Fibrosis in the kidney: is a problem shared a problem halved?

Fibrotic disorders are commonplace, take many forms and can be life-threatening. No better example of this exists than the progressive fibrosis that accompanies all chronic renal disease. Renal fibrosis is a direct consequence of the kidney's limited capacity to regenerate after injury. Renal scarring results in a progressive loss of renal function, ultimately leading to end-stage renal failure and a requirement for dialysis or kidney transplantation

A Common Model for Cytokine Receptor Activation: Combined Scissor-Like Rotation and Self-Rotation of Receptor Dimer Induced by Class I Cytokine

The precise mechanism by which the binding of a class I cytokine to the extracellular domain of its corresponding receptor transmits a signal through the cell membrane remains unclear. Receptor activation involves a cytokine-receptor complex with a 1∶2 stoichiometry. Previously we used our transient-complex theory to calculate the rate constant of the initial cytokine-receptor binding to form a 1∶1 complex. Here we computed the binding pathway leading to the 1∶2 activation complex. Three cytokine systems (growth hormone, erythropoietin, and prolactin) were studied, and the focus was on the binding of the extracellular domain of the second receptor molecule after forming the 1∶1 complex. According to the transient-complex theory, translational and rotation diffusion of the binding entities bring them together to form a transient complex, which has near-native relative separation and orientation but not the short-range specific native interactions. Subsequently conformational rearrangement leads to the formation of the native complex. We found that the changes in relative orientations between the two receptor molecules from the transient complex to the 1∶2 native complex are similar for the three cytokine-receptor systems. We thus propose a common model for receptor activation by class I cytokines, involving combined scissor-like rotation and self-rotation of the two receptor molecules. Both types of rotations seem essential: the scissor-like rotation separates the intracellular domains of the two receptor molecules to make room for the associated Janus kinase molecules, while the self-rotation allows them to orient properly for transphosphorylation. This activation model explains a host of experimental observations. The transient-complex based approach presented here may provide a strategy for designing antagonists and prove useful for elucidating activation mechanisms of other receptors

PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer

There is a strong rationale to therapeutically target the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway in breast cancer since it is highly deregulated in this disease and it also mediates resistance to anti-HER2 therapies. However, initial studies with rapalogs, allosteric inhibitors of mTORC1, have resulted in limited clinical efficacy probably due to the release of a negative regulatory feedback loop that triggers AKT and ERK signaling. Since activation of AKT occurs via PI3K, we decided to explore whether PI3K inhibitors prevent the activation of these compensatory pathways. Using HER2-overexpressing breast cancer cells as a model, we observed that PI3K inhibitors abolished AKT activation. However, PI3K inhibition resulted in a compensatory activation of the ERK signaling pathway. This enhanced ERK signaling occurred as a result of activation of HER family receptors as evidenced by induction of HER receptors dimerization and phosphorylation, increased expression of HER3 and binding of adaptor molecules to HER2 and HER3. The activation of ERK was prevented with either MEK inhibitors or anti-HER2 monoclonal antibodies and tyrosine kinase inhibitors. Combined administration of PI3K inhibitors with either HER2 or MEK inhibitors resulted in decreased proliferation, enhanced cell death and superior anti-tumor activity compared with single agent PI3K inhibitors. Our findings indicate that PI3K inhibition in HER2-overexpressing breast cancer activates a new compensatory pathway that results in ERK dependency. Combined anti-MEK or anti-HER2 therapy with PI3K inhibitors may be required in order to achieve optimal efficacy in HER2-overexpressing breast cancer. This approach warrants clinical evaluation

Sex Differences in Dietary Intake in British Army Recruits undergoing Phase One training

Background: British Army Phase One training exposes men and women to challenging distances of 13.5 km·d⁻¹ vs. 11.8 km·d⁻¹ and energy expenditures of ~4000 kcal·d⁻¹ and ~3000 kcal·d⁻¹, respectively. As such, it is essential that adequate nutrition is provided to support training demands. However, to date, there is a paucity of data on habitual dietary intake of British Army recruits. The aims of this study were to: (i) compare habitual dietary intake in British Army recruits undergoing Phase One training to Military Dietary Reference Values (MDRVs), and (ii) establish if there was a relative sex difference in dietary intake between men and women. Method: Researcher led weighed food records and food diaries were used to assess dietary intake in twenty-eight women (age 21.4 ± 3.0 yrs., height: 163.7 ± 5.0 cm, body mass 65.0 ± 6.7 kg), and seventeen men (age 20.4 ± 2.3 yrs., height: 178.0 ± 7.9 cm, body mass 74.6 ± 8.1 kg) at the Army Training Centre, Pirbright for 8-days in week ten of training. Macro and micronutrient content were estimated using dietary analysis software (Nutritics, Dublin) and assessed via an independent sample t-test to establish if there was a sex difference in daily energy, macro or micronutrient intakes. Results: Estimated daily energy intake was less than the MDRV for both men and women, with men consuming a greater amount of energy compared with women (2846 ± 573 vs. 2207 ± 585 kcal·day⁻¹, p0.030, ES=0.67). There were no differences in dietary fat intake between men and women (1.5 ± 0.2 vs. 1.5 ± 0.5 g·kg⁻¹·day⁻¹, p=0.483, ES=0.00). Conclusions: Daily EI in men and women in Phase One training does not meet MDRVs. Interventions to increase macronutrient intakes should be considered along with research investigating the potential benefits for increasing different macronutrient intakes on training adaptations