Data from whole-animal tests of the downstream outcomes would not be required for risk assessment of these outcomes.
Hence, although S phase arrest activates the initial stages of the DDR pathway similarly in both cell types, the downstream outcomes are different: fibroblasts undergo apoptosis, whereas hMECs activate a senescence-like programme but do not die.
In considering an upstream biological end point that is measured as a continuous variable [e.g., thyroid-stimulating hormone (TSH ], what approach should be taken in deciding whether a certain degree of upstream change will lead to the overt downstream outcomes (e.g., neurodevelopmental change)?
It has been unclear whether the crossover bias in C. elegans is a consequence of DSB distribution, or instead reflects a mechanism that biases the downstream repair outcome of DSBs.
Studies suggest that early ventilator settings influence downstream outcome of critically ill patients [34].
Biochemically, the signaling state of a protein can be examined in the absence of such reagents directly by antibody immunoprecipitation of the protein followed by an in vitro kinase assay with substrate and radioactively labeled ATP or indirectly by transfection with a reporter construct that measures a downstream outcome of kinase activation such as ERK activation of AP-1.
They include 18 targets and 48 progress indicators that, among other things, monitor both upstream root causes of poverty and poor health, and the downstream health outcomes such as child mortality.
Infectious disease was split between acute infections which could employ final outcomes (cure rates) for 64% of these submissions, and chronic infections where the time horizon of downstream outcomes required use of surrogates (36% of submissions: hepatitis B and C).
However, these were therapeutic areas for which outcomes were clearly a challenge: there was considerable consternation across agencies regarding hepatitis drugs because of the long horizon for downstream outcomes, and with respect to pulmonary arterial hypertension drugs, because of uncertain value of improved exercise tolerance and any putative relationship to overall survival.
We must subtract the 'background noise' of pre-existing conditions, and must specifically explore both the potential mechanisms of action for new decrements and the numerous interactions between different downstream outcomes.
