Consequently, because requesters may seek to supplement or even to circumvent existing discovery mechanisms through the FOIA, agency FOIA personnel should always determine whether requested documents relate to pending litigation and, if so, carefully coordinate their disclosure actions with the pertinent litigation counsel. In this regard, special attention should be given to the possible applicability of FOIA Exemptions 5 and 7(A), in order to ensure the protection of information which would not be routinely discoverable in the ongoing litigation, see generally United States v. Weber Aircraft Corp., 104 S. Ct. 1488, 1492-93 (1984), and to avoid any harmful premature revelation of the government's case in court, see, e.g., NLRB v. Robbins Tire & Rubber Co., 437 U.S. 214, 224 (1978).
As with any targeted cancer therapy, it is important to identify potential mechanisms of venetoclax resistance, not only to inform patient selection but also to develop strategies to circumvent resistance as it emerges . Previously we demonstrated that MCL-1 overexpression is an inherent resistance factor for ABT-737, a potent BCL-2/BCL-XL inhibitor, in a panel of SCLC cell lines, as well as an acquired resistance factor in H146 cells that had been selected for survival in the presence of ABT-737 . To more fully elucidate the potential mechanisms that may be involved in resistance to venetoclax, we undertook a study to assess potential changes in the expression levels of BCL-2 family members following extended treatment with venetoclax. We generated resistant variants from venetoclax-sensitive cell lines of different leukemia and lymphoma subtypes (two diffuse large B-cell lymphomas, two follicular lymphomas, one leukemia line, and two mantle cell lymphomas) by increasing exposure to venetoclax in a stepwise manner over time. We identified alterations in both pro-apoptotic and anti-apoptotic family members that account for resistance mechanisms. In several cases where the anti-apoptotic BCL-2 relatives MCL-1 or BCL-XL were upregulated, sensitivity to venetoclax could be restored by co-treating with the appropriate MCL-1-selective or BCL-XL-selective inhibitor, confirming both are causally related in mediating resistance to venetoclax. These data will help facilitate the rational design of combination strategies to circumvent venetoclax resistance and guide patient selection in future clinical trials.
The data presented here indicate that diverse mechanisms have the potential to contribute to venetoclax resistance. However, most have in common a clear alteration in the expression of at least one pro-apoptotic or anti-apoptotic BCL-2 family protein that is likely to have a strong impact on the action of venetoclax. Although mechanisms of venetoclax resistance have yet to be defined in the clinic, the findings presented here suggest a number of hypotheses that can be explored. Hopefully these studies will provide a basis for further investigation and will enable the research community to develop the next generation of therapeutics that can reverse or circumvent resistance to this promising therapeutic.
TSA accepts donations of Capability listed on the ACL to support screening operations. The ACL lists all Capability that are currently able to be donated to TSA based on the approval of applicable phases of the DHS ALF (i.e., receiving an approved ADE-3 Acquisition Decision Memorandum). Accepting donations of the Capability on the ACL does not circumvent acquisition and procurement guidelines.
mid-15c., "to surround by hostile stratagem," from Latin circumventus, past participle of circumvenire "to get around, be around, encircle, surround," in figurative sense "to oppress, assail, cheat," from circum "around" (see circum-) + venire "to come," from a suffixed form of PIE root *gwa- "to go, come." Meaning "to go round" is from 1840. Related: Circumvented; circumventing.
