Mechanisms Controlling PD-L1 Expression in Cancer.

The engagement of programmed cell death protein 1 (PD-1; encoded by the PDCD1 gene) receptor expressed on activated T cells and its ligand, programmed death-ligand 1 (PD-L1; encoded by the CD274 gene), is a major co-inhibitory checkpoint signaling that controls T cell activities. Various types of cancers express high levels of PD-L1 and exploit PD-L1/PD-1 signaling to evade T cell immunity. Blocking the PD-L1/PD-1 pathway has consistently shown remarkable anti-tumor effects in patients with advanced cancers and is recognized as the gold standard for developing new immune checkpoint blockade (ICB) and combination therapies. However, the response rates of anti-PD-L1 have been limited in several solid tumors. Therefore, furthering our understanding of the regulatory mechanisms of PD-L1 can bring substantial benefits to patients with cancer by improving the efficacy of current PD-L1/PD-1 blockade or other ICBs. In this review, we provide current knowledge of PD-L1 regulatory mechanisms at the transcriptional, posttranscriptional, post-translational, and extracellular levels, and discuss the implications of these findings in cancer diagnosis and immunotherapy.

Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1.

Metformin has been reported to possess antitumor activity and maintain high cytotoxic T lymphocyte (CTL) immune surveillance. However, the functions and detailed mechanisms of metformin's role in cancer immunity are not fully understood. Here, we show that metformin increases CTL activity by reducing the stability and membrane localization of programmed death ligand-1 (PD-L1). Furthermore, we discover that AMP-activated protein kinase (AMPK) activated by metformin directly phosphorylates S195 of PD-L1. S195 phosphorylation induces abnormal PD-L1 glycosylation, resulting in its ER accumulation and ER-associated protein degradation (ERAD). Consistently, tumor tissues from metformin-treated breast cancer patients exhibit reduced PD-L1 levels with AMPK activation. Blocking the inhibitory signal of PD-L1 by metformin enhances CTL activity against cancer cells. Our findings identify a new regulatory mechanism of PD-L1 expression through the ERAD pathway and suggest that the metformin-CTLA4 blockade combination has the potential to increase the efficacy of immunotherapy.

Ephrin receptor A10 monoclonal antibodies and the derived chimeric antigen receptor T cells exert an antitumor response in mouse models of triple-negative breast cancer.

Expression of the receptor tyrosine kinase ephrin receptor A10 (EphA10), which is undetectable in most normal tissues except for the male testis, has been shown to correlate with tumor progression and poor prognosis in several malignancies, including triple-negative breast cancer (TNBC). Therefore, EphA10 could be a potential therapeutic target, likely with minimal adverse effects. However, no effective clinical drugs against EphA10 are currently available. Here, we report high expression levels of EphA10 in tumor regions of breast, lung, and ovarian cancers as well as in immunosuppressive myeloid cells in the tumor microenvironment. Furthermore, we developed anti-EphA10 monoclonal antibodies (mAbs) that specifically recognize cell surface EphA10, but not other EphA family isoforms, and target tumor regions precisely in vivo with no apparent accumulation in other organs. In syngeneic TNBC mouse models, we found that anti-EphA10 mAb clone #4 enhanced tumor regression, therapeutic response rate, and T cell-mediated antitumor immunity. Notably, the chimeric antigen receptor T cells derived from clone #4 significantly inhibited TNBC cell viability in vitro and tumor growth in vivo. Together, our findings suggest that targeting EphA10 via EphA10 mAbs and EphA10-specific chimeric antigen receptor-T cell therapy may represent a promising strategy for patients with EphA10-positive tumors.

Feeding practice during infancy is associated with attention-deficit/hyperactivity disorder and autism spectrum disorder: a population-based study in South Korea.

Attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) are representative neurodevelopmental disorders. Using a nationwide database, we aimed to investigate whether feeding practices in infancy (breastfeeding and the timing of supplementary food introduction) could impact ADHD or ASD development. We evaluated 1,173,448 children aged 4-6 months who were included in the National Screening Program for Infants and Children (NHSPIC) between 2008 and 2014. We observed individuals until 6-7 years of age. Data on feeding type (milk feeding: exclusive breastfeeding [EBF], partial breastfeeding [PBF], exclusive formula feeding [EFF] at 4-6 months of age; supplementary food introduction: < 6 or > 6 months of age) were obtained from the NHSPIC, and diagnoses were based on the International Classification of Diseases, Tenth Revision. In a generalized linear model, children who received EBF had significantly lower incidence of both ADHD (odds ratio [OR]: 0.77, 95% confidence interval [CI]: 0.72-0.82) and ASD (OR: 0.64, 95% CI: 0.60-0.67) than that of children who received EFF. PBF also had a significant protective effect on both ADHD (0.91; 0.85-0.98), and ASD (0.89; 0.83-0.95). The timing of supplementary food introduction was not associated with either ADHD or ASD, although there was an increased risk of ASD in the EFF infants who had supplementary food introduced at > 6 months of age.  Conclusion: Our study strengthens and supports the beneficial effect of breastfeeding on neurodevelopmental disorders in children. Breastfeeding should be encouraged and recommended to promote desirable neurodevelopmental outcomes. What is Known: • Breastfeeding is beneficial for the overall health of children, including neurodevelopmental outcomes and cognitive functions. What is New: • Breastfeeding, especially exclusive breastfeeding, was protective against neurodevelopmental disorders. • The effect of the timing of supplementary food introduction was limited.

TMEM9-v-ATPase Activates Wnt/ß-Catenin Signaling Via APC Lysosomal Degradation for Liver Regeneration and Tumorigenesis.

BACKGROUND AND AIMS: How Wnt signaling is orchestrated in liver regeneration and tumorigenesis remains elusive. Recently, we identified transmembrane protein 9 (TMEM9) as a Wnt signaling amplifier. APPROACH AND RESULTS: TMEM9 facilitates v-ATPase assembly for vesicular acidification and lysosomal protein degradation. TMEM9 is highly expressed in regenerating liver and hepatocellular carcinoma (HCC) cells. TMEM9 expression is enriched in the hepatocytes around the central vein and acutely induced by injury. In mice, Tmem9 knockout impairs hepatic regeneration with aberrantly increased adenomatosis polyposis coli (Apc) and reduced Wnt signaling. Mechanistically, TMEM9 down-regulates APC through lysosomal protein degradation through v-ATPase. In HCC, TMEM9 is overexpressed and necessary to maintain ß-catenin hyperactivation. TMEM9-up-regulated APC binds to and inhibits nuclear translocation of ß-catenin, independent of HCC-associated ß-catenin mutations. Pharmacological blockade of TMEM9-v-ATPase or lysosomal degradation suppresses Wnt/ß-catenin through APC stabilization and ß-catenin cytosolic retention. CONCLUSIONS: Our results reveal that TMEM9 hyperactivates Wnt signaling for liver regeneration and tumorigenesis through lysosomal degradation of APC.

RIPK3 activation induces TRIM28 derepression in cancer cells and enhances the anti-tumor microenvironment.

