Post-reflux swallow-induced peristaltic wave (PSPW): physiology, triggering factors and role in reflux clearance in healthy subjects.

BACKGROUND AND AIMS: The underlying physiology of post-reflux swallow-induced peristaltic wave (PSPW) is unclear. We aimed to: 1) calculate the probability of a random association between reflux and PSPW; 2) characterize factors that could underlie triggering of PSPW and 3) assess the chemical clearance effect of PSPW in healthy asymptomatic subjects. METHODS: A total of 251 impedance-pH tracings from healthy asymptomatic subjects were analysed. Twenty consecutive tracings from this pool with 20-40 reflux episodes/24 h and a PSPW index higher than 50% were separately analyzed to evaluate the probability of a random association between reflux and PSPW. The characteristics of reflux episodes followed by a PSPW were compared with those not associated with PSPW. RESULTS: A mean time interval of 29.3 s between a reflux episode and the first swallow captured 71% of total reflux episodes, and 67% of accompanying swallows were non-random. Compared to reflux without PSPW, reflux episodes with PSPW were more frequently acidic (P = 0.048), mixed with gas (P < 0.0001), of high proximal extent (P < 0.0001), while awake (P < 0.0001), and with shorter chemical clearance time (P = 0.040). High proximal extent, gas presence and occurring while awake were independent factors associated with PSPW (P < 0.0001). CONCLUSION: Using a time window between reflux and PSPW of around 30 s, the probability of a chance association is around 30%. Reflux episodes with high proximal extent, containing gas and occurring while awake are important factors associated with PSPW in healthy subjects. Reflux episodes with PSPW have a shorter chemical clearance time.

The breast cancer oncogene IKKε coordinates mitochondrial function and serine metabolism.

IκB kinase ε (IKKε) is a key molecule at the crossroads of inflammation and cancer. Known to regulate cytokine secretion via NFκB and IRF3, the kinase is also a breast cancer oncogene, overexpressed in a variety of tumours. However, to what extent IKKε remodels cellular metabolism is currently unknown. Here, we used metabolic tracer analysis to show that IKKε orchestrates a complex metabolic reprogramming that affects mitochondrial metabolism and consequently serine biosynthesis independently of its canonical signalling role. We found that IKKε upregulates the serine biosynthesis pathway (SBP) indirectly, by limiting glucose-derived pyruvate utilisation in the TCA cycle, inhibiting oxidative phosphorylation. Inhibition of mitochondrial function induces activating transcription factor 4 (ATF4), which in turn drives upregulation of the expression of SBP genes. Importantly, pharmacological reversal of the IKKε-induced metabolic phenotype reduces proliferation of breast cancer cells. Finally, we show that in a highly proliferative set of ER negative, basal breast tumours, IKKε and PSAT1 are both overexpressed, corroborating the link between IKKε and the SBP in the clinical context.