Active use of local exercise facilities can improve physical performance of community-dwelling older adults.

[Purpose] In this study, we investigated the effects of local exercise facility use on physical function of Japanese community-dwelling older adults. [Participants and Methods] We analyzed data obtained from a cohort project initiated in 1991. The study included approximately 4,800 individuals from suburban areas of central Japan; we investigated 322 older individuals residing in Municipality A, who underwent physical fitness assessments in 2018 and 2019. We recorded participants' exercise facility use frequency and physical performance, based on handgrip strength, open-eye single-leg standing, timed up-and-go, and walking speed tests. [Results] Baseline values in the open-eye single-leg standing test were significantly higher in the no-use than in the low- and high-use groups. Follow-up assessments revealed that grip strength was significantly higher in the high-use than in the no- and low-use groups. [Conclusion] Active use of exercise facilities was positively correlated with maintenance and improvement in physical fitness among participants, which highlights the benefits of easily accessible exercise facilities in maintaining long-term physical function. Future studies should focus on functions that extend beyond physical fitness to develop effective support programs that address the evolving health needs of the aging population.

Vaccine Effectiveness against SARS-CoV-2 among Household Contacts during Omicron BA.2-Dominant Period, Japan.

We calculated attack rates for household contacts of COVID-19 patients during the SARS-CoV-2 Omicron BA.2-dominant period in Japan. Attack rates among household contacts without recent (<3 months) vaccination was lower for contacts of index patients with complete vaccination than for contacts of index patients without complete vaccination, demonstrating indirect vaccine effectiveness.

Social Frailty and Functional Status in Japanese Older Adults: The Mediating Role of Subjective Cognitive Function.

OBJECTIVE: This study aimed to explore the direct and indirect effects of social frailty on functional state trajectories mediated by subjective cognitive function in older adults. DESIGN: Longitudinal study. SETTING AND PARTICIPANTS: Overall, 514 adults aged ≥65 years living in a suburban area of central Japan were included in this study. METHODS: Five-item social frailty index (going out, visiting, feeling helpful, living alone, and talking to others), subjective cognitive function from the Kihon Checklist, and instrumental activities of daily living disability. Latent growth curve models were applied to examine the longitudinal relations among the variables. RESULTS: During the 6-year follow-up in latent growth curve models, the initial level of social frailty in older adults was negatively associated with that of functional status (ß = -0.53, P < .001), and the rate of change in social frailty was negatively associated with that in functional status (ß = -0.78, P < .001). In the mediation model, the indirect effect from the social frailty level to functional status level through subjective cognitive function level was significant (ß = -0.14, 95% CI -0.29, -0.09); the rates of change in subjective cognitive function mediated the relationship between those in social frailty and functional status (ß = -0.35, 95% CI -0.46, -0.25). CONCLUSIONS AND IMPLICATIONS: This study found that there is an association between social frailty and functional status in Japanese older adults. Subjective cognitive function mediated this relationship. Hence, additional research is required to investigate additional potential factors linking social frailty and functional status in order to gain a better understanding of the underlying mechanisms.

Longitudinal assessment of the relationship between frailty and social relationships among Japanese older adults: a random intercept cross-lagged panel model.

OBJECTIVES: This study aimed to explore the bidirectional association between frailty and social relationships in older adults while distinguishing between interpersonal and intrapersonal effects. METHODS: A prospective cohort study of community-dwelling older adults was conducted in Japan in three waves spanning six years with follow-ups in every three years. Random intercept cross-lagged panel model was used to explore temporal associations between frailty and social relationships. RESULTS: Data for 520 participants (mean age 73.02 [SD 6.38] years, 56.7% women) were analyzed. Across individuals, frailty was associated with social relationships (ß = -0.514, p < 0.001). At the interpersonal level, frailty was cross-sectionally associated with social relationships separately at T1(ß = -0.389, p < 0.01), T2 (ß = -0.343, p < 0.001) and T3 (ß = -0.273, p < 0.05). Moreover, social relationships were associated with subsequent increases in symptoms of frailty in all measurement waves (ß = -0.332, p < 0.001; ß = -0.169, p < 0.01) and vice versa (ß = -0.149, p < 0.05; ß = -0.292, p < 0.001). CONCLUSIONS: The results suggest that frailty was associated with lower levels of social relationships. Frailty improvement programs can be combined with interventions to enhance social relationships, which will be beneficial in preventing frailty. The results emphasize the importance of combining clinical treatments of frailty with interventions to improve social relationships.

