Acute myeloid leukemia (AML) is a clonal disorder arising from hematopoietic myeloid progenitors. Aberrantly activated tyrosine kinases (TK) are involved in leukemogenesis and are associated with poor treatment outcome. Kinase inhibitor (KI) treatment has shown promise in improving patient outcome in AML. However, inhibitor selection for patients is suboptimal.

In a preclinical effort to address KI selection, we analyzed a panel of 16 AML cell lines using phosphotyrosine (pY) enrichment-based, label-free phosphoproteomics. The Integrative Inferred Kinase Activity (INKA) algorithm was used to identify hyperphosphorylated, active kinases as candidates for KI treatment, and efficacy of selected KIs was tested.

Heterogeneous signaling was observed with between 241 and 2764 phosphopeptides detected per cell line. Of 4853 identified phosphopeptides with 4229 phosphosites, 4459 phosphopeptides (4430 pY) were linked to 3605 class I sites (3525 pY). INKA analysis in single cell lines successfully pinpointed driver kinases (PDGFRA, JAK2, KIT and FLT3) corresponding with activating mutations present in these cell lines. Furthermore, potential receptor tyrosine kinase (RTK) drivers, undetected by standard molecular analyses, were identified in four cell lines (FGFR1 in KG-1 and KG-1a, PDGFRA in Kasumi-3, and FLT3 in MM6). These cell lines proved highly sensitive to specific KIs. Six AML cell lines without a clear RTK driver showed evidence of MAPK1/3 activation, indicative of the presence of activating upstream RAS mutations. Importantly, FLT3 phosphorylation was demonstrated in two clinical AML samples with a FLT3 internal tandem duplication (ITD) mutation.

Our data show the potential of pY-phosphoproteomics and INKA analysis to provide insight in AML TK signaling and identify hyperactive kinases as potential targets for treatment in AML cell lines. These results warrant future investigation of clinical samples to further our understanding of TK phosphorylation in relation to clinical response in the individual patient.

T-type (Cav3) Ca2+ channels are important regulators of excitability and rhythmic activity of excitable cells. Among other voltage-gated Ca2+ channels, Cav3 channels are uniquely sensitive to oxidation and zinc. Using recombinant protein expression in HEK293 cells, patch clamp electrophysiology, site-directed mutagenesis, and homology modeling, we report here that modulation of Cav3.2 by redox agents and zinc is mediated by a unique extracellular module containing a high-affinity metal-binding site formed by the extracellular IS1–IS2 and IS3–IS4 loops of domain I and a cluster of extracellular cysteines in the IS1–IS2 loop. Patch clamp recording of recombinant Cav3.2 currents revealed that two cysteine-modifying agents, sodium (2-sulfonatoethyl) methanethiosulfonate (MTSES) and N-ethylmaleimide, as well as a reactive oxygen species–producing neuropeptide, substance P (SP), inhibit Cav3.2 current to similar degrees and that this inhibition is reversed by a reducing agent and a zinc chelator. Pre-application of MTSES prevented further SP-mediated current inhibition. Substitution of the zinc-binding residue His191 in Cav3.2 reduced the channel's sensitivity to MTSES, and introduction of the corresponding histidine into Cav3.1 sensitized it to MTSES. Removal of extracellular cysteines from the IS1–IS2 loop of Cav3.2 reduced its sensitivity to MTSES and SP. We hypothesize that oxidative modification of IS1–IS2 loop cysteines induces allosteric changes in the zinc-binding site of Cav3.2 so that it becomes sensitive to ambient zinc.

Expert

A. G. Sergeev and Kh. A. Khachatryan
Trans. Moscow Math. Soc. 80 (2020), 95-111.
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S. A. Kashchenko
Trans. Moscow Math. Soc. 80 (2020), 53-71.
Abstract, references and article information

Votes are cast by the full membership in each house of Congress, but much of the important maneuvering occurs in committees. Graph theory and linear algebra are two mathematics subjects that have revealed a level of organization in Congress groups of committees above the known levels of subcommittees and committees. The result is based on strong connections between certain committees that can be detected by examining their memberships, but which were virtually unknown until uncovered by mathematical analysis. Mathematics has also been applied to individual congressional voting records. Each legislator.s record is represented in a matrix whose larger dimension is the number of votes cast (which in a House term is approximately 1000). Using eigenvalues and eigenvectors, researchers have shown that the entire collection of votes for a particular Congress can be approximated very well by a two-dimensional space. Thus, for example, in almost all cases the success or failure of a bill can be predicted from information derived from two coordinates. Consequently it turns out that some of the values important in Washington are, in fact, eigenvalues. For More Information: Porter, Mason A; Mucha, Peter J.; Newman, M. E. J.; and Warmbrand, Casey M., A Network Analysis of Committees in the United States House of Representatives, Proceedings of the National Academy of Sciences, Vol. 102 [2005], No. 20, pp. 7057-7062.

