Prolonged interval between neoadjuvant chemoradiotherapy and esophagectomy does not benefit the outcome in esophageal cancer: a systematic review and meta-analysis.

Whether a prolonged interval between neoadjuvant chemoradiotherapy (nCRT) and esophagectomy could benefits conditions such as rectal cancer, still remains unknown. We therefore performed the current study to evaluate the influence of the interval between nCRT and esophagectomy on the clinical outcomes in patients with esophageal cancer. PubMed and Embase were searched to identify eligible cohort studies. The primary outcome was five-year overall survival (OS), and secondary outcomes included the incidence of anastomotic complications, perioperative mortality, pathologic complete response (pCR) rate, positive circumferential resection margin (CRM) rate, and R0 resection rate. A random-effects model was used for all meta-analyses irrespective of heterogeneity. Ten cohort studies with 2383 patients were included. Overall, the pooled estimate revealed that the prolonged interval has no impact on five-year OS (odds ratio (OR) 0.87, 95% CI 0.66 to 1.14, P = 0.30), with low heterogeneity (PH = 0.78, I2 = 0%). However, it was associated with an increased risk of anastomotic complication (OR 1.71, 95% CI 1.15 to 2.54, P = 0.008), with no effect on perioperative mortality (OR 1.20, 95% CI 0.79 to 1.83, P = 0.40). Additionally, the prolonged interval failed to increase the pCR rate (OR 1.02, 95% CI 0.78 to 1.33, P = 0.89). Even worse, it was correlated with a decreased R0 resection rate (OR 0.60, 95% CI 0.41 to 0.88, P = 0.009) and increased positive CRM rate (OR 2.20, 95% CI 1.44 to 3.36, P < 0.001). This study suggests that the prolonged interval between nCRT and esophagectomy fails to result in better outcomes, and in fact, could worsen clinical outcomes, with increasing anastomotic complications, and undermine resection completeness. However, this conclusion should be treated with caution because of the limitations of retrospective cohort study and substantial clinical heterogeneity. (The study was registered at PRESPERO as CRD42016048210).

Comparative effects of azimilide and ambasilide on the human ether-a-go-go-related gene (HERG) potassium channel.

OBJECTIVE: To evaluate the effects of azimilide and ambasilide on the biophysical properties of the human-ether-a-go-go-related (HERG) channel. METHODS: HERG was stably transfected into Chinese hamster ovary (CHO-K1) cells and currents were measured using a whole cell, voltage-clamp technique. RESULTS: Azimilide had a 'dual effect', inhibiting current at voltage steps above -40 mV and augmenting current at -40 and -50 mV. Tail current inhibition following a step to +30 mV did not vary with temperature (IC(50) 610 nM at 22 degrees C and 560 nM at 37 degrees C). The agonist effect at -50 mV was concentration-dependent and correlated with a hyperpolarizing shift in the V(1/2) of activation (r=0.98, P<0.05). Time constants of inactivation were faster and there was a -10 mV shift in the V(1/2) of steady state inactivation suggestive of open and inactivated state binding. By comparison, ambasilide inhibited HERG channels with lower potency (IC(50) 3.6 microM), in a voltage- and time-dependent but frequency-independent manner (0.03-1 Hz). Ambasilide had no effect on activation or inactivation gating but prolonged both fast and slow components of deactivation consistent with unbinding from the open state. The net effect of both drugs was similar during a voltage ramp which simulated a cardiac action potential. CONCLUSIONS: Inhibition of HERG channels by azimilide and ambasilide exhibits a similar time and voltage-dependence. While both exhibit affinity for the open state, azimilide also binds to inactivated channels.

Inhibition of HERG potassium channels by the antimalarial agent halofantrine.