Latent Subtype of Cognitive Frailty among Multimorbidity Older Adults and Their Association with Social Relationships.

This study aimed to explore all the relevant subtypes of cognitive frailty among Japanese community-dwelling older adults with multimorbidity. Moreover, it examined the associations between these potential subtypes of cognitive frailty and social relationships. This study targeted relevant cross-sectional data regarding community-based older adults with multimorbidity. It employed a person-centered method to perform a latent class analysis and explore the subtypes of cognitive frailty among older adults. Moreover, a multinominal logistic regression analysis was employed to examine the association between potential subtypes of cognitive frailty and social relationships. Data for 396 participants (mean age, 75.8 [SD, 7.3] years; 51.3% females) were analyzed. Three cognitive frailty subtypes were subsequently revealed: the robust group (42.0%), the group with partial cognitive frailty (38.6%), and the group with cognitive frailty (19.4%). People with high levels of social relationships were more likely to be in the robust and the partial cognitive frailty groups. This study identified different subtypes of cognitive frailty among multimorbid older adults and highlighted the significance of social relationships. These findings could serve as a reference for conceptualizing cognitive frailty through the person-centered method. Promoting a high level of social relationships could be useful to prevent the cognitive frailty among older adults with multimorbidity.

Social Relationships and Onset of Functional Limitation among Older Adults with Chronic Conditions: Does gender matter?

Objectives: This study aimed to examine the longitudinal association between social relationships and physical functioning among community-dwelling older adults with chronic conditions. Methods: Self-reported questionnaires were distributed and collected between 2014 and 2017 from participants ≥65 years old. The Index of Social Interaction was used to evaluate social relationships and the instrumental activities of daily living (IADL) subscale of the Tokyo Metropolitan Institute of Gerontology Index of Competence was used to examine functional status. Results: A total of 422 participants (190 males and 232 females) were included in the final analysis. High social relationships demonstrated significant adverse effects (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.64-0.93) on the decline of IADL in the overall sample, particularly for females (OR = 0.71, 95% CI: 0.55-0.93) but not as much for males (P = 0.131). Conclusion: This finding suggests that functional limitation was influenced by social relationships among disabled older adults and the influence of social relationships on functional limitation differed based on gender.

Patterns of Movement Performance among Japanese Children and Effects of Parenting Practices: Latent class analysis.

Objectives: This study aimed to examine the long-term effects of parenting practice during preschool years on children's movement performance in primary school. Methods: This three-year longitudinal study included 225 children aged 3-6-years-old. Parents reported baseline parenting practice and evaluated children's movement performance three years later. Latent class analysis was used to explore latent classes of movement performance. A post hoc test was used to identify the characteristics of different patterns. Finally, adjusted multinomial logistic regression models were used to test the influence of parenting practice on identified patterns of movement performance. Results: Children in this study were grouped into three movement performance patterns, labelled as 'least difficulties' (n = 131, 58.2%), 'low back pain' (n = 68, 30.2%) and 'most difficulties' (n = 26, 11.6%). After controlling for age, gender, having siblings or not, family structure, standardised body mass index, sleep condition and dietary habits, the researchers found that if parents played games with children frequently, the children would have a 0.287 times lower probability of being in the 'low back pain' class (95% confidence interval [CI]: 0.105-0.783). In addition, if parents take children to meet peers of a similar age frequently, children would have a 0.339 times lower probability of being in 'most difficulties' class (95% CI: 0.139-0.825). Conclusion: Primary healthcare providers should pay careful attention to children with movement difficulties. The study provides longitudinal evidence to support the applicability of positive parenting practice in early childhood to prevent children's movement difficulties.

Changes in Social Relationships and Physical Functions in Community-Dwelling Older Adults.

