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"Wing, John"
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Mutations Affecting Genes in the Proximal T-Cell Receptor Signaling Pathway in Peripheral T-Cell Lymphoma
Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of mature T-cell malignancies. Recurrent activating mutations and fusions in genes related to the proximal TCR signaling pathway have been identified in preclinical and clinical studies. This review summarizes the genetic alterations affecting proximal TCR signaling identified from different subgroups of PTCL and the functional impact on TCR signaling and downstream pathways. These genetic abnormalities include mostly missense mutations, occasional indels, and gene fusions involving CD28, CARD11, the GTPase RHOA, the guanine nucleotide exchange factor VAV1, and kinases including FYN, ITK, PLCG1, PKCB, and PI3K subunits. Most of these aberrations are activating mutations that can potentially be targeted by inhibitors, some of which are being tested in clinical trials that are briefly outlined in this review. Finally, we focus on the molecular pathology of recently identified subgroups of PTCL-NOS and highlight the unique genetic profiles associated with PTCL-GATA3.
Journal Article
Pathogenesis of diffuse large B cell lymphoma
Substantial additional insight has been obtained in the past decade regarding the pathogenesis of diffuse large B cell lymphoma (DLBCL). Distinct subtypes of DLBCL have been defined by gene expression profiling (GEP) and they differ not only in GE profiles but also in the pattern of genetic abnormalities. The ability to correlate corresponding genetic and GEP data markedly facilitates the identification of target genes in regions with copy number abnormalities. Oncogenic pathways are often differentially activated in these different subtypes of DLBCL, suggesting that therapy should be targeted according to these differences. The tumor microenvironment plays a significant role in determining outcome and may be a novel target for therapy. The role of microRNA in lymphomagenesis is increasingly being recognized and mutation of key genes has been demonstrated to drive the activation of the NF-κB pathway and B cell receptor signaling. The pace of discovery will be even more rapid in the near future with the convergence of data from multiple complementary genome-wide studies and technological innovations including the rapid advance in the technology of high-throughput sequencing.
Journal Article
Keeping Spain Afloat: • State Forestry and Imperial Defense in the Sixteenth Century
Timber resources were essential for maintaining the fleets that controlled Spain's transatlantic empire in the sixteenth century. This article argues that although the forest clearances for building the Armada during the reign of Felipe II (r. 1556–98) have been characterized as politically and ecologically destructive, this demand for timber as a strategic resource for war marked the beginning of systematic management of Spanish forests. It also connects forest conservation and the replanting of species valued by the navy, such as oaks and pines, with the militarization and expansion of bureaucratic state power. Finally, this article sheds light on social history by describing the ways in which agents of the crown faced practical limitations to their authority, primarily in the well-forested northern regions. To harvest naval timber without disrupting the social order, Madrid had to balance local interests and imperial demands. Even as international conflicts drained the finances of Spain and rapidly consumed its material and human resources, the crown continued to reaffirm the long-standing legal rights of local communities to access forest resources. Still, by the end of the century, Spain had begun using advanced techniques to gather and communicate information about forests in more regions, expanding its forestry bureaucracy into the largest of its kind in Europe.
Journal Article
Roots of Empire
Roots of Empire examines the forest management policies of Spain's global monarchy from the sixteenth century to the middle of the eighteenth century, connecting imperial strategies with local lived experiences in forest communities impacted by this manifestation of expanded state power.
eBook
Molecular analysis of the anthocyanin2 gene of petunia and its role in the evolution of flower color
The shape and color of flowers are important for plant reproduction because they attract pollinators such as insects and birds. Therefore, it is thought that alterations in these traits may result in the attraction of different pollinators, genetic isolation, and ultimately, (sympatric) speciation. Petunia integrifolia and P. axillaris bear flowers with different shapes and colors that appear to be visited by different insects. The anthocyanin2 (an2) locus, a regulator of the anthocyanin biosynthetic pathway, is the main determinant of color differences. Here, we report an analysis of molecular events at the an2 locus that occur during Petunia spp evolution. We isolated an2 by transposon tagging and found that it encodes a MYB domain protein, indicating that it is a transcription factor. Analysis of P. axillaris subspecies with white flowers showed that they contain an2 alleles with two alternative frameshifts at one site, apparently caused by the insertion and subsequent excision of a transposon. A third an2(-) allele has a nonsense mutation elsewhere, indicating that it arose independently. The distribution of polymorphisms in an2- alleles suggests that the loss of an2 function and the consequent changes in floral color were not the primary cause for genetic separation of P. integrifolia and P. axillaris. Rather, they were events that occurred late in the speciation process, possibly to reinforce genetic isolation and complete speciation.
Journal Article