LMO2 and IL2RG synergize in thymocytes to mimic the evolution of SCID-X1 gene therapy-associated T-cell leukaemia

The SCID-X1 disease occurs in males that lack a functional X-linked gene encoding the interleukin 2 receptor subunit gamma (IL2RG) and thus are immuno-deficient (reviewed in Rochman et al.). Gene therapy has been a success in curing SCID-X1 in patients receiving autologous CD34+-bone marrow cells infected with retroviruses expressing IL2RG. This treatment protocol has, however, produced adverse T-cell effects where clonal T-cell leukaemias arose, and four have insertional mutagenesis of the T-cell oncogene LMO2. LMO2 is a T-cell oncogene first discovered via chromosomal translocations in T-cell acute leukaemia (T-ALL) (reviewed in Chambers and Rabbitts). It is unclear if the T-cell neoplasias in the SCID-X1 patients are simply due to insertional activation of the LMO2 gene or reflect synergy between LMO2 and IL2RG. Further, the recurrent involvement of LMO2 in SCID-X1 leukaemias is puzzling as other T-cell oncogenes (for example, TAL1/SCL, HOX11 and LYL1) might equally have been targets. This suggests that specific properties of LMO2 per se are required in these adverse events. The oncogenic potential of IL2RG itself also remains controversial. Although it causes T-cell lymphomas in mice transplanted with virally transduced haematopoetic stem cells, other studies have indicated that IL2RG is not an oncogene. Here we provide evidence that synergy is required between LMO2 and IL2RG proteins specifically in the T-cell lineage to elicit neoplasias and that additional mutations are required such as Notch1 mutations like those in human T-ALL

Leader Cells Define Directionality of Trunk, but Not Cranial, Neural Crest Cell Migration.

Collective cell migration is fundamental for life and a hallmark of cancer. Neural crest (NC) cells migrate collectively, but the mechanisms governing this process remain controversial. Previous analyses in Xenopus indicate that cranial NC (CNC) cells are a homogeneous population relying on cell-cell interactions for directional migration, while chick embryo analyses suggest a heterogeneous population with leader cells instructing directionality. Our data in chick and zebrafish embryos show that CNC cells do not require leader cells for migration and all cells present similar migratory capacities. In contrast, laser ablation of trunk NC (TNC) cells shows that leader cells direct movement and cell-cell contacts are required for migration. Moreover, leader and follower identities are acquired before the initiation of migration and remain fixed thereafter. Thus, two distinct mechanisms establish the directionality of CNC cells and TNC cells. This implies the existence of multiple molecular mechanisms for collective cell migration.D11I1096 Fondo de Fomento al Desarrollo Científico y TecnológicoThis is the final version of the article. It first appeared from Cell Press via httsp://doi.org/10.1016/j.celrep.2016.04.06

Genetic variation in sorghum germplasm from Sudan, ICRISAT, and USA assessed by simple sequence repeats (SSRs)

Assessment of genetic variability in crops has a strong impact on plant breeding and conservation of genetic resources. It is particularly useful in the characterization of individuals, accessions, and cultivars in determining duplications in germplasm collections and for selecting parents. The objective of this study was to estimate genetic diversity and to obtain information on the genetic relationship among 96 sorghum [Sorghum bicolor (L.) Moench] accessions from Sudan, ICRISAT, and Nebraska, USA, using 16 simple sequence repeats (SSRs). In total, 117 polymorphic bands were detected with a mean of 7.3 alleles per SSR locus. By this approach each accession is uniquely fingerprinted. Genetic similarity estimates ranged from 0 to 0.91, with a mean of 0.30. The polymorphic information content (PIC) for SSRs ranged from 0.46 (SB4-72) to 0.87 (SBAGF06). Diversity index (DI) for all accessions was 0.71. Within subgroups, DI was 0.63 for Sudanese landraces and improved cultivars, 0.49 for PI accessions, 0.42 for Nebraska derivatives, 0.39 for the ICRISAT advanced breeding lines (ABLs), 0.65 for the Feterita group, 0.71 for the Milo group, 0.63 for a Synthetic group (new breeding materials), 0.68 for the Hegiri group, and 0.47 for the Mugud group. Mantel statistics revealed a good fit of the unweighted pair-grouped method with arithmetic average (UPGMA) cluster to the original genetic similarity (GS) data (r = 0.867). UPGMA clustering produced two main clusters comprising mainly nonimproved germplasm (gene bank accessions and Nebraska population derivatives), and improved genotypes (cultivars, Gadarif collections, and ICRISAT advanced lines). Grouping of accessions by UPGMA cluster analysis matched with the geographical origin and/or pedigree information (Sudan, USA, ICRISAT), the adaptation zone (Gadarif area, Sudan), and morphological characters (Feterita, Mugud, and Milo types), indicating the strong differentiation among the sorghum materials

Can video mobile phones improve CPR quality when used for dispatcher assistance during simulated cardiac arrest?

