Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific).

Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations.

Unlabelled: Resistance to immune checkpoint blockade remains challenging in patients with non-small cell lung cancer (NSCLC). Tumor-infiltrating leukocyte (TIL) quantity, composition, and activation status profoundly influence responsiveness to cancer immunotherapy. This study examined the immune landscape in the NSCLC tumor microenvironment by analyzing TIL profiles of 281 fresh resected NSCLC tissues.

A long-acting anti-IL-8 antibody improves inflammation and fibrosis in endometriosis.

Current pharmacological treatments for endometriosis are limited to hormonal agents that can relieve pain but cannot cure the disease. Therefore, the development of a disease-modifying drug for endometriosis is an unmet medical need. By studying human endometriotic samples, we found that the progression of endometriosis was associated with the development of inflammation and fibrosis.

Combination of T cell-redirecting bispecific antibody ERY974 and chemotherapy reciprocally enhances efficacy against non-inflamed tumours.

Identifying a strategy with strong efficacy against non-inflamed tumours is vital in cancer immune therapy. ERY974 is a humanized IgG4 bispecific T cell-redirecting antibody that recognizes glypican-3 and CD3. Here we examine the combination effect of ERY974 and chemotherapy (paclitaxel, cisplatin, and capecitabine) in the treatment of non-inflamed tumours in a xenograft model.

Determination of starting dose of the T cell-redirecting bispecific antibody ERY974 targeting glypican-3 in first-in-human clinical trial.

Currently, ERY974, a humanized IgG4 bispecific T cell-redirecting antibody recognizing glypican-3 and CD3, is in phase I clinical trials. After a first-in-human clinical trial of an anti-CD28 agonist monoclonal antibody resulting in severe life-threatening adverse events, the minimal anticipated biological effect level approach has been considered for determining the first-in-human dose of high-risk drugs. Accordingly, we aimed to determine the first-in-human dose of ERY974 using both the minimal anticipated biological effect level and no observed adverse effect level approaches.

Ultra high-resolution seawater density sensor based on a refractive index measurement using the spectroscopic interference method.

The interference method is one of the most sensitive methods for measuring the refractive index of seawater. We developed a state-of-the-art density sensor for seawater measurements based on measuring the refractive index by the interference method. The resolution of the density sensor is 0.

Engineering a bispecific antibody with a common light chain: Identification and optimization of an anti-CD3 epsilon and anti-GPC3 bispecific antibody, ERY974.

The antibody drug market is rapidly expanding, and various antibody engineering technologies are being developed to create antibodies that can provide better benefit to patients. Although bispecific antibody drugs have been researched for more than 30 years, currently only a limited number of bispecific antibodies have achieved regulatory approval. Of the few successful examples of industrially manufacturing a bispecific antibody, the "common light chain format" is an elegant technology that simplifies the purification of a whole IgG-type bispecific antibody.

An anti-glypican 3/CD3 bispecific T cell-redirecting antibody for treatment of solid tumors.

Cancer care is being revolutionized by immunotherapies such as immune checkpoint inhibitors, engineered T cell transfer, and cell vaccines. The bispecific T cell-redirecting antibody (TRAB) is one such promising immunotherapy, which can redirect T cells to tumor cells by engaging CD3 on a T cell and an antigen on a tumor cell. Because T cells can be redirected to tumor cells regardless of the specificity of T cell receptors, TRAB is considered efficacious for less immunogenic tumors lacking enough neoantigens.

[Primary insomnia].

Primary insomnia is relatively common. According to The International Classification of Sleep Disorders, primary insomnia is a syndrome mainly composed of psychophysiological insomnia, paradoxical insomnia and idiopathic insomnia. Primary insomnia is difficulty initiating sleep (sleep onset insomnia), difficulty maintaining sleep (mid-sleep awakening, early morning awakening) or chronic non restorative sleep, which persist longer than three weeks despite having adequate opportunity for sleep and result in impaired daytime functioning.

Risk factors for obstructive sleep apnea syndrome screening in mood disorder patients.

Aims: Previous studies have reported that the incidence of obstructive sleep apnea syndrome (OSAS) in patients with depression is higher than in the general population. We examined the risk factors to predict OSAS in mood disorder patients with depressive symptoms.

Method: We conducted polysomnography for patients who satisfied the following criteria: (i) diagnosis of major depressive disorder or bipolar disorder according to the Mini-International Neuropsychiatric Interview (MINI); (ii) a score of > or =10 on the Hamilton Rating Scale for Depression (HAM-D); (iii) fulfillment of either (a) or (b) below: (a) at least one of the following: severe snoring, witnessed apnea during sleep, excessive daytime sleepiness; (b) at least one of the following plus an oxygen desaturation index of 4% > or =5 times/h by pulse oximeter: mild snoring, sleep disturbance, headache, high blood pressure.