BACKGROUND: Necroptosis is emerging as a new target for cancer immunotherapy as it is now recognized as a form of cell death that increases tumor immunogenicity, which would be especially helpful in treating immune-desert tumors. De novo synthesis of inflammatory proteins during necroptosis appears especially important in facilitating increased anti-tumor immune responses. While late-stage transcription mediated by NF-κB during cell death is believed to play a role in this process, it is otherwise unclear what cell signaling events initiate this transactivation of inflammatory genes. METHODS: We employed tandem-affinity purification linked to mass spectrometry (TAP-MS), in combination with the analysis of RNA-sequencing (RNA-Seq) datasets to identify the Tripartite Motif Protein 28 (TRIM28) as a candidate co-repressor. Comprehensive biochemical and molecular biology techniques were used to characterize the role of TRIM28 in RIPK3 activation-induced transcriptional and immunomodulatory events. The cell composition estimation module was used to evaluate the correlation between RIPK3/TRIM28 levels and CD8+ T cells or dendritic cells (DC) in all TCGA tumors. RESULTS: We identified TRIM28 as a co-repressor that regulates transcriptional activity during necroptosis. Activated RIPK3 phosphorylates TRIM28 on serine 473, inhibiting its chromatin binding activity, thereby contributing to the transactivation of NF-κB and other transcription factors, such as SOX9. This leads to elevated cytokine expression, which then potentiates immunoregulatory processes, such as DC maturation. The expression of RIPK3 has a significant positive association with the tumor-infiltrating immune cells populations in various tumor type, thereby activating anti-cancer responses. CONCLUSION: Our data suggest that RIPK3 activation-dependent derepression of TRIM28 in cancer cells leads to increased immunostimulatory cytokine production in the tumor microenvironment, which then contributes to robust cytotoxic anti-tumor immunity.

ATXN7L3B promotes hepatocellular carcinoma stemness and is downregulated by metformin.

Hepatocellular carcinoma (HCC) is the major cause of liver cancer-associated morality. Metformin, used for treating type 2 diabetes, has antitumor activity and reduces the risk of some diabetes-related tumors, such as liver and breast cancer. However, the mechanisms underlying metformin's effects in HCC remain unclear. To identify genes associated with metformin treatment in HCC, we conducted transcriptomic and proteomic analyses in HCC cells treated with or without metformin. We identified 41 differentially expressed genes upon metformin treatment. Among them, Ataxin 7 Like 3B (ATXN7L3B), which is a negative regulator of the Spt-Ada-Gcn5 acetyltransferase (SAGA) deubiquitinase (DUB) module and has relatively unknown functions in cancer, attracted our attention. We observed that metformin reduced ATXN7L3B level in HCC cells. ATXN7L3B expression was significantly negatively correlated with survival in liver cancer patients. We also demonstrated that ATXN7L3B promoted HCC stemness. Metformin treatment decreased ATXN7L3B-induced tumor-initiating ability in a HCC mouse model, implying that metformin may inhibit cancer stemness by downregulating ATXN7L3B. Our study supports the antitumor activity of metformin and its potential as an anticancer drug for HCC treatment.

MT4-MMP promotes invadopodia formation and cell motility in FaDu head and neck cancer cells.

Hypoxia-inducible factor-1α (HIF-1α) induces cancer metastasis. We previously demonstrated that HIF-1α-induced membrane-type 4 matrix metalloproteinase (MT4-MMP) is involved in hypoxia-mediated metastasis in head and neck squamous cell carcinoma (HNSCC). However, the functions and detailed mechanisms of MT4-MMP in cancer metastasis are not well understood. In this study, we investigated whether MT4-MMP regulates invadopodia formation or individual cell movement-both critical to cancer migration and invasion-in three-dimensional (3D) environments. By expressing MT4-MMP in the HNSCC cell line FaDu, we demonstrated that MT4-MMP increases invadopodia formation and gelatin degradation. Furthermore, the amoeboid-like cell movement on collagen gel was increased by MT4-MMP expression in FaDu cells. Mechanistically, MT4-MMP may induce invadopodia formation by binding with Tks5 and PDGFRα to result in Src activation and promote amoeboid-like movement by stimulating the small GTPases Rho and Cdc42. Altogether, our data indicate that MT4-MMP induces two crucial mechanisms of cancer dissemination, invadopodia formation and amoeboid movement, and elucidate the prometastatic role of MT4-MMP in hypoxia-mediated cancer metastasis.

Ninjurin1 enhances the basal motility and transendothelial migration of immune cells by inducing protrusive membrane dynamics.

