Characterization of a Clp Protease Gene Regulator and the Reaeration Response in Mycobacterium tuberculosis

Mycobacterium tuberculosis (MTB) enters a non-replicating state when exposed to low oxygen tension, a condition the bacillus encounters in granulomas during infection. Determining how mycobacteria enter and maintain this state is a major focus of research. However, from a public health standpoint the importance of latent TB is its ability to reactivate. The mechanism by which mycobacteria return to a replicating state upon re-exposure to favorable conditions is not understood. In this study, we utilized reaeration from a defined hypoxia model to characterize the adaptive response of MTB following a return to favorable growth conditions. Global transcriptional analysis identified the ∼100 gene Reaeration Response, induced relative to both log-phase and hypoxic MTB. This response includes chaperones and proteases, as well as the transcription factor Rv2745c, which we characterize as a Clp protease gene regulator (ClgR) orthologue. During reaeration, genes repressed during hypoxia are also upregulated in a wave of transcription that includes genes crucial to transcription, translation and oxidative phosphorylation and culminates in bacterial replication. In sum, this study defines a new transcriptional response of MTB with potential relevance to disease, and implicates ClgR as a regulator involved in resumption of replication following hypoxia

From spatial ecology to spatial epidemiology: Modeling spatial distributions of different cancer types with principal coordinates of neighbor matrices

Epidemiology and ecology share many fundamental research questions. Here we describe how principal coordinates of neighbor matrices (PCNM), a method from spatial ecology, can be applied to spatial epidemiology. PCNM is based on geographical distances among sites and can be applied to any set of sites providing a good coverage of a study area. In the present study, PCNM eigenvectors corresponding to positive autocorrelation were used as explanatory variables in linear regressions to model incidences of eight most common cancer types in Finnish municipalities (n = 320). The dataset was provided by the Finnish Cancer Registry and it included altogether 615,839 cases between 1953 and 2010. Results: PCNM resulted in 165 vectors with a positive eigenvalue. The first PCNM vector corresponded to the wavelength of hundreds of kilometers as it contrasted two main subareas so that municipalities located in southwestern Finland had the highest positive site scores and those located in midwestern Finland had the highest negative scores in that vector. Correspondingly, the 165thPCNM vector indicated variation mainly between the two small municipalities located in South Finland. The vectors explained 13 - 58% of the spatial variation in cancer incidences. The number of outliers having standardized residual > |3| was very low, one to six per model, and even lower, zero to two per model, according to Chauvenet's criterion. The spatial variation of prostate cancer was best captured (adjusted r 2= 0.579). Conclusions: PCNM can act as a complementary method to causal modeling to achieve a better understanding of the spatial structure of both the response and explanatory variables, and to assess the spatial importance of unmeasured explanatory factors. PCNM vectors can be used as proxies for demographics and causative agents to deal with autocorrelation, multicollinearity, and confounding variables. PCNM may help to extend spatial epidemiology to areas with limited availability of registers, improve cost-effectiveness, and aid in identifying unknown causative agents, and predict future trends in disease distributions and incidences. A large advantage of using PCNM is that it can create statistically valid reflectors of real predictors for disease incidence models with only little resources and background information

TEL/AML1 fusion resulting from a cryptic t(12;21) is the most common genetic lesion in pediatric ALL and defines a subgroup of patients with an excellent prognosis

The t(12;21)(p13;q22) is identified by routine cytogenetics in less than 0.05% of pediatric acute lymphoblastic leukemia (ALL) patients. This translocation encodes a TEL/AML-1 chimeric product comprising the helix-loop-helix domain of TEL, a member of the ETS-like family of transcription factors, fused to AML-1, the DNA-binding subunit of the AML-1/CBFβ transcription factor complex. Both TEL and AML-1 are involved in several myeloid leukemia-associated translocations with AML-1/CBFβ being altered in 20-30% of de novo acute myeloid leukemia (AML) cases. We now demonstrate that a TEL/AML1 chimeric transcript encoded by a cryptic t(12;21) is observed in 22% of pediatric ALL, making it the most common genetic lesion in these patients. Moreover, TEL/AML1 expression defined a distinct subgroup of patients characterized by an age between 1 and 10 years, B lineage immunophenotype, nonhyperdiploid DNA content and an excellent prognosis. These data demonstrate that molecular diagnostic approaches are invaluable in identifying clinically distinct subgroups, and that the AML1/CBFβ transcription complex is the most frequent target of chromosomal rearrangements in human leukemia.link_to_subscribed_fulltex

Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia.

BACKGROUND: About a fifth of children with acute -lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. METHODS: Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL. FINDINGS: 30 patients (12.6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a(-), CD8(-), CD5(weak) with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial). INTERPRETATION: ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy. FUNDING: US National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC)