Olfactory transduction is thought to be mediated by a G protein-coupled increase in intracellular adenosine 3',5'-monophosphate (cAMP) that triggers the opening of cAMP-gated cation channels and results in depolarization of the plasma membrane of olfactory neurons. In olfactory neurons isolated from the channel catfish, Ictalurus punctatus, stimulation with olfactory stimuli (amino acids) elicits an influx of calcium that leads to a rapid increase in intracellular calcium. In addition, in a reconstitution assay a plasma membrane calcium channel has been identified that is gated by inositol-1,4,5-trisphosphate (IP3), which could mediate this calcium influx. Together with previous studies indicating that stimulation with olfactory stimuli leads to stimulation of phosphoinositide turnover in olfactory cilia, these data suggest that an influx of calcium triggered by odor stimulation of phosphoinositide turnover may be an alternate or additional mechanism of olfactory transduction.

The prevalence of serum antibodies to hepatitis C virus (HCV) was assessed by an enzyme-linked immunosorbent assay (ELISA) in 66 patients (46 male and 20 female; mean age +/- SEM, 61.5 +/- 10.1 yr) with idiopathic pulmonary fibrosis (IPF). Nineteen (28.8%) were positive for this test. The frequency of HCV positiveness was significantly higher in the patients with IPF than in the 9,464 control subjects, whose ages were comparable with those of the patients (3.66%, p less than 0.05). Importantly, 12 of the 19 patients with IPF and positive ELISA results (63.2%) had positive results on the Chiron recombinant immunoblotting assay (RIBA), which is known to be more specific for HCV. We judged the 12 perceptible reactions as eight reactive and four indeterminate. When we examined liver function retrospectively, only two of eight patients who tested positive for the HCV had liver dysfunction, suggesting that anti-HCV positivity in IPF was not observed as a result of liver disease. These results lead us to speculate that HCV infection may play an important role in the pathogenesis of IPF, or that the sera of patients with IPF may contain some antibody against an unknown epitope and cross-react with the anti-HCV assay.

To investigate the time-course of changes in transverse relaxation time (T2) and cross-sectional area (CSA) of the quadriceps muscle after a single session of eccentric exercise, magnetic resonance imaging was performed on six healthy male volunteers before and at 0, 7, 15, 20, 30 and 60 min and 12, 24, 36, 48, 72 and 168 h after exercise. Although there was almost no muscle soreness immediately after exercise, it started to increase 1 day after, peaking 1-2 days after the exercise (P < 0.01). Immediately after exercise, T2 increased significantly in the rectus femoris, vastus lateralis and intermedius muscles (P < 0.05) and decreased quickly continuing until 60 min after exercise. At and after the 12th h, a significant increase was perceived again in the T2 values of the vastus lateralis and intermedius muscles (P < 0.01) [maximum 9.3 (SEM 2.8)% and 10.9 (SEM 2.2)%, respectively]. The maximal values were exhibited at 24-36 h after exercise. In contrast, the rectus femoris muscle showed no delayed-stage increase. Also, in CSA, an increase after 12 h was observed in addition to the one immediately after exercise in the vastus lateralis, intermedius and medialis and quadriceps muscles as a whole (P < 0.01), reaching the maximal values at 12-24 h after exercise. The plasma creatine kinase activity remained unchanged up to 24 h after and then increased significantly 48 h after exercise (P < 0.05). Beginning 12 h after exercise, the subjects whose T2 and CSA increased less than the others displayed a faster decrease in muscle soreness.(ABSTRACT TRUNCATED AT 250 WORDS)