Ninjurin1 is involved in the pathogenesis of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, by mediating leukocyte extravasation, a process that depends on homotypic binding. However, the precise regulatory mechanisms of Ninjurin1 during inflammation are largely undefined. We therefore examined the pro-migratory function of Ninjurin1 and its regulatory mechanisms in macrophages. Interestingly, Ninjurin1-deficient bone marrow-derived macrophages exhibited reduced membrane protrusion formation and dynamics, resulting in the impairment of cell motility. Furthermore, exogenous Ninjurin1 was distributed at the membrane of filopodial structures in Raw264.7 macrophage cells. In Raw264.7 cells, RNA interference of Ninjurin1 reduced the number of filopodial projections, whereas overexpression of Ninjurin1 facilitated their formation and thus promoted cell motility. Ninjurin1-induced filopodial protrusion formation required the activation of Rac1. In Raw264.7 cells penetrating an MBEC4 endothelial cell monolayer, Ninjurin1 was localized to the membrane of protrusions and promoted their formation, suggesting that Ninjurin1-induced protrusive activity contributed to transendothelial migration. Taking these data together, we conclude that Ninjurin1 enhances macrophage motility and consequent extravasation of immune cells through the regulation of protrusive membrane dynamics. We expect these findings to provide insight into the understanding of immune responses mediated by Ninjurin1.

Ninjurin1 deficiency attenuates susceptibility of experimental autoimmune encephalomyelitis in mice.

Ninjurin1 is a homotypic adhesion molecule that contributes to leukocyte trafficking in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, in vivo gene deficiency animal studies have not yet been done. Here, we constructed Ninjurin1 knock-out (KO) mice and investigated the role of Ninjurin1 on leukocyte trafficking under inflammation conditions such as EAE and endotoxin-induced uveitis. Ninjurin1 KO mice attenuated EAE susceptibility by reducing leukocyte recruitment into the injury regions of the spinal cord and showed less adhesion of leukocytes on inflamed retinal vessels in endotoxin-induced uveitis mice. Moreover, the administration of a custom-made antibody (Ab26-37) targeting the Ninjurin1 binding domain ameliorated the EAE symptoms, showing the contribution of its adhesion activity to leukocyte trafficking. In addition, we addressed the transendothelial migration (TEM) activity of bone marrow-derived macrophages and Raw264.7 cells according to the expression level of Ninjurin1. TEM activity was decreased in Ninjurin1 KO bone marrow-derived macrophages and siNinj1 Raw264.7 cells. Consistent with this, GFP-tagged mNinj1-overexpressing Raw264.7 cells increased their TEM activity. Taken together, we have clarified the contribution of Ninjurin1 to leukocyte trafficking in vivo and delineated its direct functions to TEM, emphasizing Ninjurin1 as a beneficial therapeutic target against inflammatory diseases such as multiple sclerosis.

Growth trajectories of children born preterm and full term with low birth weight to preschool ages: A nationwide study.

CONTEXT: Preterm (PT) and full term with low birth weight (FT-LBW) children are at a high-risk of poor growth outcomes. OBJECTIVE: To investigate the growth trajectories of PT and FT-LBW children from birth to preschool ages. METHODS: This study included 1,150,508 infants (PT, 41,454; FT-LBW, 38,250) who underwent the first three rounds (4-6, 9-12, and 18-24 months) of the National Health Screening Program for Infants and Children (NHSPIC). Growth measurements were obtained from the NHSPIC database and converted into Z-scores. Growth data at 2, 4, and 6 years old were measured as outcome variables. The impact of being born small on poor growth outcomes was investigated using a generalized estimating equation and Cox proportional-hazards regression analysis. RESULTS: The median birth weights of the PT, FT-LBW, and full term (FT) groups were 2.3, 2.4, and 3.2 kg, respectively. The incidence of short stature (height Z-score < -2 standard deviation score [SDS]) and failure to thrive (FTT) (body mass index (BMI) Z-score < -2 SDS) was the highest in the FT-LBW group, followed by the PT and FT groups. At 4 years old, the incidence rates were 6.0% vs. 5.2% vs. 1.9% for short stature and 4.6% vs. 3.9% vs. 1.7% for FTT. The ß estimate of height outcome was lower in both the PT (-0.326 SDS) and FT-LBW (-0.456 SDS) groups. CONCLUSIONS: The FT-LBW group was consistently shorter and lighter throughout the preschool period than the PT group, highlighting the significance of growth monitoring in high-risk populations.

