The STAT family of transcription factors (signal transducers and activators of transcription) transduce signals from cytokine receptors to the nucleus, where STAT dimers bind to DNA and regulate transcription. STAT3 is the most ubiquitous of the STATs, being activated by a wide variety of cytokines and growth factors. STAT3 has many roles in physiological processes such as inflammatory signalling, aerobic glycolysis and immune suppression, and was also the first family member shown to be aberrantly activated in a wide range of both solid and liquid tumours. STAT3 promotes tumorigenesis by regulating the expression of various target genes, including cellcycle regulators, angiogenic factors and anti-apoptosis genes. Paradoxically, in some circumstances, STAT3 signalling induces cell death. The best known example is the involuting mammary gland, where STAT3 is essential for induction of a lysosomal pathway of cell death. Nevertheless, direct silencing or inhibition of STAT3 diminishes tumour growth and survival in both animal and human studies. This suggests that abolishing STAT3 activity may be an effective cancer therapeutic strategy. However, despite this potential as a therapeutic target, and the extensive attempts by many laboratories and pharmaceutical companies to develop an effective STAT3 inhibitor for use in the clinic, no direct STAT3 inhibitor has been approved for clinical use. In this review, we focus on the role of STAT3 in tumorigenesis, and discuss its potential as a therapeutic target for cancer treatment.

We assessed the attentional demands of drawing and passing in rugby league players and investigated the effects of single-task and dual-task training on the acquisition, retention, and transfer of skill in these athletes. In Study 1, high-skilled and lesser-skilled rugby league players performed a standardized 2-on-1 drill under single-task (primary skill in isolation) and dual-task (primary skill while performing a secondary verbal tone recognition task) conditions. No differences were detected in primary task performance between groups, although the performance of the high-skilled players was more resistant to skill decrement under dual-task conditions. In Study 2, high-performance rugby league players were randomly allocated to either a single-task or dual-task training group. Each group underwent 8 weeks of training between the pre- and post-test sessions. While the mean improvement for draw and pass proficiency under dual-task conditions in the dual-task training group was greater than in the single-task training group (10.0% vs. 2.3%), the differences, while providing a moderate effect size (d = 0.57), were not statistically significant. These results suggest that the attentional demands of drawing and passing are reduced in high-skilled rugby league players compared with their lesser-skilled counterparts. In addition, compared with single-task training, dual-task training appears to improve the ability to perform dual-task draw and pass tasks (possibly through an improvement in time-sharing skills). Further studies are required to verify the efficacy of dual-task training as a training stimulus.

Recombinant erythropoietin (EPO) and iron substitution are a standard of care for treatment of anemias associated with chronic inflammation including anemia of chronic kidney disease. A black box warning for EPO therapy and concerns about negative side effects related to high-dose iron supplementation as well as the significant proportion of patients becoming EPO resistant over time, explains the medical need to define novel strategies to ameliorate anemia of chronic disease (ACD). As hepcidin is central to the iron-restrictive phenotype in ACD, therapeutic approaches targeting hepcidin were recently developed. We herein report the therapeutic effects of a fully human anti-BMP6 antibody (KY1070) either as monotherapy or in combination with Darbepoetin alfa on iron metabolism and anemia resolution in two different, well established and clinically relevant rodent models of ACD. In addition to counteracting hepcidin driven iron limitation for erythropoiesis, we found that the combination of KY1070 and recombinant human EPO improved the erythroid response compared to either monotherapy in a qualitative and quantitative manner. Consequently, combination of KY1070 and Darbepoetin alfa resulted in an EPO-sparing effect. Moreover, we found that suppression of hepcidin via KY1070 modulates ferroportin expression on erythroid precursor cells, thereby lowering potentially toxic free intracellular iron levels and by accelerating erythroid output as reflected by increased maturation of erythrocyte progenitors. In summary, we conclude that treatment of ACD, as a highly complex disease, becomes more effective by a multifactorial therapeutic approach upon mobilization of endogenous iron deposits and stimulation of erythropoiesis.

Bispecific antibodies (BsAbs) are emerging as an important class of biopharmaceutical. The majority of BsAbs are created from conventional antibodies or fragments engineered into more complex configurations. A recurring challenge in their development, however, is the identification of components that are optimised for inclusion in the final format in order to deliver both efficacy and robust biophysical properties. Using a modular BsAb format, the mAb-dAb, we assessed whether an 'in-format' screening approach, designed to select format-compatible domain antibodies, could expedite lead discovery. Human nerve growth factor (NGF) was selected as an antigen to validate the approach; domain antibody (dAb) libraries were screened, panels of binders identified, and binding affinities and potencies compared for selected dAbs and corresponding mAb-dAbs. A number of dAbs that exhibited high potency (IC 50 ) when assessed in-format were identified. In contrast, the corresponding dAb monomers had »1000-fold lower potency than the formatted dAbs; such dAb monomers would therefore have been omitted from further characterization. Subsequent stoichiometric analyses of mAb-dAbs bound to NGF, or an additional target antigen (vascular endothelial growth factor), suggested different target binding modes; this indicates that the observed potency improvements cannot be attributed simply to an avidity effect offered by the mAb-dAb format. We conclude that, for certain antigens, screening na€ ıve selection outputs directly in-format enables the identification of a subset of format-compatible dAbs, and that this offers substantial benefits in terms of molecular properties and development time.

No abstract