Ning Zhang, Jia Wu and Liwei Zhang
Math. Comp. 89 (2020), 1867-1894.
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Côme Huré, Huyên Pham and Xavier Warin
Math. Comp. 89 (2020), 1547-1579.
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The new rule, which will force payments platforms and online retailers to strongly authenticate purchases of £28 or more has been delayed by another six months amidst the COVID-19 pandemic

Kamen G. Ivanov and Pencho Petrushev
Trans. Amer. Math. Soc. 373 (2020), 3117-3176.
Abstract, references and article information

Hilaf Hasson and Jeffrey Yelton
Trans. Amer. Math. Soc. 373 (2020), 3009-3030.
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Yu. V. Kozachenko and I. V. Rozora
Theor. Probability and Math. Statist. 99 (2020), 113-124.
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A. Seesanea and I. E. Verbitsky
St. Petersburg Math. J. 31 (2020), 557-572.
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C. De Filippis and G. Mingione
St. Petersburg Math. J. 31 (2020), 455-477.
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S.-S. Byun, D. K. Palagachev and L. G. Softova
St. Petersburg Math. J. 31 (2020), 401-419.
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Mohamed Jleli, Bessem Samet and Philippe Souplet
Proc. Amer. Math. Soc. 148 (2020), 2579-2593.
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Michiya Mori
Proc. Amer. Math. Soc. 148 (2020), 2477-2485.
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In view of the severe economic repercussions caused by the COVID-19 pandemic globally and locally, the Government announced another package of measures to support the affected individuals and businesses last Wednesday. Two of which are particularly relevant to the legal and dispute resolution sector - the LawTech Fund and the COVID-19 Online Dispute Resolution (ODR) Scheme. The LawTech Fund was briefly introduced in this blog a few days ago. Today, I would like to give an online explanation of the COVID-19 ODR.

In anticipation of an upsurge of disputes arising from or relating to COVID-19, the scheme aims to provide speedy and cost-effective means to resolve such disputes, especially for those involving micro, small and medium-sized enterprises (MSMEs) that may be adversely affected or hard hit by the pandemic. The scheme will engage eBRAM (electronic Business Related Arbitration & Mediation system) to provide ODR services to the general public and businesses, in particular MSMEs, involved in low value disputes.

The scheme plans to cover COVID-19 related disputes with the claim amount for each case to be capped at $500,000. Either one of the parties (claimant or respondent) must be a Hong Kong resident or company and they will only be required to each pay $200 registration fees. Under the scheme, the parties are required to enter into a dispute resolution agreement to record their consent.

The process to be adopted is a multi-tiered dispute resolution mechanism where the parties will first attempt to negotiate their disputes, followed by mediation and if that does not result in settlement, then subsequently to arbitration for a final and binding award. This is in line with the "Mediate First" policy that we have been advocating under our "Mediate First" Pledge Programmes.

The scheme aims to offer a fast and effective means to resolve disputes among parties. Each tier of dispute resolution will be conducted within a limited time. The tiers are devised with a view to avoiding disputes and differences from being entrenched. If the disputes can be resolved successfully and amicably through negotiation or mediation, we hope it will help build and reinforce a harmonious society and enable the parties to preserve their long term business relationship.

We also hope the scheme will have the benefit of job creation and job advancement for mediators and arbitrators (including their pupils). Parties are at liberty to appoint the third party neutral of their choice and if no agreement is reached, there will be a mechanism for appointment. The third party neutrals and the parties or their representatives can still handle cases under the social distancing measures online and indeed to practice on the handling of cases online. We would like the scheme to be launched in June if funding is provided in April.

It is a global trend to develop and use ODR to provide reliable and efficient platform to facilitate alternative dispute resolution. The scheme is in line with the development under Asia-Pacific Economic Cooperation's Collaborative Framework on ODR (APEC Framework), with MSMEs as the major beneficiary. The mechanism of adopting negotiation and mediation in the first stage under the APEC Framework is also to prevent entrenched views on the conflicts, thereby helping to create harmony in society.

Some forms of alternative dispute resolution, such as mediation, are a more cost-effective way to resolve disputes. The costs of mediation are almost always lower than the disputed amounts, making it an economical way to resolve disputes. Mediation can save time too. Some cases may be resolved following just one day of mediation.

LawTech has greatly helped the development of dispute resolution services. The establishment of a safe, reliable and credible platform to provide enterprises with convenient and cost-effective online dispute resolution will become a new trend.

It is one of the major long-term policy objectives of the Department of Justice (DoJ) in recent years to enhance and promote Hong Kong's status as an international legal hub for deal-making and dispute resolution. A further promotion of the use of ODR will help consolidate Hong Kong's position as an international business and financial centre.

The social media accounts of the DoJ's IDAR Office have been introducing the procedure, characteristics and benefits of mediation and arbitration. You may wish to visit the dedicated pages of the IDAR Office to keep abreast of the dispute resolution services.

In addition to the relief measures announced by the Government, the DoJ has also taken the initiative to speed up payment of fees to counsel. Counsel engaged by the DoJ could submit their interim fee notes together with the interim case reports after certain work has been completed. Each case will be considered individually on a case-by-case basis and interim payments could be made. I have enquired and am also glad to learn from the Legal Aid Department and the Duty Lawyer Service that they made similar arrangements.

We are confident that Hong Kong can weather the storm with our fundamental strengths and resilience. We also trust that we would overcome this unprecedented challenge by standing in solidarity.

Secretary for Justice Teresa Cheng wrote this article and posted it on her blog on April 13.