US policymakers have voiced concerns that the Russian government, as well as sanctioned corporate entities and individuals, could use cryptocurrencies to circumvent western sanctions. Indeed, a group of US senators, led by Senator Elizabeth Warren, wrote a letter to Secretary Yellen inquiring about the Department of the Treasury's progress enforcing and monitoring sanctions compliance by the cryptocurrency industry and raising concerns that the Treasury's Office of Foreign Assets Control "has not developed sufficiently strong and effective procedures for enforcement in the cryptocurrency industry."1 The executive branch shares their concerns: President Biden's Executive Order on Ensuring Responsible Development of Digital Assets, announced on March 9, 2022, specifically lists "sanctions risk" and "sanctions evasion" among the issues presented by digital assets such as cryptocurrencies.2 In addition, the G7's Joint Statement on March 11, 2022 made it clear that it is "commonly understood that our current sanctions already cover crypto-assets."3
The FinCEN alert also explained that it is unlikely that the Russian government can use cryptocurrency to mitigate or circumvent the impact of sanctions in any meaningful way, finding that "large scale sanctions evasion using CVC by a government such as the Russian Federation is not necessarily practicable."18 Additionally, FinCEN Acting Director Him Das said the agency had "not seen widespread evasion of our sanctions using methods such as cryptocurrency."19 This echoes the sentiment expressed by Carol House, Director of Cybersecurity at the National Security Council, when she stated, "[t]he scale that the Russian state would need to successfully circumvent all US and partners' financial sanctions would almost certainly render cryptocurrency as an ineffective primary tool for the state."20
Senate Bill 348 would postpone the permit requirement for most firearms until July 2024 and some weapons, like hunting rifles, could be purchased without a permit until 2026. People would have to be at least 21 years to apply for a firearm. Critics say the bill is an attempt to circumvent the judicial process. But Sen. Floyd Prozanski, D-Eugene, chairman of the Senate Judiciary Committee, said lawmakers have a duty to implement approved ballot measures to the best of their ability. His committee discussed the bill in two separate hearings on Monday. It faces a vote on Thursday.
California's housing crisis is acute, and the state wants cities to do something about it. But when cities fail to act, there's a tool that allows developers to circumvent local regulations. From member station KQED, Adhiti Bandlamudi reports on the, quote, "builder's remedy."
BANDLAMUDI: That's Chris Elmendorf, a land-use law professor at UC Davis. Thanks to some recently passed state laws, the builder's remedy has more teeth. Every eight years, the state has to sign off on a city's housing plan, or a city can face consequences. Those include the loss of funding for transportation and affordable housing, lawsuits and, you guessed it, the builder's remedy. Elmendorf says it allows developers to circumvent local building rules.
Europe has found a way of circumventing U.S. sanctions on Iran. The governments of France, Germany and the United Kingdom have developed a special purpose vehicle (SPV) to enable European businesses to maintain non-dollar trade with Iran without breaking U.S. sanctions. That SPV, known as INSTEX, is now up and running.
Washington has not yet responded to the announcement that INSTEX is up and running. But it could regard such defiance of its stance on Iran as an unfriendly act, particularly as tensions escalate between the two countries over the shooting down of an American drone. Arguably, by helping companies circumvent sanctions, the EU is inviting retaliatory action. But should the U.S. really be able to force other countries to follow its lead when those countries fundamentally disagree with its stance?
Recently, two clinical studies have demonstrated that certain OVs can be delivered to tumor beds despite the presence of some level of circulating antibody (47, 48). Nevertheless, it is widely believed that nAbs that arise during therapy will significantly abrogate therapeutic efficacy of repeated systemic OV applications (13, 49). Remarkably, even when administered intravenously at therapeutic doses, rVSV(GP) did not elicit detectable nAb titers (Fig. 6A). This is consistent with earlier findings by Pinschewer and colleagues as well as Planz and colleagues. Although VSV rapidly induces nAbs against VSV-G, nAbs directed against LCMV-GP are, if at all, induced only in chronically infected mice after more than 50 days (34, 50). Hence, although we could not observe nAbs in our experiments, long-term repeated applications may possibly lead to low-titer nAb response as described for chronic LCMV infections. However, here, the observed escape from humoral adaptive immunity even allows for efficient systemic delivery of rVSV(GP) to subcutaneous tumors in preimmunized mice, whereas nAbs induced by rVSVΔM51 preimmunization completely block rVSVΔM51 delivery (Fig. 6B). Even in the absence of nAbs VSV can be at least partially inactivated by human complement, whereas rVSV(GP) is completely resistant to complement inactivation (Fig. 6C). Taken together, escape from humoral immune responses is expected to allow an effective long-term, systemic multidosing rVSV(GP) regimen in the clinical setting, an attribute that may well be unique among OV platforms. In this regard, an extensive study is currently ongoing in which we are analyzing the effectiveness of rVSV versus rVSV(GP) upon repeated applications in syngeneic tumor models. As the humoral immune escape properties are mediated by the envelope glycoprotein, LCMV-GP pseudotyping might be a comprehensive strategy to circumvent nAb induction that is also feasible for other enveloped OVs and vectored vaccines. 041b061a72