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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 (http://mct.aacrjournals.org/).

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A 124-page long email conversation between team members and the MIT-affiliated Digital Currency Initiative was leaked to air jordan i og high gatorade collection shield
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 nike air max thea womens white ebay auction
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) nike air max 180 force pump diagram

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 free runs 40 womens Nz2EljTk
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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