[Excessive daytime sleepiness and low CSF orexin-A/hypocretin-I levels in a patient with probable progressive supranuclear palsy].

We report a 74-year-old woman with excessive daytime sleepiness (EDS) who were diagnosed as probable progressive supranuclear palsy (PSP). Her EDS mimicked narcolepsy without cataplexy, because multiple sleep latency tests showed short latencies, human leukocyte antigen testing was positive for DR2/DQB1, and orexin A (hypocretin-I) concentration in her cerebrospinal fluid was undetectable. In PSP, neurofibrillary tangles appears in the hypothalamus, neuronal loss and gliosis are seen in a number of pontine and mesencephalic tegmental nuclei, substantia nigra, locus caeruleus.

Cross-regional survey of seasonal affective disorders in adults and high-school students in Japan.

Background: In Asian countries, there is no epidemiological report on seasonal affective disorder (SAD) in different age groups and different geographic regions surveyed at the same time. The aim of this study was to estimate the prevalence rates of SAD and risk factors for SAD in adults and high-school students, with special reference to the difference of winter SAD between northern and southern regions in Japan.

Methods: A total of 3237 high-school students and 4858 workers living in Japan (31.

Rapid eye movement-localized apnea in a female patient with chronic insomnia.

A middle-aged female patient with chronic insomnia showed rapid eye movement (REM)- localized obstructive sleep apnea. She visited the Sleep Disorders Clinic and complained of insomnia with loud snoring. Once, in the past, her sleep complaints had disappeared after weight reduction but, 6 months later, she complained of excessive daytime sleepiness.

Evaluating mental fatigue in patients with obstructive sleep apnea syndrome by the Maastricht Questionnaire.

Mental fatigue in patients with obstructive sleep apnea syndrome (OSAS) was investigated and compared with subjects without OSAS. The study series comprised 189 habitual snoring patients and 75 controls. To measure subjective mental fatigue and somnolence, subjects were asked to complete the Maastricht Questionnaire (MQ) and the Epworth Sleepiness Scale (ESS), respectively, and patients also underwent diagnostic polysomnography.

Inhibition of K(+)-evoked release of rat striatal 5-hydroxytryptamine by an atypical antidepressant: trazodone.

Using microdialysis, extracellular concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in the striatum of rats. In rats given trazodone, m-chlorophenylpiperazine dihydrochloride, or imipramine, the concentrations of 5-HT were unchanged. 5-HIAA in trazodone- or imipramine-treated rats, however, was respectively, decreased to 80 or 65% of preinjections levels.

Clozapine, but not haloperidol, reverses social behavior deficit in mice during withdrawal from chronic phencyclidine treatment.

Phencyclidine (PCP) reduced social behavior (SB) in a dose- and time-dependent fashion. However, no such SB deficit was observed on repeated treatment with methamphetamine for 14 days. The SB deficit produced by treatment with PCP (10 mg/kg/day) for 14 days, which persisted for 28 days after withdrawal, was attenuated by clozapine (10 mg/kg/day) given for 7 days, whereas haloperidol for 7 days had no effect.

Habitual snoring in an outpatient population in Japan.

In order to investigate the occurrence and history of sleep problems in Japan, the 11-Centre Collaborative Study on Sleep Problems (COSP) project was carried out. Complaints of snoring are examined, and its prevalence, risk factors and screening reliability are discussed. The subjects who participated in the study were 6445 new outpatients from a general hospital.

Daytime sleepiness and automobile accidents in patients with obstructive sleep apnea syndrome.

We evaluated the rate of automobile accidents and daytime sleepiness using the Epworth sleepiness scale (ESS) in 44 patients with obstructive sleep apnea syndrome (OSAS). We defined the automobile accident score as a sum of two points for every one automobile accident and one point for every near-miss accident. Automobile accidents and near-misses were found in 54.

Differences in arousal response between aged and middle-aged patients with obstructive sleep apnea syndrome.

The aim of this study is to show the clinical significance of the differences in arousal response at a termination of apnea/hypopnea between aged and middle-aged patients with obstructive sleep apnea syndrome (OSAS). We polygraphically assessed electrocardiographic (ECG) and electroencephalographic (EEG) arousal. Electrocardiographic arousal was defined as an abrupt increase in heart rate at a termination of apnea/hypopnea.

Sleep problems in the aged in relation to senility.

As a part of an epidemiologic survey of dementia in a community of aged persons, correlation between sleep complaints and physical illness and senility were studied. A total of 3302 randomly sampled aged individuals(aged > or = 65 years) were studied using a questionnaire. In this sample the prevalence of poor sleep and habitual snoring did not increase with age.