Mycobacterium tuberculosis Rv3802c Encodes a Phospholipase/Thioesterase and Is Inhibited by the Antimycobacterial Agent Tetrahydrolipstatin

The cell wall of M. tuberculosis is central to its success as a pathogen. Mycolic acids are key components of this cell wall. The genes involved in joining the α and mero mycolates are located in a cluster, beginning with Rv3799c and extending at least until Rv3804c. The role of each enzyme encoded by these five genes is fairly well understood, except for Rv3802c. Rv3802 is one of seven putative cutinases encoded by the genome of M. tuberculosis. In phytopathogens, cutinases hydrolyze the waxy layer of plants, cutin. In a strictly mammalian pathogen, such as M. tuberculosis, it is likely that these proteins perform a different function. Of the seven, we chose to focus on Rv3802c because of its location in a mycolic acid synthesis gene cluster, its putative essentiality, its ubiquitous presence in actinomycetes, and its conservation in the minimal genome of Mycobacterium leprae. We expressed Rv3802 in Escherichia coli and purified the enzymatically active form. We probed its activities and inhibitors characterizing those relevant to its possible role in mycolic acid biosynthesis. In addition to its reported phospholipase A activity, Rv3802 has significant thioesterase activity, and it is inhibited by tetrahydrolipstatin (THL). THL is a described anti-tuberculous compound with an unknown mechanism, but it reportedly targets cell wall synthesis. Taken together, these data circumstantially support a role for Rv3802 in mycolic acid synthesis and, as the cell wall is integral to M. tuberculosis pathogenesis, identification of a novel cell wall enzyme and its inhibition has therapeutic and diagnostic implications

The genetic basis of transformation and progression in follicular lymphoma

The clonal evolution theory of cancer has been recognized for decades and follows principles of Darwinian selection, in which there is selection of the fittest clones in an ecosystem that is fundamentally heterogeneous and undergoes selective pressure. Follicular lymphoma (FL) emerges as a prototypical disease in which to study clonal evolution. It is the most common indolent lymphoma and, although the median overall survival largely surpasses 10 years, patients almost invariably experience progressive disease. Furthermore, a subset of FL patients is at risk of early lymphoma-related death due to rapid progression or transformation to aggressive lymphoma. Yet, the clonal dynamics and the landscape of genomic alterations underlying progression and transformation remain to be uncovered. Herein, we applied whole genome sequencing to a discovery set of transformed, progressed and non-progressed FL cases, re-constructed clonal phylogenies, and interrogated a larger set of transformed FLs and clinical extremes by capture-based targeted sequencing. Moreover, we applied the Lymph2Cx cell-of-origin assay to determine whether molecular subtypes can be defined in transformed follicular lymphoma (TFL) by gene-expression profiling. We discovered that transformation is typically the result of drastic clonal shifts during which TFL-specific clones rapidly outcompete indolent clones. In a subset of cases, these aggressive clones can be found at low levels (< 1% of tumour cells) at diagnosis. In contrast, primary progression generally results from the outgrowth of subclones that are readily detectable at diagnosis, suggesting that the genomic features conferring treatment resistance can be detected prior to initial treatment using low-pass sequencing technology. In addition, we identified discrete gene mutations that are associated with early progression and transformation, and uncovered that a subset of TFLs (16%) have an activated B-cell phenotype and are enriched for mutations in CD79B and BCL10. In summary, we found striking contrast in clonal trajectories between distinct clinical scenarios and described novel associations of gene mutations with transformation and progression. Our findings have translational relevance as they suggest that early progression, and to a lesser extent transformation, can potentially be predicted at diagnosis and thus provide a rationale for novel therapeutic approaches in TFL.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Bullough, Robert V., Jr., and Craig Kridel, Adolescent Needs, Curriculum, and the Eight-Year Study, Journal of Curriculum Studies, 35(March, 2003), 151-169.

Describes the historical debate over adolescent needs among members of the Progressive Education Association during the period of the Eight-Year Study; traces views of Alberty, Zachry, Thayer, and Bode; discusses the role of social philosophy in current curriculum development

Kridel, Craig, and Robert V. Bullough, Jr., Stories of the Eight-Year Study: Reexamining Secondary Education in America. Albany, NY: State University Press of New York,2007.

Details many aspects of the history of the Eight-Year Study (1930-1942) and includes vignettes of several of its leading contributors (Aikin, Thayer, Eugene Smith, Tyler, Keliher, Zachry, Alberty, Bode, Willis). A review appears in Curriculum Inquiry, 40(March, 2010), 2905-316

Kridel, Craig, and Robert V. Bullough, Jr., Conceptions and Misperceptions of the Eight-Year Study, Journal of Curriculum and Supervision, 18(Fall, 2002), 63-82.

Re-examines the facts and interpretations of the Eight-Year Study; argues for numerous corrections and reinterpretations based on historical research

Kridel, Craig, Robert V. Bullough, Jr., and Paul Shaker, eds., Teachers and Mentors: Profiles of Distinguished Twentieth-Century Professors of Education. New York: Garland Publishing, Inc, 1996.

Contains 22 biographical sketches (8 are leading curriculum theorists from Caswell to Tyler to Macdonald, etc.) written by professors who saw them as professorial mentors

Pulmonary tumor embolism: a rare cause of acute right heart failure with elevated D-dimers

We report the case of a 49-year-old woman with a prior history of breast cancer who presented with a subacute course of progressive dyspnoea, culminating in cardiovascular collapse from acute right heart failure. D-dimer serum level was elevated. While a computed tomography of the chest was negative for pulmonary embolism, the autopsy study revealed multiple carcinomatous emboli in distal pulmonary arteries, veins, and lymphatics. Pulmonary tumor embolism may be more frequent than previously thought, and could be mistaken for pulmonary thrombo-embolism