•The mouse parafacial zone does not contain any slow-wave sleep-active neurons.•The mouse parafacial zone is not a medullary hypnogenic center.•The parafacial neurons may play a role in the control ...of masseter, facial, and/or lingual muscles during sleep and waking.
Although recent studies have reported that gamma-aminobutyric acid (GABA) neurons in the parafacial zone (PZ) of the rostral medulla are needed for the induction of slow-wave sleep (SWS) and that the PZ is a medullary SWS-promoting center, it remains unknown whether the PZ contains SWS-active or sleep-promoting neurons. In the present study, a total of 125 neurons were recorded, for the first time, in non-anesthetized, head-restrained mice during the complete wake–sleep cycle throughout the PZ of the rostral medulla. The vast majority (87.2%) of the neurons displayed increased activity during both wakefulness (W) and paradoxical (or rapid eye movement) sleep (PS) compared to during SWS (W/PS-active neurons) and a few (8.0%) discharged phasically and selectively during PS (PS-active neurons), but none discharged maximally during SWS (SWS-active neurons) or displayed a higher rate of spontaneous discharge during both SWS and PS than during W (SWS/PS-active neurons). These findings do not support the view that the GABAergic PZ is a medullary SWS-promoting center.
A total of 668 single units were recorded in the mouse periaqueductal gray (PAG) and adjacent deep mesencephalic nucleus (DpMe) to determine their role in the switching of sleep–wake states, that is, ...wakefulness (W), slow‐wave sleep (SWS) and paradoxical (or rapid eye movement) sleep (PS) in general, and, in particular, to determine whether PS‐on and PS‐off neurons involved in PS state switching are present in these structures and to identify neuronal substrates for the SWS‐PS switching mediated by DpMe neurons. Both structures were found to contain similar percentages of W/PS‐active neurons, which discharge at a higher rate during W and PS than during SWS, while W‐active neurons, which discharge maximally during W, were found mainly in the PAG. Both also contained similar percentages of SWS/PS‐active neurons, which discharge at higher rates during SWS and PS than during W, and PS‐active neurons, which discharge maximally during PS, while SWS‐active neurons, which discharge maximally during SWS, were found almost exclusively in the PAG. Both structures contained virtually no PS‐on or PS‐off neurons, which, respectively, discharge or cease firing selectively and tonically just prior to, and during, PS. Unlike the PAG, the DpMe contained many SWS/PS‐on neurons, which discharge selectively at high rates during SWS and PS, but show a decrease in discharge rate at the transition from SWS to PS. Analysis of discharge profiles and trends in spike activity at the state transitions strongly suggests that PAG and DpMe neurons play an important role in the W‐SWS, SWS‐PS and/or PS‐W switches.
This single‐unit recording study in mice shows that neither the PAG nor the adjacent DpMe contains presumed GABAergic PS‐on and PS‐off neurons, which have previously been postulated to be present in these structures. Instead, these two regions were found to contain presumed GABAergic or glutamatergic state‐specific neurons, that is, SWS‐selective (SWS‐on), SWS/PS‐selective (SWS/PS‐on), W/PS‐selective and W‐selective neurons, which may play an important role in the W‐SWS, SWS‐PS and PS‐W switches.
Highlights • The mouse SubLDT contains both PS-on and SWS/PS-on neurons. • PS-on and SWS/PS-on neurons are heterogeneous. • PS-on neurons may play an important role in PS generation. • SWS/PS-on ...neurons may play an important role in the sleep switch. • The mouse SubLDT may be homologous to the cat peri-LCα.
The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired ...resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3months for T790M-negative and T790M-positive patients, respectively (P=0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3months for patients with a PD-L1 expression level of≥1% or<1%, respectively (P=0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of≥10% and≥50%. The proportion of tumors with a PD-L1 level of≥10% or≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
Abstract We have recorded, for the first time, in non-anesthetized, head-restrained mice, a total of 407 single units throughout the dorsal raphe nucleus (DR), which contains serotonin ...(5-hydroxytryptamine, 5-HT) neurons, during the complete wake-sleep cycle. The mouse DR was found to contain a large proportion (52.0%) of waking (W)-active neurons, together with many sleep-active (24.8%) and W/paradoxical sleep (PS)-active (18.4%) neurons and a few state-unrelated neurons (4.7%). The W-active, W/PS-active, and sleep-active neurons displayed a biphasic narrow or triphasic broad action potential. Of the 212 W-active neurons, 194 were judged serotonergic (5-HT W-active neurons) because of their triphasic long-duration action potential and low rate of spontaneous discharge, while the remaining 18 were judged non-serotonergic (non-5-HT W-active neurons) because of their biphasic narrow action potential and higher rate of spontaneous discharge. The 5-HT W-active neurons were subdivided into four groups, types I, II, III, and IV, on the basis of differences in firing pattern during wake-sleep states, their waking selectivity of discharge being in the order type I>type II>type III>type IV. During the transition from sleep to waking, the vast majority of waking-specific or waking-selective type I and II neurons discharged after onset of waking, as seen with non-5-HT W-specific neurons. Triphasic DR W/PS-active neurons were characterized by a low rate of spontaneous discharge and a similar distribution to that of tyrosine hydroxylase-immunoreactive, dopaminergic neurons. Triphasic DR slow-wave sleep (SWS)-active and SWS/PS neurons were also characterized by slow firing. At the transition from sleep to waking, sleep-selective neurons with no discharge activity during waking ceased firing before onset of waking, while, at the transition from waking to sleep, they fired after onset of sleep. The present study shows a marked heterogeneity and functional topographic organization of both serotonergic and non-serotonergic mouse DR neurons and suggests that they play different roles in behavioral state control and the sleep/waking switch.