BACKGROUND: Social relationships are associated with physical function. However, little scholarly attention has been focused on the effect of changing social factors on physical function. PURPOSE: This study was designed to examine the effects on physical function of changes in social relationships in adults aged 65 years and older. METHODS: This study is part of a longitudinal, prospective cohort study that was conducted on community-dwelling older adults in a suburban area of central Japan. Baseline self-report data were collected in 2011, and a follow-up survey was conducted in 2017. Social relationships were assessed using the Index of Social Interaction, and physical function was evaluated using a subscale of the Kihon Checklist. Chi-square tests, Mann-Whitney U tests, and multiple logistic regression analysis were used to analyze data from 442 older adults who were functionally independent at baseline. RESULTS: After controlling for covariates in 2011, negative changes in social relationships (odds ratio [ OR ] = 3.20, 95% CI [1.18, 8.69]) were found to be associated with physical function decline. Moreover, 1-point increases in the different social-relationship values between baseline and follow-up were associated with protective effects against functional decline ( OR = 0.71, 95% CI [0.63, 0.80]). Furthermore, median trends between baseline and follow-up revealed associations between decreasing ( OR = 4.18, 95% CI [1.53, 11.39]) and continuously low ( OR = 2.98, 95% CI [1.42, 6.28]) social relationships and physical function decline. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The findings support a strong association between negative changes in social relationships and physical function decline and highlight the importance of promoting social relationships to delay physical function decline in older adults.

Increased Secondary Attack Rates among the Household Contacts of Patients with the Omicron Variant of the Coronavirus Disease 2019 in Japan.

This study investigated the household secondary attack rate (HSAR) of patients with coronavirus disease (COVID-19) during the omicron variant-dominant period. The HSAR of COVID-19 cases during the omicron variant-dominant period (4-20 January 2022) was calculated and compared with the delta variant-dominant period (20 August to 7 November 2021) in Itako, Japan. In Itako, all 47 and 119 samples tested during the omicron and delta variant-dominant periods were negative and positive, respectively, for the L452R mutation. We used a generalized estimating equation regression model. The HSAR was 31.8% (95% confidence interval (CI) 27.7-36.2) for 456 household contacts during the omicron variant-dominant period; it was higher than that during the delta variant-dominant period (25.2%) (adjusted risk ratio [aRR] 1.61, CI 1.13-2.28). During the omicron variant-dominant period, HSAR was lower for the household contacts of completely vaccinated index patients (27.3%) than for contacts of other index patients (41.2%) (vaccine effectiveness for infectee 0.43, 95% CI 0.16-0.62) and was significantly higher for female contacts than for male contacts (36.2% vs. 26.1%; aRR 1.29, 95% CI 1.01-1.65). The HSAR was significantly higher during the omicron variant-dominant period than the delta variant-dominant period. The vaccination of index patients might protect household contacts.

A low proportion of asymptomatic COVID-19 patients with the Delta variant infection by viral transmission through household contact at the time of confirmation in Ibaraki, Japan.

We conducted a study to investigate the proportion of patients with asymptomatic coronavirus disease 2019 (COVID-19) infected with the Delta variant compared with those infected with the wild-type strain at the time of confirmation. A total of 504 patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by viral transmission through household contact in Ibaraki, Japan were included. The proportion of asymptomatic COVID-19 patients at the time of confirmation was compared between patients infected with L452R mutation strain from June to September 2021 and those infected with the wild-type strain from November 2020 to January 2021, and was found to be 14.2% and 28.8%, respectively (relative risk, 0.49; 95% confidence interval, 0.35-0.70). The proportion of asymptomatic COVID-19 patients by viral transmission through household contact was lower among the Delta variant than those among the wild-type strain at the time of confirmation. It might contribute to attenuation of transmission.

Eating Behaviour-Consumption Frequency of Certain Foods in Early Childhood as a Predictor of Behaviour Problems: 6-year follow-up study.

Objectives: This study aimed to evaluate food consumption frequency in 1-6-year-olds as an eating behaviour-related predictor of behavioural problems over a span of six years. Eating behaviour in early childhood serves as a foundation for future health outcomes. Diet patterns can have long-term beneficial or adverse effects on social behaviour development. Methods: This longitudinal study was performed based on information obtained between July 2011 and August 2017 provided from a project named 'Community Empowerment and Care for Wellbeing and Health Longevity' initiated in 1991; the current study involved 124 mother-child dyads from the project. Children aged 1-6 years were studied in July 2011, with a follow-up assessment in August 2017. The primary exposure examined was the frequency of food items intake. The primary outcome was behaviour problems as assessed by the Strengths and Difficulties Questionnaire (SDQ). Results: The adjusted results suggested that a higher intake of leafy green and light-coloured vegetables were significantly associated with decreased odds of conduct problems and prosocial behaviour problems in Japanese children. However, no associations were observed among fruits, milk, small fish, eggs, soybeans, seaweed and any SDQ subscales. Conclusion: This study shows that eating leafy green and light-coloured vegetables may have a protective effect on a child's conduct and against prosocial behaviour problems. Due consideration should be given to children's eating habits in the early stages of their lives to ensure better mental health.

