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Immune evasion by tumors is promoted by low T cell infiltration, ineffective T cell activity directed against the tumor, and reduced tumor antigen presentation. The TET2 DNA dioxygenase gene is frequently mutated in hematopoietic malignancies and loss of TET enzymatic activity is found in a variety of solid tumors. We showed previously that vitamin C (VC), a cofactor of TET2, enhances tumor-associated T cell recruitment and checkpoint inhibitor therapy responses in a TET2-dependent manner. Using single-cell RNA sequencing (scRNA-seq) analysis performed on B16-OVA melanoma tumors, we have shown here that an additional function for TET2 in tumors is to promote expression of certain antigen presentation machinery genes, which is potently enhanced by VC. Consistently, VC promoted antigen presentation in cell-based and tumor assays in a TET2-dependent manner. Quantifying intercellular signaling from the scRNA-seq dataset showed that T cell-derived IFN-γ-induced signaling within the tumor and tumor microenvironment requires tumor-associated TET2 expression, which is enhanced by VC treatment. Analysis of patient tumor samples indicated that TET activity directly correlates with antigen presentation gene expression and with patient outcomes. Our results demonstrate the importance of tumor-associated TET2 activity as a critical mediator of tumor immunity, which is augmented by high-dose VC therapy.

Introduction: This study presents contemporary epidemiological data regarding the prevalence and severity of asthma and wheezing among children in Hong Kong, which provides an update to the results of the International Study of Asthma and Allergies in Childhood (ISAAC) conducted in 1994-1995 and 2001-2003., Methods: This cross-sectional investigation was based on the ISAAC study protocol. Responses from 1100 children aged 6 to 7 years (Primary 1-2) and 1048 children aged 13 to 14 years (Secondary 2-3) in Hong Kong between September 2020 and August 2021 were analysed. Sex differences within each age-group were assessed using Chi squared and independent t tests. Demographic information was entered into hierarchical logistic regression models to identify potential predictive factors associated with asthma severity. Annual change in prevalence was calculated via division of the prevalence by the number of years between surveys. Logistic regression modelling was conducted to identify risk factors associated with asthma severity., Results: The prevalences of current wheezing were 6.19% and 4.97% in the primary and secondary school groups, respectively. The prevalences of asthma ever were 5.55% and 6.12%, whereas those of wheezing ever were 20.38% and 12.05%, in the primary and secondary school groups, respectively., Conclusion: Asthma severity and prevalence have decreased in Hong Kong since 1994-1995. A followup study will explore the protective and risk factors contributing to these trends., Competing Interests: All authors have disclosed no conflicts of interest.

Endosteal stem cells are a subclass of bone marrow skeletal stem cell populations that are particularly important for rapid bone formation occurring in growth and regeneration. These stem cells are strategically located near the bone surface in a specialized microenvironment of the endosteal niche. These stem cells are abundant in young stages but eventually depleted and replaced by other stem cell types residing in a non-endosteal perisinusoidal niche. Single-cell molecular profiling and in vivo cell lineage analyses play key roles in discovering endosteal stem cells. Importantly, endosteal stem cells can transform into bone tumor-making cells when deleterious mutations occur in tumor suppressor genes. The emerging hypothesis is that osteoblast-chondrocyte transitional identities confer a special subset of endosteal stromal cells with stem cell-like properties, which may make them susceptible for tumorigenic transformation. Endosteal stem cells are likely to represent an important therapeutic target of bone diseases caused by aberrant bone formation., (© 2023 Wiley Periodicals LLC.)

Background: Studies on the relationship between childhood allergic disease and health-related quality of life (HRQOL) have mostly been confined to a single allergic condition. Therefore, a composite allergic score (CAS) was derived to assess the accumulated effect of eczema, asthma, and allergic rhinitis on HRQOL in Hong Kong schoolchildren., Methods: Parents of grade one/two or grade eight/nine schoolchildren completed a questionnaire assessing the prevalence and severity of eczema (POEM), asthma (C-ACT/ACT), and allergic rhinitis (VAS) and schoolchildren's HRQOL (PedsQL). Three rounds of recruitment were conducted. A total of 19 primary and 25 secondary schools agreed to participate., Results: Data from 1140 caregivers of grade one/two schoolchildren and 1048 grade eight/nine schoolchildren were imputed and analyzed. The proportion of female respondents were lower in grade one/two (37.7%) but higher in grade eight/nine (57.3%). 63.8% of grade one/two and 58.1% of grade eight/nine schoolchildren reported having at least one allergic disease. In general, greater disease severity was significantly associated with lower HRQOL. After controlling for age, gender, and allergic comorbidity in hierarchical regressions, CAS significantly predicted all HRQOL outcomes in both grade one/two and grade eight/nine schoolchildren. Female grade eight/nine schoolchildren reported lower HRQOL outcomes., Conclusion: Composite allergic score may be a practical tool to evaluate allergic comorbidity and the effectiveness of treatments targeting common pathological mechanisms of allergic diseases. Non-pharmaceutical approaches should be considered, especially for patients with more than one allergic disease and greater severity., (© 2023 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