Halofantrine is a widely used antimalarial agent which has been associated with prolongation of the 'QT interval' of the electrocardiogram (ECG), torsades de pointes and sudden death. Whilst QT prolongation is consistent with halofantrine-induced increases in cardiac ventricular action potential duration, the cellular mechanism for these observations has not been previously reported. The delayed rectifier potassium channel, I(Kr), is a primary site of action of drugs causing QT prolongation and is encoded by the human-ether-a-go-go-related gene (HERG). We examined the effects of halofantrine on HERG potassium channels stably expressed in Chinese hamster ovary (CHO-K1) cells. Halofantrine blocked HERG tail currents elicited on repolarization to -60 mV from +30 mV with an IC(50) of 196.9 nM. The therapeutic plasma concentration range for halofantrine is 1.67-2.98 microM. Channel inhibition by halofantrine exhibited time-, voltage- and use-dependence. Halofantrine did not alter the time course of channel activation or deactivation, but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid-activation potential of steady-state inactivation. Block was enhanced by pulses that render channels inactivated, and channel blockade increased with increasing duration of depolarizing pulses. We conclude that HERG channel inhibition by halofantrine is the likely underlying cellular mechanism for QT prolongation. Our data suggest preferential binding of halofantrine to the open and inactivated channel states.

Inhibition of HERG channels stably expressed in a mammalian cell line by the antianginal agent perhexiline maleate.

Perhexiline has been used as an anti-anginal agent for over 25 years, and is known to cause QT prolongation and torsades de pointes. We hypothesized that the cellular basis for these effects was blockade of I(Kr). A stable transfection of HERG into a CHO-K1 cell line produced a delayed rectifier, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. Perhexiline caused voltage- and frequency-dependent block of HERG (IC50 7.8 microM). The rate of inactivation was increased and there was a 10 mV hyperpolarizing shift in the voltage-dependence of steady-state inactivation, suggestive of binding to the inactivated state. In conclusion, perhexiline potently inhibits transfected HERG channels and this is the probable mechanism for QT prolongation and torsades de pointes. Channel blockade shows greatest affinity for the inactivated state.

Blockade by N-3 polyunsaturated fatty acid of the Kv4.3 current stably expressed in Chinese hamster ovary cells.

1. The Kv4.3 gene is believed to encode a large proportion of the transient outward current (Ito), responsible for the early phase of repolarization of the human cardiac action potential. There is evidence that this current is involved in the dispersion of refractoriness which develops during myocardial ischaemia and which predisposes to the development of potentially fatal ventricular tachyarrhythmias. 2. Epidemiological, clinical, animal, and cellular studies indicate that these arrhythmias may be ameliorated in myocardial ischaemia by n-3 polyunsaturated fatty acids (n-3 PUFA) present in fish oils. 3. We describe stable transfection of the Kv4.3 gene into a mammalian cell line (Chinese hamster ovary cells), and using patch clamp techniques have shown that the resulting current closely resembles human Ito. 4. The current is rapidly activating and inactivating, with both processes being well fit by double exponential functions (time constants of 3.8 +/- 0.2 and 5.3 +/- 0.4 ms for activation and 20.0 +/- 1.2 and 96.6+/-6.7 ms for inactivation at +45 mV at 23 degrees C). Activation and steady state inactivation both show voltage dependence (V1/2 of activation= -6.7+/-2.5 mV, V1,2 of steady state inactivation= -51.3+/-0.2 mV at 23 degrees C). Current inactivation and recovery from inactivation are faster at physiologic temperature (37 degrees C) compared to room temperature (23 degrees C). 5. The n-3 PUFA docosahexaenoic acid blocks the Kv4.3 current with an IC50 of 3.6 micromol L(-1). Blockade of the transient outward current may be an important mechanism by which n-3 PUFA provide protection against the development of ventricular fibrillation during myocardial ischaemia.

Electroretinographic oscillatory potentials in different aged rats: an analysis in the domains of time and frequency.

OBJECTIVES: Electroretinographic Oscillatory Potentials (Ops) are considered to be the optimal parameter to study the retinal circulation disturbances the present we compared parameters of OPs between different aged rats under dark adaptation. METHODS: The scotopic ERG were performed in anaesthetized rats aged 3, 12, 24 months. According a window of collective power spectrum field of the OPs was isolated by using the FFT and IFFT of the spectrum analysis program. The parameters in the time and frequency domains were calculated. RESULTS: Results showed that the amplitudes of wavelets and the summed amplitudes of OPs declined with the increase of age. A reduction of the total power and dominated power of OPs was also found after the FFT. But implicit time of each OP and dominant frequency did not change obviously. CONCLUSIONS: The present study indicated that change of OPs of rat might be related to senile degeneration of the retina and circulative deficiency in retina in elder rats.