Molecular Imaging of PD-1 Unveils Unknown Characteristics of PD-1 Itself by Visualizing "PD-1 Microclusters".

Programmed cell death-1 (PD-1) is one of the most famous coinhibitory receptors that are expressed on effector T cells to regulate their function. The PD-1 ligands, PD-L1 and PD-L2, are expressed by various cells throughout the body at steady state and their expression was further regulated within different pathological conditions such as tumor-bearing and chronic inflammatory diseases. In recent years, immune checkpoint inhibitor (ICI) therapies with anti-PD-1 or anti-PD-L1 has become a standard treatment for various malignancies and has shown remarkable antitumor effects. Since the discovery of PD-1 in 1992, a huge number of studies have been conducted to elucidate the function of PD-1. Herein, this paper provides an overview of PD-1 biological findings and sheds some light on the current technology for molecular imaging of PD-1.

Anorexia assessment using the Simplified Nutritional Appetite Questionnaire and its association with activities of daily living in patients with stroke.

OBJECTIVE: This study aimed to validate the assessment of anorexia in patients with acute stroke using the Simplified Nutritional Appetite Questionnaire. METHODS: This cross-sectional observational study assessed appetite using the Simplified Nutritional Appetite Questionnaire in patients with acute stroke at discharge from an acute care hospital. Additionally, the relationship between the Simplified Nutritional Appetite Questionnaire and Mini Nutritional Assessment, Mini Nutritional Assessment - Short Form scores, skeletal muscle mass, muscle strength, and activities of daily living measured using the Functional Independence Measures for the motor domain was investigated. A multiple regression analysis was conducted with the Functional Independence Measure for the motor domain as the dependent variable and the Simplified Nutritional Appetite Questionnaire and other confounding factors as explanatory variables to evaluate the association between the Simplified Nutritional Appetite Questionnaire and functional outcomes. RESULTS: Among the 234 patients with stroke analyzed in this study, the median Simplified Nutritional Appetite Questionnaire score was 15 (IQR = 13-16) points. The Simplified Nutritional Appetite Questionnaire score significantly correlated with weight change, Functional Independence Measure for the motor domain, nutritional assessment index, and energy and protein intake. However, no significant differences in body mass index, muscle mass, or muscle strength were observed. In the multiple regression analysis adjusted for confounders, the Simplified Nutritional Appetite Questionnaire score (ß = 0.106; P = 0.007) was independently associated with the Functional Independence Measure for the motor domain (adjusted R2 = 0.662). CONCLUSIONS: This study's results found a significant correlation between Simplified Nutritional Appetite Questionnaire scores and nutritional status as well as an independent association with functional outcomes in patients with stroke. These findings suggest that the Simplified Nutritional Appetite Questionnaire can be a valuable tool for evaluating anorexia in this patient population.

Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters.

With recent advances in immune checkpoint inhibitors (ICIs), immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined empirically, taking individually conducted clinical trials into consideration, but without a standard method to evaluate them. Here we establish an advanced imaging system to visualize human PD-1 microclusters, in which a minimal T cell receptor (TCR) signaling unit co-localizes with the inhibitory co-receptor PD-1 in vitro. In these microclusters PD-1 dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2, upon stimulation with the ligand hPD-L1. In this system, blocking antibodies for hPD-1-hPD-L1 binding inhibits hPD-1 microcluster formation, and each therapeutic antibody (pembrolizumab, nivolumab, durvalumab and atezolizumab) is characterized by a proprietary optimal concentration and combinatorial efficiency enhancement. We propose that our imaging system could digitally evaluate PD-1-mediated T cell suppression to evaluate their clinical usefulness and to develop the most suitable combinations among ICIs or between ICIs and conventional cancer treatments.

Cachexia criteria in chronic illness associated with acute weight loss in patients with stroke.

OBJECTIVES: Weight loss after a stroke is associated with poor outcomes. However, the causes of weight loss in the acute phase of a stroke are not fully understood. The purpose of this study was to investigate the relationship between acute weight changes and cachexia criteria in patients with an acute stroke. METHODS: In this prospective-cohort study, we assessed patients' body weight change during hospitalization, and investigated the five cachexia criteria (muscle strength, fatigue, anorexia, skeletal muscle mass, and abnormal biochemistry) at time of discharge in patients with an acute stroke. A patient was defined as being cachectic if ≥3 cachexia criteria were met. A multivariate analysis was performed to investigate the relationship between weight changes and cachexia criteria. RESULTS: A total of 155 patients with an acute stroke were enrolled in this study, and 30 patients (19%) were found to have weight loss (≥5% weight loss). A univariate regression analysis found that the cachexia criteria were significantly associated with weight changes (ß = -0.338; P < 0.001). The multivariate analyses after adjusting for energy intake, age, sex, body mass index at time of admission, National Institutes of Health stroke scale score, inflammatory disease, length of hospital stay, length of bed rest, and swallowing function showed that the cachexia criteria were significantly associated with weight changes (ß = -0.154; P = 0.043). CONCLUSIONS: The cachexia criteria were independently associated with acute weight loss in patients with a stroke.