The bone marrow contains various populations of skeletal stem cells (SSCs) in the stromal compartment, which are important regulators of bone formation. It is well-described that leptin receptor (LepR) + perivascular stromal cells provide a major source of bone-forming osteoblasts in adult and aged bone marrow. However, the identity of SSCs in young bone marrow and how they coordinate active bone formation remains unclear. Here we show that bone marrow endosteal SSCs are defined by fibroblast growth factor receptor 3 (Fgfr3) and osteoblast-chondrocyte transitional (OCT) identities with some characteristics of bone osteoblasts and chondrocytes. These Fgfr3-creER-marked endosteal stromal cells contribute to a stem cell fraction in young stages, which is later replaced by Lepr-cre-marked stromal cells in adult stages. Further, Fgfr3 + endosteal stromal cells give rise to aggressive osteosarcoma-like lesions upon loss of p53 tumor suppressor through unregulated self-renewal and aberrant osteogenic fates. Therefore, Fgfr3 + endosteal SSCs are abundant in young bone marrow and provide a robust source of osteoblasts, contributing to both normal and aberrant osteogenesis., (© 2023. The Author(s).)

In endochondral bone development, bone-forming osteoblasts and bone marrow stromal cells have dual origins in the fetal cartilage and its surrounding perichondrium. However, how early perichondrial cells distinctively contribute to developing bones remain unidentified. Here we show using in vivo cell-lineage analyses that Dlx5 + fetal perichondrial cells marked by Dlx5-creER do not generate cartilage but sustainably contribute to cortical bone and marrow stromal compartments in a manner complementary to fetal chondrocyte derivatives under the regulation of Hedgehog signaling. Postnatally, Dlx5 + fetal perichondrial cell derivatives preferentially populate the diaphyseal marrow stroma with a dormant adipocyte-biased state and are refractory to parathyroid hormone-induced bone anabolism. Therefore, early perichondrial cells of the fetal cartilage are destined to become an adipogenic subset of stromal cells in postnatal diaphyseal bone marrow, supporting the theory that the adult bone marrow stromal compartments are developmentally prescribed within the two distinct cells-of-origins of the fetal bone anlage., (© 2022. The Author(s).)

Objective: Adverse left ventricular remodeling due to a mismatch between stiffness of native aortic tissue and current polyester grafts may be under-recognized. This study was conducted to evaluate the impact of proximal aortic replacement on adverse remodeling of the left ventricle., Materials and Methods: All aortic root and ascending aortic aneurysm patients were identified ( n = 2,001, 2006-2019). The study cohort consisted of a subset of patients ( n = 98) with two or more electrocardiogram (ECG)-gated CT angiograms, but without concomitant aortic valve disease or bicuspid aortic valve, connective tissue disease, acute aortic syndrome or prior history of aortic repair or mitral valve surgery. LV myocardial mass was measured from CT data and indexed to body surface area (LVMI). The study cohort was divided into a surgery group ( n = 47) and a control group; optimal medical therapy group (OMT, n = 51)., Results: The mean age was 60 ± 11 years (80% male). Beta-blocker use was significantly more frequent in the surgery group (89 vs. 57%, p < 0.001), whereas, all other antihypertensive drugs were more frequent in the OMT group. The average follow-up was 9.1 ± 4.0 months for the surgery group and 13.7 ± 6.3 months for the OMT group. Average LVMI at baseline was similar in both groups ( p = 0.934). LVMI increased significantly in the surgery group compared to the OMT group (3.7 ± 4.1 vs. 0.6 ± 4.4 g/m 2 , p = 0.001). Surgery, baseline LVMI, age, and sex were found to be independent predictors of LVMI increased on multivariable analysis., Conclusion: Proximal aortic repair with stiff polyester grafts was associated with increased LV mass in the first-year post-operative and may promote long-term adverse cardiac remodeling. Further studies should be considered to evaluate the competing effects of aortic aneurysm related mortality against risks of long-term graft induced aortic stiffening and the potential implications on current size thresholds for intervention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Houben, Chu, Yang, Kim, Fukuhara, van Herwaarden, Moll, Nordsletten, Figueroa, Burris and Patel.)

