three intra-abdominal abscesses, one superficial wound infection and one gastrointestinal bleed. There were no anastomotic leaks, injuries to the ampulla of Vater or mortalities. In conclusion, partial duodenectomy of lateral D2/D3 with Roux-en-Y D-J is a relatively safe and effective alternative to partial duodenectomy with primary repair or pancreaticoduodenectomy for certain tumors of the duodenum.
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