Impact of Advantage in Tumor Response on the Correlation Between Progression-Free Survival and Overall Survival: Meta-Analysis of Clinical Trials in Patients with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) in patients with advanced non-small cell lung cancer. OBJECTIVE: This study aimed to investigate an impact of advantage in tumor response on the correlation between PFS and OS in advanced non-small cell lung cancer. METHODS: Based on a literature search, we identified randomized controlled trials of first-line therapy for advanced non-small cell lung cancer. The impact of absolute difference in objective response rate between treatment arms on the correlation between hazard ratios (HRs) for PFS and OS was evaluated based on Spearman rank correlation coefficients. RESULTS: Sixty trials with a total of 29,134 patients were identified. The HR for PFS showed a relatively higher correlation with HR for OS (rs = 0.75) when the trials were limited to those that demonstrated a larger advantage in objective response rate, compared with the case for trials that demonstrated a smaller advantage (rs = 0.66). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (non-targeted, anti-angiogenic, and immunotherapy) except for the group of epidermal growth factor receptor-targeted agents. CONCLUSIONS: The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS-HR based on PFS-HR in clinical trials in patients with advanced non-small cell lung cancer.

Magnitude of advantage in tumor response contributes to a better correlation between treatment effects on overall survival and progression-free survival: a literature-based meta-analysis of clinical trials in patients with metastatic colorectal cancer.

BACKGROUND: Although it is suggested that the endpoints originated from the concept of tumor shrinkage dynamics, such as early tumor shrinkage and depth of response, are strongly associated with overall survival (OS) in patients with metastatic colorectal cancer (mCRC), they are yet to be validated as a single surrogate endpoint of OS by themselves. This study aimed to investigate the impact of advantage in tumor response on the correlation between treatment effects on progression-free survival (PFS) and OS in mCRC patients. METHODS: Based on an electronic search, we identified randomized controlled trials of first-line therapy for mCRC. The impact of advantage in objective response rate (ORR) on the correlation between treatment effects on PFS and OS was evaluated based on Spearman correlation coefficients (rs). RESULTS: Forty-seven trials with a total of 24,018 patients were identified. The hazard ratio for PFS showed a relatively higher correlation with that for OS (rs = 0.63) when the trials were limited to those that demonstrated a larger difference in ORR, compared to the case for trials that demonstrated a smaller difference (rs = 0.32). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (targeted or non-targeted). CONCLUSIONS: The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS benefit based on PFS in patients with mCRC. The accuracy of OS estimation in mCRC is expected to be improved by considering the degree of tumor shrinkage in conjunction with PFS.

Effect of the Management Tool for Daily Life Performance on Patients with Cardiovascular Disease: A Randomized Controlled Trial.

OBJECTIVE: Cardiovascular diseases cause psychological symptoms, such as depression and anxiety. Symptoms of depression have a major effect on patients and worsen prognosis as a result of reduced quality of life and decreased levels of physical activity. Because cardiac rehabilitation (CR) has physical, mental, and secondary preventative effects, it is necessary to evaluate the psychological factors of patients and to provide patients with psychological support based on the results. The management tool for daily life performance (MTDLP) was developed in 2006 by the Japanese Association of Occupational Therapists. Since then, its effectiveness for patients with cerebrovascular diseases and bone fractures has been verified. However, no randomized controlled trial has been conducted on the effectiveness of interventions using MTDLP on patients with cardiovascular diseases. METHODS: We examined the effectiveness of intervention using MTDLP on patients undergoing outpatient CR. Thirty-six patients who scored at least 48 on the self-rating depression scale (SDS) were included in the study. Eighteen patients were allocated to both the CR and MTDLP groups. The SDS, Barthel index, Frenchay Activities Index (FAI), and Life-Space Assessment were evaluated as outcome measures. RESULTS: The CR group (n=14) showed significantly improved post-intervention scores on the SDS (P=0.007). Furthermore, the MTDLP group (n=11) showed significantly improved post-intervention scores on the SDS (P=0.010) and FAI (P=0.003). CONCLUSIONS: CR improves depression, whereas additional intervention using MTDLP improves not only depression but also various daily activities. Consequently, intervention using MTDLP in CR appears to be effective.