Measurement invariance and country difference in children's social skills development: Evidence from Japanese and Chinese samples.

The diversity of child social skills development is not well detected among Asian countries. Culturally validated assessments are needed for practitioners to evaluate child social skills. This study tested the measurement invariance of the Social Skill Scale (SSS) across Japanese and Chinese samples and explored country differences in child social skills development. The SSS utilizes a widely used factor structure (assertion, self-control, and cooperation subdomains) and has established Japanese and Chinese versions. We conducted investigations with an identical process and materials with different language versions, collecting data from 931 Japanese kindergarten children (Mage = 4.35, SDage = 1.07; 53.6% boys) and from 1130 Chinese kindergarten children (Mage = 4.47, SDage = 1.00; 52.3% boys). We used multiple confirmatory factor analysis to test measurement invariance of the SSS and established the validity, reliability, and scalar measurement invariance for the first-order factor structure of the SSS across the two country samples. We also examined country differences on the associations between demographics, parenting practice, and child social skills development. We found that, compared to the Chinese sample, cooperation skills significantly increased more with age among the Japanese sample. However, spanking was negatively related to self-control skills development in both countries. Our findings contribute to the demonstration of the diversity of child social skills development and have important implications for assessing and developing child social skills using culture-specific strategies.

Increased Secondary Attack Rate among Unvaccinated Household Contacts of Coronavirus Disease 2019 Patients with Delta Variant in Japan.

This study aimed to elucidate the household secondary attack rate (HSAR) of the Delta variant in comparison to the Alpha variant, and evaluate the risk factors among unvaccinated household contacts of patients with coronavirus disease 2019 (COVID-19). We studied household contacts of index cases of COVID-19 infected with Delta (L452R mutation), Alpha (N501Y mutation), and wild strain from December 2020 through November 2021 in Itako, Japan. The HSARs of the entire household contact, and the contact of index case with Delta variant were calculated and compared across the risk factors. We used a generalized estimating equation regression model for the multivariate analysis. We enrolled 1257 unvaccinated contacts from 580 households. The HSAR was higher in household contacts of index patients with Delta (48.5%) than with Alpha variant (21.7%) (aOR = 3.34, p = 0.000). In Delta variants, the HSAR was higher in household contacts with spousal relationships to index patients (63.4%) than contacts with other relationships (45.5%) (aOR 1.94, p = 0.026), and was lower in household contacts of index patients aged ≤19 (33.1%) than for contacts of index cases aged 20-59 years (52.6%) (aOR = 0.50, p = 0.027). The result of our study can be used to devise informed strategy to prevent transmission within households.

Subtyping of Internalizing and Externalizing Behaviors in Japanese Community-Based Children: A Latent Class Analysis and Association with Family Activities.

Externalizing and internalizing behavioral problems occurs at a high rate among children. However, this has rarely been examined among Japanese children using a person-oriented method. Hence, this study aims to explore its subtypes and clarify their association with family-based group activities. We conducted a cross-sectional survey in a typical community-based suburban area for all families with primary school children in Japan. We investigated children's internalizing and externalizing behaviors based on the Japanese version of the Strengths and Difficulties Questionnaire (SDQ), and different types of activities that family members frequently engaged in. Data from 206 families were collected and used for the analysis. The subtypes were explored using latent class analysis (LCA). The relationship between family activities and latent class membership was analyzed using a logistic regression model. Moreover, three latent class models and their probabilities were identified, namely, risk group (31.3%), moderate group (44.9%), and normal group (23.8%). Frequent family activities including play sports, traveling or hiking, watching TV and communicating, cooking or making a dessert, and doing housework, which were significantly related to the normal group. These results would add evidence to potential types of children's behavioral problems and preventive childcare practices needed in the primary gate of families.

Patterns of social relationships among community-dwelling older adults in Japan: latent class analysis.