NAMPT-Driven M2 Polarization of Tumor-Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer.

Nicotinamide phosphoribosyltransferase (NAMPT) is a metabolic enzyme with key roles in inflammation. Previous studies have examined the consequences of its upregulated expression in cancer cells themselves, but studies are limited with respect to its role in the other cells within the tumor microenvironment (TME) during colorectal cancer (CRC) progression. Using single-cell RNA sequencing (scRNA-seq) data, it is founded that NAMPT is highly expressed in SPP1+ tumor-associated macrophages (TAMs), a unique subset of TAMs associated with immunosuppressive activity. A NAMPThigh gene signature in SPP1+ TAMs correlated with worse prognostic outcomes in CRC patients. The effect of Nampt deletion in the myeloid compartment of mice during CRC development is explored. NAMPT deficiency in macrophages resulted in HIF-1α destabilization, leading to reduction in M2-like TAM polarization. NAMPT deficiency caused significant decreases in the efferocytosis activity of macrophages, which enhanced STING signaling and the induction of type I IFN-response genes. Expression of these genes contributed to anti-tumoral immunity via potentiation of cytotoxic T cell activity in the TME. Overall, these findings suggest that NAMPT-initiated TAM-specific genes can be useful in predicting poor CRC patient outcomes; strategies aimed at targeting NAMPT may provide a promising therapeutic approach for building an immunostimulatory TME in CRC progression.

Association between smartphone usage and health outcomes of adolescents: A propensity analysis using the Korea youth risk behavior survey.

OBJECTIVES: We aimed to investigate the association between smartphone use and adverse behavioral health outcomes using nationwide Korea Youth Risk Behavior Web-based Survey data for 2017 and 2020. METHODS: The 2020 data (N = 54,809) were used to analyze the relationships between daily smartphone usage time (non-user, 0-2 h [hour], 2-4 h, 4-6 h, 6-8 h, and > 8 h), and adverse health outcomes (stress, sleep, depression, suicide, substance use, and smartphone overdependence). A 1:1 propensity score matching (PSM) was used to control for confounding variables. RESULTS: A total of 40,998 adolescents with < 4 h/day and > 4 h/day of usage were included. Adolescents' mean smartphone usage time in 2020 increased compared to that in 2017 (weighted % of > 2 h/day; 64.3% vs. 85.7%). The curvilinear relationships between smartphone usage time and adverse health outcomes were prominent after > 4 h/day. Adolescents using smartphones 2-4 h/day showed no increased adverse health outcomes compared to non-users, except for smartphone overdependence. Using a smartphone > 4 h/day was significantly associated with stress perception (1.16; 1.11-1.22), suicidal ideation (1.22; 1.13-1.31), and substance use (alcohol, 1.66; 1.57-1.75) after PSM. CONCLUSIONS: Our study demonstrated the curvilinear relationship between smartphone usage time and adverse health outcomes in adolescents. Our findings can help establish smartphone usage guidelines for adolescents.

The risk of pediatric cardiovascular diseases in offspring born to mothers with systemic lupus erythematosus: a nationwide study.