Denne artikkelen er en del av doktorgradsavhandlingen til Stein Roar Bolle. Avhandlingen finnes i Munin http://hdl.handle.net/10037/3597Background: Because mobile telephones may support video calls, emergency medical dispatchers may now connect visually with bystanders during pre-hospital cardiopulmonary resuscitation (CPR). We studied the quality of simulated dispatcher-assisted CPR when guidance was delivered to rescuers by video calls or audio calls from mobile phones. Methods: One hundred and eighty high school students were randomly assigned in groups of three to communicate via video calls or audio calls with experienced nurse dispatchers at a Hospital Emergency Medical Dispatch Center. CPR was performed on a recording resuscitation manikin during simulated cardiac arrest. Quality of CPR and time factors were compared depending on the type of communication used. Results: The median CPR time without chest compression (‘hands-off time’) was shorter in the video-call group vs. the audio-call group (303 vs. 331 s; P50.048), but the median time to first compression was not shorter (104 vs. 102 s; P50.29). The median time to first ventilation was insignificantly shorter in the video-call group (176 vs. 205 s; P50.16). This group also had a slightly higher proportion of ventiliations without error (0.11 vs. 0.06; P50.30). Conclusion: Video communication is unlikely to improve telephone CPR (t-CPR) significantly without proper training of dispatchers and when using dispatch protocols written for audio-only calls. Improved dispatch procedures and training for handling video calls require further investigation

Lack of correlation of stem cell markers in breast cancer stem cells

BACKGROUND: Various markers are used to identify the unique sub-population of breast cancer cells with stem cell properties. Whether these markers are expressed in all breast cancers, identify the same population of cells, or equate to therapeutic response is controversial. METHODS: We investigated the expression of multiple cancer stem cell markers in human breast cancer samples and cell lines in vitro and in vivo, comparing across and within samples and relating expression with growth and therapeutic response to doxorubicin, docetaxol and radiotherapy. RESULTS: CD24, CD44, ALDH and SOX2 expression, the ability to form mammospheres and side-population cells are variably present in human cancers and cell lines. Each marker identifies a unique rather than common population of cancer cells. In vivo, cells expressing these markers are not specifically localized to the presumptive stem cell niche at the tumour/stroma interface. Repeated therapy does not consistently enrich cells expressing these markers, although ER-negative cells accumulate. CONCLUSIONS: Commonly employed methods identify different cancer cell sub-populations with no consistent therapeutic implications, rather than a single population of cells. The relationships of breast cancer stem cells to clinical parameters will require identification of specific markers or panels for the individual cancer

Evidence and Ideology in Macroeconomics: The Case of Investment Cycles

The paper reports the principal findings of a long term research project on the description and explanation of business cycles. The research strongly confirmed the older view that business cycles have large systematic components that take the form of investment cycles. These quasi-periodic movements can be represented as low order, stochastic, dynamic processes with complex eigenvalues. Specifically, there is a fixed investment cycle of about 8 years and an inventory cycle of about 4 years. Maximum entropy spectral analysis was employed for the description of the cycles and continuous time econometrics for the explanatory models. The central explanatory mechanism is the second order accelerator, which incorporates adjustment costs both in relation to the capital stock and the rate of investment. By means of parametric resonance it was possible to show, both theoretically and empirically how cycles aggregate from the micro to the macro level. The same mathematical tool was also used to explain the international convergence of cycles. I argue that the theory of investment cycles was abandoned for ideological, not for evidential reasons. Methodological issues are also discussed

Rapidly progressive dementia with thalamic degeneration and peculiar cortical prion protein immunoreactivity, but absence of proteinase K resistant PrP: a new disease entity?

BACKGROUND: Human prion diseases are a group of rare fatal neurodegenerative conditions with well-developed clinical and neuropathological diagnostic criteria. Recent observations have expanded the spectrum of prion diseases beyond the classically recognized forms. RESULTS: In the present study we report six patients with a novel, apparently sporadic disease characterised by thalamic degeneration and rapidly progressive dementia (duration of illness 2-12 months; age at death: 55-81 years). Light and electron microscopic immunostaining for the prion protein (PrP) revealed a peculiar intraneuritic distribution in neocortical regions. Proteinase K resistant PrP (PrPres) was undetectable by Western blotting in frontal cortex from the three cases with frozen tissue, even after enrichment for PrPres by centrifugation or by phosphotungstic acid precipitation. Conformation-dependent immunoassay analysis using a range of PK digestion conditions (and no PK digestion) produced only very limited evidence of meaningful D-N (denatured/native) values, indicative of the presence of disease-associated PrP (PrPSc) in these cases, when the results were compared with appropriate negative control groups. CONCLUSIONS: Our observation expands the spectrum of conditions associated with rapidly progressive dementia and may have implications for the understanding of the pathogenesis of prion diseases