BACKGROUND: Social relationships may be the key to successful aging among older adults. However, little is known about the variability of social relationships among community-dwelling older people. This study aimed to describe the patterns of social relationships and examine the differences in sociodemographic characteristics and mental and physical health status among these patterns. METHODS: We obtained the data from a questionnaire survey in 2017 for older adults aged 65 and above who lived in a suburban area in Japan. The Index of Social Interaction (ISI) was used to evaluate social relationships. The final sample comprised 964 people who were independently mobile and answered at least one item of the ISI. To clarify the patterns of social relationships, latent class analysis was performed with five subscales of ISI treated as indicator variables. Multinomial logistic regression was conducted to examine the factors associated with the patterns of social relationships. RESULTS: The patterns of social relationships were classified into three classes: "Active" (73.6%), "Socially isolated" (14.7%), and "Less motivated" (11.7%). Persons who had depressive symptoms were more likely to be allocated to the "Socially isolated" (Odds Ratio [OR] 1.80, 95% Confidence Interval [CI] 1.13-2.86) or the "Less motivated" groups (OR 1.69, 95% CI 1.00-2.85) compared to the "Active" group. In addition, men (OR 1.72, 95% CI 1.07-2.76) and those living alone (OR 3.07, 95% CI 1.43-6.61) were more likely to be allocated to the "Socially isolated" group. Moreover, those who were dependent, according to the instrumental activities and daily living functions, were more likely to be assigned to the "Socially isolated" (OR 2.19, 95% CI 1.21-3.97) or "Less motivated" (OR 6.29, 95% CI 3.47-11.39) groups. CONCLUSION: This study revealed the patterns of social relationships in older adults and suggested that there may be variations of social relationships among community dwellers. The results also indicated the necessity of assessing individual patterns of social relationships and devising strategies for each pattern in public health practice.

Role of Multifaceted Social Relationships on the Association of Loneliness with Depression Symptoms: A Moderated Mediation Analysis.

Strong relationship exists between loneliness and depression in older adults. However, the effect of multifaceted social relationships on the relationship between loneliness and depression has not been explored. The purpose of the current study was to find out how multifaceted social relationships affect the aforementioned processes. We investigated and evaluated the loneliness status, depression symptoms, social relationships, and demographic information of 1116 older adults aged ≥65 years living in rural Japan. The final 555 participants were included in the analysis. Statistical evidence showed a direct effect between loneliness and depression symptoms. Additionally, the mediation model found that social curiosity and participation acted as mediators between loneliness and depression symptoms. Further, independence and participation, independence, and feeling safe played a conditional moderating role in the model of loneliness-social curiosity-depression symptoms and loneliness-participation-depression symptoms, respectively. Interaction can be an individual moderator in the link between loneliness and depression symptoms without any mediator. The moderated mediation model suggests that social curiosity and participation could mediate the association between loneliness and depression symptoms. In this process, independence, participation, and feeling safe may act as moderators.

Development of Social Skills in Kindergarten: A Latent Class Growth Modeling Approach.

Social skills acquired during early childhood are often the foundation for success later in life. Using a nationwide survey dataset in Japan, this study aims to explore the multiple growth trajectories of social skills among children in kindergarten by using a latent class growth modeling approach. It also examines whether, and to what extent, the home-rearing environment at early age predict trajectories of social skills development. Children in this study were assessed on social skills at three waves, four home-rearing environment dimensions (human stimulation, social stimulation, avoidance of punishment, and social support for parenting) and demographic background were measured at wave 1. The results indicated that three distinct growth trajectories of social skills existed during kindergarten: high increase levels, moderate increase levels, and decreased levels. The avoidance of punishment and children's gender significantly predicted the growth trajectories of social skills. Thus, the results suggest that more attention should be paid to the home-rearing environment and boys.

Multimorbidity and functional limitation: the role of social relationships.