Background: Systemic lupus erythematosus (SLE), a common autoimmune disease predominantly affecting women, has been linked to various complications during pregnancy. The transfer of anti-Ro/SSA antibodies from SLE-affected mothers to their offspring can lead to neonatal lupus and cardiac issues. This study investigated the association between maternal SLE and the risk of pediatric cardiovascular disorders. Methods: The study utilized South Korea's National Health Insurance Service (NHIS) database, covering 3,505,737 children born between 2007 and 2017 and tracked until 2020. Maternal SLE cases were identified using the World Health Organization's International Classification of Diseases Tenth revision (ICD-10) codes and linked with delivery records. Cardiologic disorders were categorized into congenital heart disease (CHD), arrhythmic disorders, and acquired heart disease. Propensity score matching with 1:4 ratios was applied to the set control group. Results: Among 3,505,737 children, 0.7% (n = 23,330) were born to mothers with SLE. The incidence of preterm birth was significantly higher in the maternal SLE group (5.9% vs. 3.0%). Compared with the control group, children born to mothers with SLE exhibited a significantly elevated risk of overall CHDs (5.5%, adjusted odds ratio [aOR] 1.21; 95% confidence interval [CI] 1.14-1.29), including atrial septal defect (1.18; 1.09-1.28) and patent ductus arteriosus (1.15; 1.03-1.30). In addition, a notably higher risk was observed in arrhythmic disorders (complete atrioventricular block 7.20; 2.41-21.49) and acquired cardiac disorders, including cardiomyopathy (1.40; 1.17-1.68) and mucocutaneous lymph node syndrome (MCLS) (1.27; 1.15-1.43). Conclusions: Maternal SLE is associated with congenital and acquired cardiac disorders in offspring, including structural, arrhythmic, and MCLS. This study highlights the need for continuous cardiovascular monitoring from the prenatal stage to preadolescence in these children due to multifactorial influences involving maternal autoantibodies, genetic predisposition, and environmental factors.

Protective Effect of Breastfeeding Against Febrile Seizure: A Nationwide Study in Korea.

BACKGROUND: Breastfeeding is known to protect against febrile seizure (FS). Whether its impact continues throughout the childhood period is still controversial. Our objective was to investigate the protective effect of breastfeeding against FS stratified by age. METHODS: We included children who participated in the National Health Screening Program for Infants and Children (NHSPIC) aged between four and six months between 2008 and 2014. Feeding type was confirmed based on the NHSPIC questionnaire, and data from the Korean National Health Insurance Service were used to determine FS cases during a five-year follow-up period. RESULTS: Among the 1,791,335 children, the most prevalent feeding type was exclusive breastfeeding (EB) (42.3%). FS occurred most frequently in the exclusive formula feeding (EF) group (12.2%), followed by the partial breastfeeding (PB) (11.3%) and EB groups (10.7%). Compared with the EF group, the adjusted odds ratio for FS was 0.87 (95% confidence interval, 0.86 to 0.88, P < 0.001) and 0.93 (0.92 to 0.94, P < 0.001) in the EB and PB groups, respectively. The protective effect by age 2.5 years was significant in both the EB (0.85; 0.84 to 0.86, P < 0.001) and PB (0.92; 0.90 to 0.93, P < 0.001) groups. In contrast, the protective effect was not significant in the PB group and inconsistent in the EB group after 2.5 years. CONCLUSION: Breastfeeding has a protective effect against FS in the most prevalent age period, from 0 to 2.5 years. Despite the limited effect after age 2.5 years, we support the current recommendation for prolonged breastfeeding to promote childhood health.

Learning-Based Longitudinal Prediction Models for Mortality Risk in Very-Low-Birth-Weight Infants: A Nationwide Cohort Study.

