Mitochondria Targeted Protein-Ruthenium Photosensitizer for Efficient Photodynamic Applications

Organelle-targeted photosensitization represents a promising approach in photodynamic therapy where the design of the active photosensitizer (PS) is very crucial. In this work, we developed a macromolecular PS with multiple copies of mitochondria-targeting groups and ruthenium complexes that displays highest phototoxicity toward several cancerous cell lines. In particular, enhanced anticancer activity was demonstrated in acute myeloid leukemia cell lines, where significant impairment of proliferation and clonogenicity occurs. Finally, attractive two-photon absorbing properties further underlined the great significance of this PS for mitochondria targeted PDT applications in deep tissue cancer therapy

Association Between a Prognostic Gene Signature and Functional Gene Sets

Background: The development of expression-based gene signatures for predicting prognosis or class membership is a popular and challenging task. Besides their stringent validation, signatures need a functional interpretation and must be placed in a biological context. Popular tools such as Gene Set Enrichment have drawbacks because they are restricted to annotated genes and are unable to capture the information hidden in the signature’s non-annotated genes. Methodology: We propose concepts to relate a signature with functional gene sets like pathways or Gene Ontology categories. The connection between single signature genes and a specific pathway is explored by hierarchical variable selection and gene association networks. The risk score derived from an individual patient’s signature is related to expression patterns of pathways and Gene Ontology categories. Global tests are useful for these tasks, and they adjust for other factors. GlobalAncova is used to explore the effect on gene expression in specific functional groups from the interaction of the score and selected mutations in the patient’s genome. Results: We apply the proposed methods to an expression data set and a corresponding gene signature for predicting survival in Acute Myeloid Leukemia (AML). The example demonstrates strong relations between the signature and cancer-related pathways. The signature-based risk score was found to be associated with development-related biological processes. Conclusions: Many authors interpret the functional aspects of a gene signature by linking signature genes to pathways o

A novel role for Lef-1, a central transcription mediator of Wnt signaling, in leukemogenesis

Canonical Wnt signaling is critically involved in normal hematopoietic development and the self-renewal process of hematopoietic stem cells (HSCs). Deregulation of this pathway has been linked to a large variety of cancers, including different subtypes of leukemia. Lef-1 is a major transcription factor of this pathway and plays a pivotal role in lymphoid differentiation as well as in granulopoiesis. Here, we demonstrate Lef-1 expression in murine HSCs as well as its expression in human leukemia. Mice transplanted with bone marrow retrovirally transduced to express Lef-1 or a constitutive active Lef-1 mutant showed a severe disturbance of normal hematopoietic differentiation and finally developed B lymphoblastic and acute myeloid leukemia (AML). Lef-1–induced AMLs were characterized by immunoglobulin (Ig) DH-JH rearrangements and a promiscuous expression of lymphoid and myeloid regulatory factors. Furthermore, single cell experiments and limiting dilution transplantation assays demonstrated that Lef-1–induced AML was propagated by a leukemic stem cell with lymphoid characteristics displaying Ig DH-JH rearrangements and a B220+ myeloid marker− immunophenotype. These data indicate a thus far unknown role of Lef-1 in the biology of acute leukemia, pointing to the necessity of balanced Lef-1 expression for an ordered hematopoietic development

Magnetic resonance investigation of magnetic-labeled baker's yeast cells

In this study, the interaction of DMSA-coated magnetite nanoparticles (5 and 10 nm core-size) with Saccharomyces cerevisae was investigated using magnetic resonance (MR) and transmission electron microscopy (TEM). The TEM micrographs revealed magnetite nanoparticles attached externally to the cell wall. The MR data support the strong interaction among the nanoparticles supported by the cells. A remarkable shift in the resonance field was used as signature of particle attachment to the cell wall

A 68 ka precipitation record from the hyperarid core of the Atacama Desert in northern Chile

