Impact of lymph node dissection on the efficacy of immune checkpoint inhibitors in patients with postoperative recurrence of non-small cell lung cancer.

Background: The effect of lymph node dissection (LND) on the efficacy of immune checkpoint inhibitor (ICI) remains unclear. The purpose of this study was to examine the difference in the effect of ICI between patients with non-small cell lung cancer (NSCLC) according to the extent of LND performed in surgery prior to postoperative recurrence. Methods: A total of 134 patients with postoperative recurrence (surgery group, n=26) or unresectable advanced lung cancer (non-surgery group, n=108) who were treated with ICIs between January 2016 and December 2022 were included for analysis. In the surgery group, 16 patients underwent systematic LND, whereas the remaining 10 patients underwent selective LND. Progression-free survival with ICI treatment (ICI-PFS) and overall survival (OS) were compared between the surgery and non-surgery groups and between the systematic and selective LND groups using the inverse probability of treatment weighting (IPTW) method to adjust for patient background characteristics. Results: In the IPTW-adjusted analysis, the 2-year PFS rate with ICI treatment was 31.2% in the surgery group and 27.3% in the non-surgery group (P=0.19); the corresponding 2-year OS rates were 69.6% and 62.2%, respectively (P=0.10). In the surgery group, the 2-year PFS rates under ICI were 20.0% in the systematic LND group and 45.7% in the selective LND group (P=0.03). Conclusions: IPTW-adjusted analysis indicated no difference in prognosis between patients with postoperative recurrence and those with advanced unresectable lung cancer. However, in patients with postoperative recurrence, the extent of LND was a significant predictor of ICI-PFS. These findings suggest that systematic LND may reduce the efficacy of ICI, indicating that preoperative ICI administration may be warranted.

A tailored tetravalent peptide displays dual functions to inhibit amyloid ß production and aggregation.

Inhibition of amyloid-ß peptide (Aß) accumulation in the brain is a promising approach for treatment of Alzheimer's disease (AD). Aß is produced by ß-secretase and γ-secretase in endosomes via sequential proteolysis of amyloid precursor protein (APP). Aß and APP have a common feature to readily cluster to form multimers. Here, using multivalent peptide library screens, we identified a tetravalent peptide, LME-tet, which binds APP and Aß via multivalent interactions. In cells, LME-tet-bound APP in the plasma membrane is transported to endosomes, blocking Aß production through specific inhibition of ß-cleavage, but not γ-cleavage. LME-tet further suppresses Aß aggregation by blocking formation of the ß-sheet conformation. Inhibitory effects are not observed with a monomeric peptide, emphasizing the significance of multivalent interactions for mediating these activities. Critically, LME-tet efficiently reduces Aß levels in the brain of AD model mice, suggesting it may hold promise for treatment of AD.

Docosahexaenoic Acid Selectively Suppresses U46619- and PGF2α-Induced Contractions in Guinea Pig Tracheal Smooth Muscles.

We investigated the potential inhibitory effects of docosahexaenoic acid (DHA) on the contractions of guinea pig tracheal smooth muscles in response to U46619 (a thromboxane A2 (TXA2) mimetic) and prostaglandin F2α (PGF2α) to examine whether this n-3 polyunsaturated fatty acid suppresses prostanoid-induced tracheal contractions. DHA (3 × 10-5 M) significantly suppressed tracheal contractions elicited by lower concentrations of U46619 (10-8 M) and PGF2α (5 × 10-7 M) (vs. control), although it did not suppress the contractions induced by higher concentrations (U46619: 10-7 M; PGF2α: 10-5 M). Supporting these findings, DHA (4 × 10-5 M/6 × 10-5 M) shifted the concentration-response curves for U46619 (10-9-10-6 M) and PGF2α (10-8-10-5 M) to the right. However, the slope of the regression line in the Schild plot of DHA vs. U46619/PGF2α was larger than unity. The tracheal contractions induced by U46619 (10-8 M) and PGF2α (5 × 10-7 M) were significantly suppressed by the prostanoid TP receptor antagonist SQ 29,548 (10-6 M) (vs. ethanol-treated). In contrast, DHA (4 × 10-5 M) did not show significant inhibitory effects on the contractions induced by acetylcholine (10-8-10-4 M), histamine (10-8-10-4 M), and leukotriene D4 (10-11-10-7 M) (vs. ethanol-treated). These findings indicate that DHA selectively suppresses tracheal contractions induced by U46619 and PGF2α. Therefore, DHA may be a useful therapeutic agent against asthma associated with tracheal/bronchial hyper-constriction caused by prostanoids including TXA2 and PGF2α.

Pharmacological evidence showing significant roles for potassium channels and CYP epoxygenase metabolites in the relaxant effects of docosahexaenoic acid on the rat aorta contracted with U46619.

Docosahexaenoic acid (DHA) shows more pronounced relaxation when blood vessel is contracted with prostanoid receptor agonists than other stimulants. The present study was carried out to obtain information on the mechanisms underlying prostanoid receptor-selective relaxant action of DHA, particularly focusing on the possible roles for K(+) channels and its CYP epoxygenase (EOX) metabolites. In endothelium-denuded rat thoracic aorta, DHA (10(-5) M) almost completely relaxed U46619 (a thromboxane A2 (TP) receptor agonist)-contracted muscle without substantially affecting noradrenaline (NA)-induced contraction. DHA-induced relaxation was not affected by a large conductance, calcium- and voltage-activated K(+) (BK) channels inhibitor iberiotoxin (IbTX, 10(-7) M) but was almost abolished by high-KCl (8×10(-2) M) or 10(-2) M tetraethylammonium (TEA) which non-selectively inhibits K(+) channel activity. DHA also prominently relaxed U46619-contracted aorta even in the presence of CYP inhibitors (SKF525A or miconazole, each at 10(-5) M). However, in the presence of these CYP inhibitors, the relaxant action of DHA was not affected by 10(-2) M TEA. In supporting a significant role for CYP EOX metabolites in the blood vessel relaxation to DHA, 16,17-epoxy docosapentaenoic acid (16,17-EpDPE), but not 19,20-EpDPE, showed a potent relaxation in U46619-contracted aorta, and this action was significantly attenuated by 10(-2) M TEA. The present findings suggest that the relaxant action of DHA shown in the rat aorta contracted through the stimulation with TP receptor is generated by DHA itself and its CYP EOX metabolites. The relaxant effect of DHA metabolites seems to be partly triggered by the activation of K(+) channels though the role for BK channel is insignificant.