INTRODUCTION: Prediction models assessing the mortality of very-low-birth-weight (VLBW) infants were confined to models using only pre- and perinatal variables. We aimed to construct a prediction model comprising multifactorial clinical events with data obtainable at various time points. METHODS: We included 15,790 (including 2,045 in-hospital deaths) VLBW infants born between 2013 and 2020 who were enrolled in the Korean Neonatal Network, a nationwide registry. In total, 53 prenatal and postnatal variables were sequentially added into the three discrete models stratified by hospital days: (1) within 24 h (TL-1d), (2) from day 2 to day 7 after birth (TL-7d), (3) from day 8 after birth to discharge from the neonatal intensive care unit (TL-dc). Each model predicted the mortality of VLBW infants within the affected period. Multilayer perception (MLP)-based network analysis was used for modeling, and ensemble analysis with traditional machine learning (ML) analysis was additionally applied. The performance of models was compared using the area under the receiver operating characteristic curve (AUROC) values. The Shapley method was applied to reveal the contribution of each variable. RESULTS: Overall, the in-hospital mortality was 13.0% (1.2% in TL-1d, 4.1% in TL-7d, and 7.7% in TL-dc). Our MLP-based mortality prediction model combined with ML ensemble analysis had AUROC values of 0.932 (TL-1d), 0.973 (TL-7d), and 0.950 (TL-dc), respectively, outperforming traditional ML analysis in each timeline. Birth weight and gestational age were constant and significant risk factors, whereas the impact of the other variables varied. CONCLUSION: The findings of the study suggest that our MLP-based models could be applied in predicting in-hospital mortality for high-risk VLBW infants. We highlight that mortality prediction should be customized according to the timing of occurrence.

Rapid weight gain in early life is associated with central precocious puberty in girls, not in boys - a nationwide population-based study in Korea.

Objectives: This study aimed to investigate the effect of rapid weight gain (RWG) on the incidence of central precocious puberty (CPP) using nationwide population-based data. Methods: A total of 253,967 children (101,841 boys and 152,126 girls) who underwent regular health consultations under the National Health Insurance Service from 2007 to 2010 were followed up until the age of 10 years for boys and 9 years for girls. We calculated differences in the weight Z-scores from 4-6 months to 9-12 months (infancy) and from 9-12 months to 18-24 months or 30-36 months (toddlerhood) using the lambda-mu-sigma method. The population was subdivided into four groups: RWGinf/tod (infancy > + 0.67 standard deviation score [SDS], toddlerhood > 0 SDS), RWGinf (infancy > + 0.67 SDS, toddlerhood < 0 SDS), RWGtod (toddlerhood > + 0.67 SDS), and control (no RWG). The diagnosis of CPP was based on the diagnostic codes of the International Classification of Diseases 10th revision and the prescription of gonadotropin-releasing hormone agonists. The cumulative risk of CPP based on age was analyzed using Kaplan-Meier survival curves, and the association between the RWG groups and CPP was assessed using multivariate logistic regression analysis. Results: CPP was diagnosed in 268 boys and 9,225 girls. For the girls, the CPP-free probability was the highest in the control group, followed by the RWGtod, RWGinf, and RWGinf/tod groups (log-rank p < 0.001). However, the incidence of CPP did not vary significantly for the boys. Compared to the control group, the other groups had a higher risk of CPP in girls (RWGinf/tod: adjusted odds ratio [aOR] 1.35, 95%, confidence interval [95% CI] 1.13-1.62; RWGinf: aOR 1.25, 95% CI 1.13-1.38; and RWGtod: aOR 1.18, 95% CI 1.09-1.28). Conclusions: This nationwide population-based study demonstrated that any RWG from birth to 3 years of age contributed to an increased risk of CPP in girls but not in boys. Girls who experienced RWG during both infancy and toddlerhood had the highest risk of developing CPP. These findings suggest that early detection and appropriate management of excessive weight gain in early life may be important for preventing CPP in girls.

T-cell exhaustion and stemness in antitumor immunity: Characteristics, mechanisms, and implications.

T cells play a crucial role in the regulation of immune response and are integral to the efficacy of cancer immunotherapy. Because immunotherapy has emerged as a promising treatment for cancer, increasing attention has been focused on the differentiation and function of T cells in immune response. In this review, we describe the research progress on T-cell exhaustion and stemness in the field of cancer immunotherapy and summarize advances in potential strategies to intervene and treat chronic infection and cancer by reversing T-cell exhaustion and maintaining and increasing T-cell stemness. Moreover, we discuss therapeutic strategies to overcome T-cell immunodeficiency in the tumor microenvironment and promote continuous breakthroughs in the anticancer activity of T cells.