増田 秀幸

Although cancer treatment saves many lives, some types of cancer, such as pancreatic ductal adenocarcinoma (PDAC), exhibit therapeutic resistance and continue to show high mortality. Tumors in cancers such as PDAC contain a substantial amount of cancer-associated fibroblast (CAF)-secreted collagen and other extracellular matrix (ECM) components, which significantly contribute to cancer therapeutic resistance. In the tumor microenvironment, CAFs stabilize the tissue by producing ECM components, remodel ECM through degradation, induce metastasis through epithelial-mesenchymal transition, and suppress cancer immune responses. Recent advances in single-cell analysis have gradually elucidated the subtypes of CAFs and their functions, leading to the emergence of CAF-targeting therapeutic strategies. In this review, I provide an overview of CAFs, their functions and classifications, the mechanisms underlying their role in therapeutic resistance, and the current status of CAF-targeting therapeutic strategies. Moreover, I explored how we can advance cancer treatment by leveraging our understanding of CAFs.

Objectives To examine the association between maternal plasma cotinine concentrations during pregnancy and attention-deficit/hyperactivity disorder (ADHD) related characteristics in children. Design Prospective birth cohort study from the Hokkaido Study on Environment and Children’s Health. Setting Hokkaido, Japan. Participants A total of 7217 children were included in the analysis. Their mothers were recruited to this study between 2003 and 2012 during early pregnancy. Blood samples of mothers in their third trimester of pregnancy were obtained. Main outcome measures ADHD-related characteristics screened by the ADHD-Rating Scale (ADHD-RS) in children at 6 and 8 years of age. Results The mothers were classified into three groups according to plasma cotinine levels (median=0.22 ng/mL)—non-smokers (≤0.21 ng/mL), passive smokers (0.22–11.48 ng/mL) and active smokers (≥11.49 ng/mL). ADHD was suspected in 302 (8.6%), 334 (10.9%) and 90 (14.5%) children in the non-smoker, passive smoker and active smoker groups, respectively. Children born to mothers in the smoking group had a statistically significant increased risk of ADHD-related characteristics (adjusted RR=1.49, 95% CI=1.19–1.86 and adjusted RR=1.20, 95% CI=1.03–1.40 for the active and passive smoking groups, respectively). Conclusion This large Japanese cohort study suggests an association between smoking during pregnancy and the risk of ADHD in children 6 and 8 years of age.

Kawasaki disease (KD) is common among pediatric patients and is associated with an increased risk of later cardiovascular complications, though the precise pathophysiology of KD remains unknown. Per- and polyfluoroalkyl substances (PFAS) have gathered notoriety as the causal pathogens of numerous diseases as well as for their immunosuppressive effects. The present epidemiological study aims to assess whether PFAS may affect KD risk. We evaluated research participants included in the ongoing prospective nationwide birth cohort of the Japan Environment and Children's Study (JECS). Among the over 100,000 pregnant women enrolled in the JECS study, 28 types of PFAS were measured in pregnancy in a subset of participants (N = 25,040). The JECS followed their children born between 2011 and 2014 (n total infants = 25,256; n Kawasaki disease infants = 271), up to age four. Among the 28 types of PFAS, those which were detected in >60 % of participants at levels above the method reporting limit (MRL) were eligible for analyses. Multivariable logistic regressions were implemented on the seven eligible PFAS, adjusting for multiple comparison effects. Finally, we conducted Weighted Quantile Sum (WQS) and Bayesian kernel machine regression (BKMR) to assess the effects of the PFAS mixture on KD. Therefore, we ran the BKMR model using kernel mechanical regression equations to examine PFAS exposure and the outcomes of KD. Upon analysis, the adjusted multivariable regression results did not reach statistical significance for the seven eligible substances on KD, while odds ratios were all under 1.0. WQS regression was used to estimate the mixture effect of the seven eligible PFAS, revealing a negative correlation with KD incidence; similarly, BKMR implied an inverse association between the PFAS mixture effect and KD incidence. In conclusion, PFAS exposure was not associated with increased KD incidence.