Comparison of the Effect of Sensory-Level and Conventional Motor-Level Neuromuscular Electrical Stimulations on Quadriceps Strength After Total Knee Arthroplasty: A Prospective Randomized Single-Blind Trial.

OBJECTIVE: To compare sensory-level neuromuscular electrical stimulation (NMES) and conventional motor-level NMES in patients after total knee arthroplasty. DESIGN: Prospective randomized single-blind trial. SETTING: Hospital total arthroplasty center: inpatients. PARTICIPANTS: Patients with osteoarthritis (N=66; mean age, 73.5±6.3y; 85% women) were randomized to receive either sensory-level NMES applied to the quadriceps (the sensory-level NMES group), motor-level NMES (the motor-level NMES group), or no stimulation (the control group) in addition to a standard rehabilitation program. INTERVENTIONS: Each type of NMES was applied in 45-minute sessions, 5d/wk, for 2 weeks. MAIN OUTCOME MEASURES: Data for the quadriceps maximum voluntary isometric contraction, the leg skeletal muscle mass determined using multiple-frequency bioelectrical impedance analysis, the timed Up and Go test, the 2-minute walk test, the visual analog scale, and the range of motion of the knee were measured preoperatively and at 2 and 4 weeks after total knee arthroplasty. RESULTS: The motor-level NMES (P=.001) and sensory-level NMES (P=.028) groups achieved better maximum voluntary isometric contraction results than did the control group. The motor-level NMES (P=.003) and sensory-level NMES (P=.046) groups achieved better 2-minute walk test results than did the control group. Some patients in the motor-level NMES group dropped out of the experiment because of discomfort. CONCLUSIONS: Motor-level NMES significantly improved muscle strength and functional performance more than did the standard program alone. Motor-level NMES was uncomfortable for some patients. Sensory-level NMES was comfortable and improved muscle strength and functional performance more than did the standard program alone.

The regulation of exon-specific brain-derived neurotrophic factor mRNA expression by protein kinase C in rat cultured dorsal root ganglion neurons.

Although brain-derived neurotrophic factor (BDNF) is localized in primary sensory neurons and has crucial roles in nociceptive transduction, the mechanisms involved in regulation of BDNF exon-specific mRNA expression in dorsal root ganglion (DRG) neurons have yet to be determined. Rat primary cultures of DRG neurons were stimulated with phorbol-12-myristate-13-acetate (PMA), a potent activator of protein kinase C (PKC), which resulted in the robust expression of both BDNF mRNA and protein. Among each BDNF mRNA exon, it was found that exons I, IV and VI were especially induced after PMA stimulation. The induction of these exons was significantly blocked by Gö6983 (a broad spectrum PKC inhibitor), Gö6976 (a conventional PKCs and PKCµ inhibitor), and rottlerin (a PKCδ inhibitor), but not by a PKCε inhibitor. The effect of PMA on exons I and VI was blocked by either U0126 (a MAP kinase kinase (MEK) inhibitor) or SB202190 (a p38 inhibitor), and PMA's effect on exon IV was inhibited by U0126 but not by SB202190. Furthermore, the activation of cAMP-responsive element-binding protein (CREB) was associated with the induction of exons I and IV, and the activation of nuclear factor-κB (NF-κB) contributed to the induction of exons I, IV and VI. These results show that the activation of PKCs induces the expression of BDNF mRNA exons I, IV and VI through exon-specific mechanisms, including extracellular signal-regulated kinase, p38, CREB and NF-κB, in cultured DRG neurons. These data suggest multiple pathways in the expression of BDNF in nociceptive sensory neurons.

Neural stem/progenitor cells damaged by reactive oxygen species evolved in photosensitizing reaction.

We want to know how the growth of neural stem/progenitor cells and their differentiation are affected by reactive oxygen species evolved in photosensitizing reaction, because of the similarity between the stem cells and the tumor cells in central nervous system. We investigated the effects of two photosensitizers (rhodamine 123 and hematoporphyrin) on the mouse neural stem/progenitor cells cultured in vitro under the illumination. ABC transporters were expressed in the cells, and could pump rhodamine 123 and hematoporphyrin out of the cells. Under the illumination of strong actinic light with those photosensitizers, reactive oxygen species was evolved to injure the cells. Number of viable cells decreased under illumination through apoptosis and necrosis. Those cell-killing activities were not clearly dependent on the presence of inhibitors for ABC transporters. Immunocytochemical staining with showed that immature cells with markers of neural stem/progenitor cells (Sox 2, CD133, nestin) were more sensitive to the reactive oxygen species than the differentiated cells.