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Aberrant energy metabolism represents a hallmark of cancer and contributes to numerous aggressive behaviors of cancer cells, including cell death and survival. Despite the poor prognosis of mantle cell lymphoma (MCL), due to the inevitable development of drug resistance, metabolic reprograming of MCL cells remains an unexplored area. Posttranslational modification of proteins via O- GlcNAcylation is an ideal sensor for nutritional changes mediated by O -GlcNAc transferase (OGT) and is removed by O -GlcNAcase (OGA). Using various small-molecule inhibitors of OGT and OGA, we found for the first time that O- GlcNAcylation potentiates MCL response to bortezomib. CRISPR interference of MGEA5 (encoding OGA) validated the apoptosis sensitization by O- GlcNAcylation and OGA inhibition. To identify the potential clinical candidates, we tested MCL response to drug-like OGA inhibitor, ketoconazole, and verified that it exerts similar sensitizing effect on bortezomib-induced apoptosis. Investigations into the underlying molecular mechanisms reveal that bortezomib and ketoconazole act in concert to cause the accumulation of truncated Bid (tBid). Not only does ketoconazole potentiate tBid induction, but also increases tBid stability through O- GlcNAcylation that interferes with tBid ubiquitination and proteasomal degradation. Remarkably, ketoconazole strongly enhances bortezomib-induced apoptosis in de novo bortezomib-resistant MCL cells and in patient-derived primary cells with minimal cytotoxic effect on normal peripheral blood mononuclear cells and hepatocytes, suggesting its potential utility as a safe and effective adjuvant for MCL. Together, our findings provide novel evidence that combination of bortezomib and ketoconazole or other OGA inhibitors may present a promising strategy for the treatment of drug-resistant MCL. Mol Cancer Ther; 17(2); 484–96. ©2017 AACR .

Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (


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between team members and the MIT-affiliated Digital Currency Initiative was leaked to nike roshe run black and grey mens prestos
over the weekend, and it sheds light on the debate over IOTA’s security. The leak details a months-long conversational volley between David Sønstebø and Sergey Ivancheglo of IOTA and Ethan Heilman and Neha Narula of DCI, and it pulls back the curtain on the behind-the-scenes conversation between both teams surrounding an alleged vulnerability in IOTA’s system.

As an organization, we have tried to stay out of the DCI controversy, and leave it to the individuals involved to lead the discussion. However, there is one public clarificaction to make: no Foundation member was involved in the email leaks in any way.

— Dominik Schiener (@DomSchiener) air jordan 11 legend blue restock date

Back in May of 2017, the IOTA team reached out to DCI, an MIT-affiliated academic research group of Ph.D. graduate students, developers, and research scientists, to audit IOTA’s nike air max 2014 champ sports careers
for any vulnerabilities. Come the 15th of July, they received a response from Ethan Heilman, alerting the team that DCI had executed a successful attack against the system:

“We have found serious cryptographic weaknesses in the cryptographic hash function Curl used by IOTA, Curl. These weaknesses threaten the security of signatures and PoW in IOTA as PoW and Signatures rely on Curl to be pseudo-random and collision resistant.”

Ivancheglo responds in good faith, thanking the team for their interest in and review of IOTA and Curl, the crypto’s hashing function. He then goes on to inquire as to how the team exploited the vulnerabilities, adding that “what [they] identified as weaknesses are [sic] features added intentionally.”

Dominik Schiener then steps in to ask whether or not the DCI team would like to take the conversation to the IOTA Slack channel. Narula refuses the invite for her “slack fatigue,” but Sønstebø presses the issue, stating, “What could be achieved in 1 hour Slack chat will take at least a month via mail.”

And he was right. The emails continue on into the first two weeks of September, an epistolary goulash of cryptographic concepts and code. Throughout the talks, Heilman expands on the logic of the attack, and the IOTA team coaches him on the ins-and-outs of Curl and the Tangle. In fact, Ivancheglo goes into an in-depth explanation on IOTA’s hashing function, even claiming that the “attack is based on a wrong assumption about IOTA signing scheme.”

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The CCM Gift Shop is the place to shop for educational toys that WOW!

At the CCM Gift shop, you’ll find an assortment of one-of-a-kind dolls, puzzles, games and more for kids (and grownups) of all ages. The Gift Shop also carries a variety of CCM-logo merchandise and exhibit-related books and toys you won’t find anywhere else. To reach the CCM Gift Shop, call 1-312-527-4276 or email .

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Remember your Ferris Wheel ride forever with a special souvenir photo of you and your loved ones! Order online today!

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