[Abstract] The Atacama Desert in northern Chile is one of the driest deserts on Earth. Hyperaridity persists at least since the Miocene and was punctuated by pluvial phases. However, very little is known about the timing, regional spread and intensities of precipitation changes. Here, we present a new precipitation record from a sedimentary sequence recovered in a tectonically blocked endorheic basin that is located in the hyperarid core of the Atacama Desert. The chronostratigraphic framework of the record is given by a multi-disciplinary dating approach, suggesting an age of ca. 68 ka BP for the core base. The sequence consists of three sediment types, whose sedimentological and geochemical characteristics suggest different depositional processes that reflect different degrees in humidity. First, particularly fine-grained sediments with high clastic but low calcium sulfate and carbonate contents reflect a particularly dry climate with only sporadic precipitation events and fluvial supply via channel systems. Second, more coarse-grained sediments with lower clastic and higher calcium sulfate and carbonate contents reflect more moist conditions with stronger precipitation events that lead to fluvial activity not restricted to the channels but involving the slopes and plains in the catchment. Third, normally graded layers with an equally high proportion of calcium sulfate and carbonate reflect occasional high-precipitation events that caused sediment supply also from most distant parts of the catchment via severe flash floods. The sedimentary succession suggests that precipitation changes took place on orbital but also on millennial time scales. Rather moist periods occurred during most of MIS 2, several shorter periods within MIS 3 and parts of MIS 4. Comparison of the findings from the Huara record with selected climate records from continental and marine sites in South America suggests a strong precipitation heterogeneity across the Atacama. This heterogeneity is caused by pronounced differences in the dominating climate patterns and a shift from predominant summer rain in the north to winter rain in the south. Precipitation supply to the Huara clay plan is controlled by the atmospheric circulation rather than the surface temperature of the adjacent ocean

Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström’s Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

[Purpose]: The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. [Methods]: Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. [Results]: With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade ≥ 3 adverse events of clinical interest generally decreased over time. [Conclusion]: In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.Supported by Pharmacyclics LLC, an AbbVie Company. Pharmacyclics LLC sponsored and designed the study.Peer reviewe

Physician supply forecast: better than peering in a crystal ball?

<p>Abstract</p> <p>Background</p> <p>Anticipating physician supply to tackle future health challenges is a crucial but complex task for policy planners. A number of forecasting tools are available, but the methods, advantages and shortcomings of such tools are not straightforward and not always well appraised. Therefore this paper had two objectives: to present a typology of existing forecasting approaches and to analyse the methodology-related issues.</p> <p>Methods</p> <p>A literature review was carried out in electronic databases Medline-Ovid, Embase and ERIC. Concrete examples of planning experiences in various countries were analysed.</p> <p>Results</p> <p>Four main forecasting approaches were identified. The supply projection approach defines the necessary inflow to maintain or to reach in the future an arbitrary predefined level of service offer. The demand-based approach estimates the quantity of health care services used by the population in the future to project physician requirements. The needs-based approach involves defining and predicting health care deficits so that they can be addressed by an adequate workforce. Benchmarking health systems with similar populations and health profiles is the last approach. These different methods can be combined to perform a gap analysis. The methodological challenges of such projections are numerous: most often static models are used and their uncertainty is not assessed; valid and comprehensive data to feed into the models are often lacking; and a rapidly evolving environment affects the likelihood of projection scenarios. As a result, the internal and external validity of the projections included in our review appeared limited.</p> <p>Conclusion</p> <p>There is no single accepted approach to forecasting physician requirements. The value of projections lies in their utility in identifying the current and emerging trends to which policy-makers need to respond. A genuine gap analysis, an effective monitoring of key parameters and comprehensive workforce planning are key elements to improving the usefulness of physician supply projections.</p

The EHA Research Roadmap : Malignant Lymphoid Diseases

Peer reviewe

Determining crystal structures through crowdsourcing and coursework

We show here that computer game players can build high-quality crystal structures. Introduction of a new feature into the computer game Foldit allows players to build and real-space refine structures into electron density maps. To assess the usefulness of this feature, we held a crystallographic model-building competition between trained crystallographers, undergraduate students, Foldit players and automatic model-building algorithms. After removal of disordered residues, a team of Foldit players achieved the most accurate structure. Analysing the target protein of the competition, YPL067C, uncovered a new family of histidine triad proteins apparently involved in the prevention of amyloid toxicity. From this study, we conclude that crystallographers can utilize crowdsourcing to interpret electron density information and to produce structure solutions of the highest quality