JAK2 Alterations in Acute Lymphoblastic Leukemia: Molecular Insights for Superior Precision Medicine Strategies

published: 12 July 2022Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, arising from immature lymphocytes that show uncontrolled proliferation and arrested differentiation. Genomic alterations affecting Janus kinase 2 (JAK2) correlate with some of the poorest outcomes within the Philadelphia-like subtype of ALL. Given the success of kinase inhibitors in the treatment of chronic myeloid leukemia, the discovery of activating JAK2 point mutations and JAK2 fusion genes in ALL, was a breakthrough for potential targeted therapies. However, the molecular mechanisms by which these alterations activate JAK2 and promote downstream signaling is poorly understood. Furthermore, as clinical data regarding the limitations of approved JAK inhibitors in myeloproliferative disorders matures, there is a growing awareness of the need for alternative precision medicine approaches for specific JAK2 lesions. This review focuses on the molecular mechanisms behind ALL-associated JAK2 mutations and JAK2 fusion genes, known and potential causes of JAK-inhibitor resistance, and how JAK2 alterations could be targeted using alternative and novel rationally designed therapies to guide precision medicine approaches for these high-risk subtypes of ALL.Charlotte EJ. Downes, Barbara J. McClure, Daniel P. McDougal, Susan L. Heatley, John B. Bruning, Daniel Thomas, David T. Yeung and Deborah L. Whit

Cinética de Degradação de Alguns Volumosos Usados na Alimentação de Cabras Leiteiras por Intermédio da Técnica de Produção de Gases sob Diferentes Níveis de pH Degradation Kinetics of Forages Fed to Dairy Goats by Using the Gas Production Approach under Different pH levels

Os objetivos do presente estudo foram a caracterização e a determinação das estimativas dos parâmetros relativos à cinética de degradação ruminal dos carboidratos contidos nas amostras dos volumosos feno de alfafa, capim-elefante, feno de Tifton 85 e silagem de milho em cabras submetidas a diferentes relações volumoso:concentrado. Os parâmetros cinéticos da degradação ruminal da matéria seca e da fibra em detergente neutro destes volumosos, submetidos a diferentes níveis de pH, foram estimados por meio de incubações anaeróbicas, usando as técnicas da produção cumulativa de gases e de subtração de curvas e contrastado com os resultados obtidos por intermédio das técnicas in sito e in vitro, para os parâmetros de degradabilidade específica (DE) e taxa de digestão da fração insolúvel potencialmente digerível (c). A interpretação cinética foi feita pelo modelo logístico V(t) = Vf /(1+exp(2+4c(L-T))). No ensaio de digestibilidade, utilizou-se o tampão de McDougall, adaptado por Gonzáles, ajustado com solução de ácido cítrico 1 M, para os pHs observados nos animais, conforme a relação volumoso:concentrado (100:0, 80:20, 60:40, 40:60 e 20:80). Observou-se comportamento similar nas curvas da degradabilidade específica, bem como para a taxa de digestão da fração insolúvel potencialmente digerível, o que confirma a interferência do nível do pH sobre os parâmetros relativos à cinética de degradação ruminal dos carboidratos. As leituras de produção de gás resultaram em menores coeficientes de variação para a cinética de degradação da MS, mas apresentaram valores inferiores aos obtidos pelas técnicas in situ e in vitro. Já para a FDN, mostraram valores e comportamento bem próximos dos obtidos pelas outras técnicas. Conclui-se que as estimativas das taxas de degradação ruminal da FDN podem ser realizadas precisamente pela técnica da produção de gás.<br>The objectives of the present study were to characterize and estimate parameters of kinetics of carbohydrate degradation using alfalfa hay, elephant grass, tifton 85, and corn silage, fed to dairy goats under different forage: concentrate ratio. Kinetic parameters of dry matter and neutral detergent fiber degradation at different pH values were estimated by using cumulative gas production technique and their values contrasted with those obtained by both in vitro and in situ studies. Kinetic interpretation for specific degradability, rate of degradation and the potentially digestible insoluble fraction was done by using the logistic model V(t) = Vf / (1+exp(2+4c(L-T))). A modified McDougall buffer was used for the in vitro assay to adjust pH to the values observed in the animals, by adding 1M of citric acid solution according to the roughage to concentrate ratio studied of 100:0, 80:20, 60:40, 40:60 e 20:80. Similar pattern was found for extent and rate of degradation of the potentially digestible insoluble fraction which confirm the interference of pH on kinetic parameter of carbohydrates in the rumen. Gas production approach yielded the lowest variation coefficient for the values of dry matter degradation but lower figures were found as compared to both in situ and in vitro techniques. Similar values were found for NDF as the three approaches were compared and it was suggested that they can be used interchangeably to precisely estimate NDF degradation

Viral pathogenesis, modulation of immune receptor signaling and treatment.

During the co-evolution of viruses and their hosts, the latter have equipped themselves with an elaborate immune system to defend themselves from the invading viruses. In order to establish a successful infection, replicate and persist in the host, viruses have evolved numerous strategies to counter and evade host antiviral immune responses as well as exploit them for productive viral replication. These strategies include those that target immune receptor transmembrane signaling. Uncovering the exact molecular mechanisms underlying these critical points in viral pathogenesis will not only help us understand strategies used by viruses to escape from the host immune surveillance but also reveal new therapeutic targets for antiviral as well as immunomodulatory therapy. In this chapter, based on our current understanding of transmembrane signal transduction mediated by multichain immune recognition receptors (MIRRs) and the results of sequence analysis, we discuss the MIRR-targetingviral strategies of immune evasion and suggest their possible mechanisms that, in turn, reveal new points of antiviral intervention. We also show how two unrelated enveloped viruses, human immunodeficiency virus and human cytomegalovirus, use a similar mechanism to modulate the host immune response mediated by two functionally different MIRRs-T-cell antigen receptor and natural killer cell receptor, NKp30. This suggests that it is very likely that similar general mechanisms can be or are used by other viral and possibly nonviral pathogens