Highlights ► Mouse LDT and SubLDT Ach neurons are characterized by a triphasic broad-spike form. ► LDT and SubLDT Ach neurons display a waking/paradoxical sleep-active profile. ► LDT and SubLDT Ach ...neurons exhibit a single-spike mode and burst mode. ► The Ach neurons play an important role in both tonic and phasic processes of arousal. ► The LDT and SubLDT neuronal discharge anticipates the oncoming waking or sleep state.
Abstract The median preoptic nucleus (MnPO), part of the anteroventral third ventricular region, plays a key role in body fluid homeostasis and cardiovascular regulation. Recently, a cluster of ...neurons showing sleep-related c-fos immunoreactivity was found in the rat MnPO, and a subsequent electrophysiological study found that nearly 76% of rat MnPO neurons exhibit increased discharge during sleep. In a recent single unit recording study in mice, we found that sleep-active neurons are not localized in any specific region of the preoptic/basal forebrain (POA/BFB). However, the discharge profiles of mouse MnPO neurons across wake-sleep states remained to be determined. In this study, we therefore examined whether the mouse MnPO contains a high proportion of sleep-active neurons and constitutes a distinct cluster of sleep-promoting neurons in the median preoptic region. We recorded a total of 234 single units in the MnPO, the laterally adjacent peri-MnPO, the dorsally adjacent medial septum (MS), and the ventrally adjacent periventricular (Pe)/medial preoptic (MPO) area (Pe/MPO). We found that the MnPO contained similar proportions of sleep-active (31.9%) and waking (W)-active (33.0%) neurons, together with many waking/paradoxical sleep (W/PS)-active neurons (23.4%), whereas the Pe/MPO and MS contained a high proportion of sleep-active neurons (66.0 and 62.9%, respectively), while the peri-MnPO contained a high proportion of W-active neurons (57.1%). In the MnPO, both W-active and W/PS-active neurons were distributed throughout the nucleus, whereas sleep-active neurons were mostly located on its border. Only slowly discharging (<5 Hz) slow-wave sleep (SWS)/PS-selective neurons were found in the MnPO. During the transition from W to SWS, all of these SWS/PS-selective neurons fired not before, but after, sleep onset, with a gradual increase in discharge rate. In addition to its well-known homeostatic and cardiovascular functions, the MnPO might modulate the sleep-waking cycle by playing different roles in sleep/wake state regulation.
Highlights • The mouse SCN is composed of a heterogeneous population of neurons. • Both regularly and irregularly firing neurons are present in the mouse SCN in vivo. • The SCN neurons display ...different discharge profiles across wake–sleep states. • The SCN neurons have functional topographic organization within the nucleus. • The SCN may play a potential role in both circadian and sleep–wake regulation.
Over the past 3 decades, thermal stress events have damaged corals globally. Few studies, however, have tracked the recovery process or assessed whether winners in the short term are also winners in ...the long term. In the present study, we repeatedly sampled a coral assemblage over a 14 yr period, from 1997 to 2010, through 2 thermal stress events (in 1998 and 2001). Our goal was to examine the consistency of short-term winner and loser outcomes over the recovery period. Although species richness had recovered after 10 yr, the reef composition had changed, and few pocilloporids were to be found. The short-term winners were the thermally tolerant encrusting and massive coral morphologies (Poritesand faviids) andAcroporacolonies <5 cm in diameter. Long-term winners were revealed as (1) thermally tolerant, locally persistent colonies, (2) remnant survivors that rapidly regrew, and (3) regionally persistent colonies that recruited.
Cancer of unknown primary (CUP) has a poor prognosis. Given the recent approval of immune checkpoint inhibitors for several cancer types, we carried out a multicenter phase II study to assess the ...efficacy of nivolumab for patients with CUP.
Patients with CUP who were previously treated with at least one line of systemic chemotherapy constituted the principal study population. Previously untreated patients with CUP were also enrolled for exploratory analysis. Nivolumab (240 mg/body) was administered every 2 weeks for up to 52 cycles. The primary endpoint was objective response rate in previously treated patients as determined by blinded independent central review according to RECIST version 1.1.
Fifty-six patients with CUP were enrolled in the trial. For the 45 previously treated patients, objective response rate was 22.2% 95% confidence interval (CI), 11.2% to 37.1%, with a median progression-free survival and overall survival of 4.0 months (95% CI, 1.9-5.8 months) and 15.9 months (95% CI, 8.4-21.5 months), respectively. Similar clinical benefits were also observed in the 11 previously untreated patients. Better clinical efficacy of nivolumab was apparent for tumors with a higher programmed death-ligand 1 expression level, for those with a higher tumor mutation burden, and for microsatellite instability-high tumors. In contrast, no differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin. Adverse events were consistent with the known safety profile of nivolumab. No treatment-related death was observed.
Our results demonstrate a clinical benefit of nivolumab for patients with CUP, suggesting that nivolumab is a potential additional therapeutic option for CUP.
•Nivolumab demonstrated clinical benefits in a statistically assessable number of patients with CUP.•Objective response rate was 22.2% in previously treated patients with CUP, which met the study primary endpoint.•Benefits were more apparent in patients with known biomarkers for ICIs, but also observed in those without such markers.•No differences in efficacy were apparent between tumor subgroups based on estimated tissue of origin.•Nivolumab could be an additional therapeutic option for these unmet medical needs.
PDF