BackgroundNivolumab showed a survival benefit for advanced gastric cancer (AGC). However, an acceleration of tumour growth during immunotherapy, (hyperprogressive disease, HPD) has been reported in various cancers. This study reviewed the HPD in patients with AGC treated with nivolumab or irinotecan.MethodsThe subjects of this retrospective study were patients with AGC with measurable lesions, and their tumour growth rates (TGR) during nivolumab or irinotecan were compared with those during prior therapy. HPD was defined as an increase in TGR more than twofold.Results34 and 66 patients received nivolumab and irinotecan in third or later line between June 2009 and September 2018 at our hospital; 22 patients receiving nivolumab had prior treatment with irinotecan, and one patient received irinotecan after nivolumab. Nivolumab and irinotecan showed no differences in disease control rates (38.2% and 34.8%) and in progression-free survival (PFS) (HR 1.1, 95% CI 0.7 to 1.6, p=0.802). The incidence of HPD was slightly higher after nivolumab (29.4%) than after irinotecan (13.5%) (p=0.0656), showing no differences in background between the patients with and without HPD. Compared between HPD and PD other than HPD after nivolumab, the HRs for PFS and overall survival (OS) were 1.1 (95% CI 0.5 to 2.7; p=0.756), and 2.1 (95% CI 0.7 to 5.8; p=0.168), but such clear difference in OS was not observed after irinotecan.ConclusionsHPD was observed more frequently after nivolumab compared with irinotecan, which was associated with a poor prognosis after nivolumab but not so clearly after irinotecan.

A B S T R A C T The electrical properties of olfactory receptor neurons, enzymaticallydissociated from the channel catfish (Ictalurus punctatus), were studied using the whole-cell patch-damp technique. Six voltage-dependent ionic currents were isolated. Transient inward currents (0.1-1.7 nA) were observed in response to depolarizing voltage steps from a holding potential of -80 mV in all neurons examined. They activated between -70 and -50 mV and were blocked by addition of 1 v.M tetrodotoxin (TYX) to the bath or by replacing Na + in the bath with N-methyl-D-glucamine and were classified as Na + currents. Sustained inward currents, observed in most neurons examined when Na + inward currents were blocked with ~ and outward currents were blocked by replacing K + in the pipette solution with Cs ÷ and by addition of 10 mM Ba 2÷ to the bath, activated between -40 and -30 mV, reached a peak at 0 mV, and were blocked by 5 p~M nimodipine. These currents were classified as L-type Ca 2÷ currents. Large, slowly activating outward currents that were blocked by simultaneous replacement of K ÷ in the pipette with Cs ÷ and addition of Ba 2÷ to the bath were observed in all olfactory neurons examined. The outward K ÷ currents activated over approximately the same range as the Na ÷ currents (-60 to -50 mV), but the Na ÷ currents were larger at the normal resting potential of the neurons (-45 _ 11 mV, mean _ SD, n --52). Four different types of K ÷ currents could be differentiated: a Ca2+-activated K ÷ current, a transient K ÷ current, a delayed rectifier K + current, and an inward rectifier K + current. Spontaneous action potentials of varying amplitude were sometimes observed in the cell-attached recording configuration. Action potentials were not observed in whole-cell recordings with normal internal solution (K ÷ = 100 mM) in the pipette, but frequently appeared when K ÷ was reduced to 85 mM. These observations suggest that the membrane potential and action potential amplitude of catfish olfactory neurons are significantly affected by the activity of single channels due to the high input resistance (6.6 -+ 5.2 G~, n = 20) and low membrane capacitance (2.1 -+ 1.1 pF, n = 46) of the cells. Stimulation of voltage-clamped receptor neurons with a mixture of amino acids (100 tzM each of L-arginine, L-alanine, and L-norleucine with or without L-glutamate), which act at independent classes of receptor sites, elicited receptor currents that were heterogeneous in terms of voltage and ion dependence, time course, reversal potential, and sensitivity to drugs, and appeared to result from at least two different processes. These different types of receptor cell responses to odorant amino acids may reflect activation of different transduction pathways.

4049 Background: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. Therefore, in this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab. Methods: The subjects of this study were AGC patients that had received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups. Results: Of the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3–407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that high ALP level (HR = 2.88; 95% CI, 1.51 to 5.51) and absence of irAEs (HR = 3.06, 95% CI, 3.06 to 23.46 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), increased aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). One of the 14 patients experienced the irAE after discontinuation of nivolumab due to progression of disease. There were no grade 4 or 5 adverse events related to nivolumab. Conclusions: Development of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.

No abstract

BackgroundRecent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. In this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab.MethodsThe subjects of this study were AGC patients received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups.ResultsOf the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3–407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that number of metastatic sites ≥2 (HR = 2.15; 95% CI, 1.02 to 4.54), high ALP level (HR = 2.50; 95% CI, 1.27 to 4.54), and absence of irAEs (HR = 9.54, 95% CI, 3.34 to 27.30 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). There were no grade 4 or 5 adverse events related to nivolumab.ConclusionsDevelopment of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.