Immune complexome analysis of serum samples from non-small-cell lung cancer patients identifies predictive biomarkers for nivolumab therapy.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have achieved important outcomes in cancer treatment. However, current clinical biomarker tests are not suitable for some patients because they require tumor tissues and have poor predictive value for treatment responses. Therefore, the identification of biomarkers that enable screening tests in all patients is necessary. METHODS: We performed an immune complexome analysis of non-small cell lung cancer patients treated with nivolumab to comprehensively identify and compare antigens incorporated into immune complexes (IC-antigens) in serum samples from the responders (n = 15) and non-responders (n = 20). Additionally, combinations of IC-antigens characteristic to the responder group were evaluated by logistic regression analysis and receiver operating characteristics curves to examine their predictiveness for ICI treatment responses. RESULTS: The combination of predictive biomarkers detected before treatment was profilin-1, purine nucleoside phosphorylase, alpha-enolase, and nucleoside diphosphate kinase A [p = 0.0043, odds ratio = 2.26, 95% confidence interval (CI) = 1.19-4.28, area under the curve = 0.76]. The combination of predictive biomarkers detected after treatment was peptidyl-prolyl cis-trans isomerase A, ubiquitin-like modifier-activating enzyme 1, complement component C8 beta chain, and apolipoprotein L1 (p = 0.0039, odds ratio = 2.56, 95% CI = 1.25-5.23, area under the curve = 0.77). CONCLUSION: Combinations of serum IC-antigens may predict the therapeutic effect of nivolumab in non-small cell lung cancer patients.

Optimization of pH Elution Conditions in Immune Complexome Analysis for Comprehensive Identification of Immune Complex Antigens.

The identification of antigens incorporated into immune complexes (IC-antigens) is important for studying the pathophysiology of immunological diseases. Immune complexome analysis identifies IC-antigens by analyzing ICs collected from biological fluids by IC-capturing beads. In this study, we optimized the method to improve its comprehensiveness while maintaining selectivity for IC-antigens by comparing the number of identified peptides (model IC experiment) or proteins (human pooled serum) eluted from Protein G beads using different pH solutions (pH 2.0 - 11.0).

Diazepam reduces both arterial blood pressure and muscle sympathetic nerve activity in human.

It is known that benzodiazepines have a hypotensive effect, but the mechanism has not been well elucidated yet. To clarify whether this effect is due to central or peripheral mechanism, we administered 5 mg of diazepam or saline intravenously to healthy volunteers and assessed the change in blood pressure, heart rate, muscle sympathetic nerve activity and heart rate variability. After diazepam administration, systolic and mean blood pressure decreased significantly. Muscle sympathetic nerve activity was also significantly reduced but heart rate did not change, whereas the variables of spectral analysis of heart rate variability did not show significant change. We concluded that the hypotensive effect of diazepam in human is mainly due to the central mechanism.

Sleep habits of students attending elementary schools, and junior and senior high schools in Akita prefecture.

It is widely accepted that students in Japan sleep fewer hours than what they actually need. However, epidemiological data on sleep habits among students are scarce. The sleep habits and related problems among 1650 students in Akita prefecture were studied. The results revealed that schoolchildren attending elementary schools seemed to sleep for a sufficient number of hours, whereas students attending junior or senior high schools were not sleeping enough. In particular, approximately half of the students attending senior high schools answered that they slept 6 h or less on weekdays and nodded off during classes more than twice a week.

Hypocretin-1 (orexin-A) concentrations in cerebrospinal fluid are low in patients with Guillain-Barré syndrome.

It is reported that cerebrospinal fluid (CSF) hypocretin-1 (orexin-A) concentrations in patients with narcolepsy are significantly low. Human narcolepsy is also known to be closely associated with a specific human histocompatibility leukocyte antigen (HLA), suggesting that autoimmunity is involved in the pathophysiology of the disease. Thus, it is important to know whether hypocretin changes are found in definite neuroimmunological diseases such as multiple sclerosis and Guillain-Barré syndrome (GBS). The results of the present study indicate that some patients with GBS have lower levels of CSF hypocretin-1.

Effects of Yoku-kan-san-ka-chimpi-hange on the sleep of normal healthy adult subjects.

Yoku-kan-san-ka-chimpi-hange (YKCH) is a drug used for insomnia in Japanese traditional herbal medicine. The present study evaluated the effects of YKCH on sleep by all-night polysomnography using the double-blind method. Yoku-kan-san-ka-chimpi-hange increased the total sleep time significantly, and tended to cause an increase in sleep efficiency and of stage 2 sleep, as well as a decrease of sleep latency and of stage 3 + 4 sleep. There was no apparent influence on rapid eye movement (REM) sleep. In terms of non-REM sleep, the effects of YKCH exhibit a profile similar to those of benzodiazepines.

Effects of donepezil (Aricept) on the rapid eye movement sleep of normal subjects.

Donepezil (Aricept) is a therapeutic drug for the treatment of Alzheimer's disease (AD). However, there have been only two reports describing the effects of donepezil on sleep as assessed by nocturnal polysomnography (PSG). With this in mind, the effects of donepezil on the sleep of healthy subjects was evaluated using PSG. The results indicated that the percentage of rapid eye movement sleep to total sleep time was increased significantly by a single dose of 5 mg of donepezil when given to healthy subjects immediately before retiring to bed.

Hypocretin-1 (orexin-A) levels in human lumbar CSF in different age groups: infants to elderly persons.

STUDY OBJECTIVES: Recent CSF and postmortem brain hypocretin measurements in human narcolepsy suggest that hypocretin deficiency is involved in the pathophysiology of the disease. In this study, we measured CSF hypocretin-1 levels in various age ranges from infants to elder people to investigate the age-dependent change of hypocretin concentrations. DESIGN: CSF hypocretin levels were compared by age groups and gender. ANOVA was used to examine the influences of these two parameters on CSF hypocretin levels. SETTING: University-based sleep and biology laboratory. PATIENTS OR PARTICIPANTS: Two hundred seventy two patients were included in this study, with 157 males and 115 females (0-79 years old). INTERVENTIONS: CSF samples were obtained by lumber punctures with informed consents. MEASUREMENTS AND RESULTS: Hypocretin-1 levels are not different in respect to gender or age, although our samples constitute a heterogeneous group with various disease conditions. CSF hypocretin-1 levels in infants under 4 months are similar to those in adults. CONCLUSIONS: Early maturation of hypocretin transmission is suggested. No age- or gender-dependent changes in CSF hypocretin is observed.

CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia.

We measured cerebrospinal fluid (CSF) hypocretin-1 levels in 11 patients with narcolepsy-cataplexy, five with narcolepsy without cataplexy and 12 with idiopathic hypersomnia (IHS). All patients were Japanese. As reported in Caucasian patients, undetectable or very low hypocretin-1 levels were observed in most (9 out of 11) Japanese narcolepsy--cataplexy patients. Our hypocretin-deficient narcoleptics included three prepubertal cases within few months after the disease onset. All nine hypocretin-deficient patients were human leuckocyte antigen (HLA) DR2 positive, while two who had normal CSF hypocretin-1 levels were HLA DR2 negative. In contrast, none of the narcolepsy without cataplexy and IHS subjects had undetectable low levels. Low CSF hypocretin-1 is therefore very specific for HLA DR2 positive narcolepsy-cataplexy, and the deficiency is likely to be established at the early stage of the disease.