Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options.

TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease

Voluntary disclosure of corporate strategy: determinants and outcomes. An empirical study into the risks and payoffs of communicating corporate strategy.

Business leaders increasingly face pressure from stakeholders to be transparent. There appears however little consensus on the risks and payoffs of disclosing vital information such as corporate strategy. To fill this gap, this study analyzes firm-specific determinants and organisational outcomes of voluntary disclosure of corporate strategy. Stakeholder theory and agency theory help to understand whether companies serve their interest to engage with stakeholders and overcome information asymmetries. I connect these theories and propose a comprehensive approach to measure voluntary disclosure of corporate strategy. Hypotheses from the theoretical framework are empirically tested through panel regression of data on identified determinants and outcomes and of disclosed strategy through annual reports, corporate social responsibility reports, corporate websites and corporate press releases by the 70 largest publicly listed companies in the Netherlands from 2003 through 2008. I found that industry, profitability, dual-listing status, national ranking status and listing age have significant effects on voluntary disclosure of corporate strategy. No significant effects are found for size, leverage and ownership concentration. On outcomes, I found that liquidity of stock and corporate reputation are significantly influenced by voluntary disclosure of corporate strategy. No significant effect is found for volatility of stock. My contributions to theory, methodology and empirics offers a stepping-stone for further research into understanding how companies can use transparency to manage stakeholder relations

Absence of viscerosomatic inhibition with injections of lobeline designed to activate human pulmonary C fibres

Activation of pulmonary C fibres (J receptors) in animals produces inhibition of spinal motoneurones. Intravenous bolus injections of lobeline are believed to activate pulmonary C fibres (J receptors) in human subjects and to produce characteristic sensations and cardiorespiratory responses. This study quantified the respiratory sensations evoked by such injections and then used a range of suprathreshold doses of lobeline and tested for the presence of reflex or descending inhibition of motoneuronal output.Injections of lobeline produced dose-dependent sensations of respiratory discomfort referred to the throat and upper chest beginning within about 10 s and often associated with coughing. As the dose increased the latency for the sensations decreased while their duration and intensity increased. Reflex changes in blood pressure, heart rate and ventilation also occurred.Injections of lobeline at doses sufficient to evoke respiratory discomfort lasting 25-32 s (37-73 μg kg−1) increased the size of the H reflex in soleus with an onset latency of about 10 s and lasting about 20 s.The size of EMG responses evoked in upper limb muscles by transcranial magnetic stimulation of the motor cortex increased shortly after injections and remained elevated for about 30-35 s.Injections of lobeline during sustained voluntary contractions of the elbow flexors at submaximal or maximal levels did not impair the ability to produce force.Walking was not disrupted by repeated suprathreshold doses of lobeline.It is concluded that injections of lobeline sufficient to evoke cardiorespiratory reflexes and sensations of severe respiratory discomfort are not associated with functionally important inhibition of motor performance. The results cast doubt on the ability of the J reflex to limit exercise in humans