OBJECTIVES: To examine the relationship between multimorbidity and functional limitation, and how social relationships alter that association. METHODS: This cross-sectional study used data collected by self-reported questionnaires from adults aged 65 years and older living in a rural area in Japan in 2017. This analysis included complete data from 570 residents. Multimorbidity status was defined as having two chronic diseases exist simultaneously in one individual, and the function status was measured by their long-term care needs. Social relationships were assessed by the Index of Social Interaction and divided into high and low levels. Multiple logistic regression analysis was used to examine the association between social relationships and functional limitation and to assess the role of social relationships in this association. RESULTS: The logistic regression model indicated that the risk of functional limitation was higher in multimorbidity participants than free-of-multimorbidity participants (OR = 2.55, 95% CI = 1.56-4.16). Compared with participants with no multimorbidity and a high level of social relationships, low level of social relationships increased the risk of functional limitation among participants both with and without multimorbidity, with the OR = 7.71, 95% CI = 3.03-19.69 and OR = 3.28, 95% CI = 1.30-8.27, respectively. However, no significant result was found in participants with multimorbidity and a high level of social relationships (P = 0.365). CONCLUSIONS: Multimorbidity was associated with functional limitations. However, this association could be increased by a low level of social relationships and decreased by a high level of social relationships.

Effect of preoperative chemoradiotherapy on the immunological status of rectal cancer patients.

The aim of the study was to investigate the effect of chemo-radiation on the genetic and immunological status of rectal cancer patients who were treated with preoperative chemoradiotherapy (CRT). The expression of immune response-associated genes was compared between rectal cancer patients treated (n = 9) and not-treated (n = 10) with preoperative CRT using volcano plot analysis. Apoptosis and epithelial-to-mesenchymal transition (EMT) marker genes were analysed by quantitative PCR (qPCR). Other markers associated with the tumor microenvironment (TME), such as tumor-infiltrating lymphocytes (TIL) and immune checkpoint molecules, were investigated using immunohistochemistry (IHC). The clinical responses of preoperative CRT for 9 rectal cancer patients were all rated as stable disease, while the pathological tumor regression score (TRG) revealed 6 cases of grade2 and 3 cases of grade1. According to the genetic signature of colon cancers, treated tumors belonged to consensus molecular subtype (CMS)4, while not-treated tumors had signatures of CMS2 or 3. CRT-treated tumors showed significant upregulation of EMT-associated genes, such as CDH2, TGF-beta and FGF, and cancer stem cell-associated genes. Additionally, qPCR and IHC demonstrated a suppressive immunological status derived from the upregulation of inflammatory cytokines (IL-6, IL-10 and TGF-beta) and immune checkpoint genes (B7-H3 and B7-H5) and from M2-type macrophage accumulation in the tumor. The induction of EMT and immune-suppressive status in the tumor after strong CRT treatment urges the development of a novel combined therapy that restores immune-suppression and inhibits EMT, ultimately leading to distant metastasis control.

Antitumor activity of the PD-1/PD-L1 binding inhibitor BMS-202 in the humanized MHC-double knockout NOG mouse.

Recently, the first series of small molecule inhibitors of PD-1/PD-L1 were reported by Bristol-Myers Squibb (BMS), which were developed using a homogeneous time-resolved fluorescence (HTRF)-based screening investigation of the PD-1/PD-L1 interaction. Additional crystallographic and biophysical studies showed that these compounds inhibited the interaction of PD-1/PD-L1 by inducing the dimerization of PD-L1, in which each dimer binds one molecule of the stabilizer at its interface. However, the immunological mechanism of the antitumor effect of these compounds remains to be elucidated. In the present study, we focused on BMS-202 (a representative of the BMS compounds) and investigated its antitumor activity using in vitro and in vivo experiments. BMS-202 inhibited the proliferation of strongly PD-L1-positive SCC-3 cells (IC50 15 µM) and anti-CD3 antibody-activated Jurkat cells (IC50 10 µM) in vitro. Additionally, BMS-202 had no regulatory effect on the PD-1 or PD-L1 expression level on the cell surface of these cells. In an in vivo study using humanized MHC-double knockout (dKO) NOG mice, BMS-202 showed a clear antitumor effect compared with the controls; however, a direct cytotoxic effect was revealed to be involved in the antitumor mechanism, as there was no lymphocyte accumulation in the tumor site. These results suggest that the antitumor effect of BMS-202 might be partly mediated by a direct off-target cytotoxic effect in addition to the immune response-based mechanism. Also, the humanized dKO NOG mouse model used in this study was shown to be a useful tool for the screening of small molecule inhibitors of PD-1/PD-L1 binding that can inhibit tumor growth via an immune-response-mediated mechanism.