The periodontium is essential for supporting the functionality of the tooth, composed of diversity of mineralized and non-mineralized tissues such as the cementum, the periodontal ligament (PDL) and the alveolar bone. The periodontium is developmentally derived from the dental follicle (DF), a fibrous tissue surrounding the developing tooth bud. We previously showed through in vivo lineage-tracing experiments that DF contains mesenchymal progenitor cells expressing parathyroid hormone-related protein (PTHrP), which give rise to cells forming the periodontal attachment apparatus in a manner regulated by autocrine signaling through the PTH/PTHrP receptor. However, the developmental relationships between PTHrP + DF cells and diverse cell populations constituting the periodontium remain undefined. Here, we performed single-cell RNA-sequencing (scRNA-seq) analyses of cells in the periodontium by integrating the two datasets, i.e. PTHrP-mCherry + DF cells at P6 and 2.3kb Col1a1 promoter-driven GFP + periodontal cells at P25 that include descendants of PTHrP + DF cells, cementoblasts, osteoblasts and periodontal ligament cells. This integrative scRNA-seq analysis revealed heterogeneity of cells of the periodontium and their cell type-specific markers, as well as their relationships with DF cells. Most importantly, our analysis identified a cementoblast-specific metagene that discriminate cementoblasts from alveolar bone osteoblasts, including Pthlh (encoding PTHrP) and Tubb3 . RNA velocity analysis indicated that cementoblasts were directly derived from PTHrP + DF cells in the early developmental stage and did not interconvert with other cell types. Further, CellPhoneDB cell-cell communication analysis indicated that PTHrP derived from cementoblasts acts on diversity of cells in the periodontium in an autocrine and paracrine manner. Collectively, our findings provide insights into the lineage hierarchy and intercellular interactions of cells in the periodontium at a single-cell level, aiding to understand cellular and molecular basis of periodontal tissue formation., Competing Interests: Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Bone marrow houses a multifunctional stromal cell population expressing C-X-C motif chemokine ligand 12 (CXCL12), termed CXCL12-abundant reticular (CAR) cells, that regulates osteogenesis and adipogenesis. The quiescent pre-adipocyte-like subset of CXCL12 + stromal cells ("Adipo-CAR" cells) is localized to sinusoidal surfaces and particularly enriched for hematopoiesis-supporting cytokines. However, detailed characteristics of these CXCL12 + pre-adipocyte-like stromal cells and how they contribute to marrow adipogenesis remain largely unknown. Here we highlight CXCL12-dependent physical coupling with hematopoietic cells as a potential mechanism regulating the adipogenic potential of CXCL12 + stromal cells. Single-cell computational analyses of RNA velocity and cell signaling reveal that Adipo-CAR cells exuberantly communicate with hematopoietic cells through CXCL12-CXCR4 ligand-receptor interactions but do not interconvert with Osteo-CAR cells. Consistent with this computational prediction, a substantial fraction of Cxcl12-creER + pre-adipocyte-like cells intertwines with hematopoietic cells in vivo and in single-cell preparation in a protease-sensitive manner. Deletion of CXCL12 in these cells using Col2a1-cre leads to a reduction of stromal-hematopoietic coupling and extensive marrow adipogenesis in adult bone marrow, which appears to involve direct conversion of CXCL12 + cells to lipid-laden marrow adipocytes without altering mesenchymal progenitor cell fates. Therefore, these findings suggest that CXCL12 + pre-adipocyte-like marrow stromal cells prevent their premature differentiation by maintaining physical coupling with hematopoietic cells in a CXCL12-dependent manner, highlighting a possible cell-non-autonomous mechanism that regulates marrow adipogenesis. © 2021 American Society for Bone and Mineral Research (ASBMR)., (© 2021 American Society for Bone and Mineral Research (ASBMR).)

Pancreatic ductal adenocarcinoma (PDA) is characterized by an immune-suppressive tumor microenvironment that renders it largely refractory to immunotherapy. We implemented a multimodal analysis approach to elucidate the immune landscape in PDA. Using a combination of CyTOF, single-cell RNA sequencing, and multiplex immunohistochemistry on patient tumors, matched blood, and non-malignant samples, we uncovered a complex network of immune-suppressive cellular interactions. These experiments revealed heterogeneous expression of immune checkpoint receptors in individual patient's T cells and increased markers of CD8 + T cell dysfunction in advanced disease stage. Tumor-infiltrating CD8 + T cells had an increased proportion of cells expressing an exhausted expression profile that included upregulation of the immune checkpoint TIGIT , a finding that we validated at the protein level. Our findings point to a profound alteration of the immune landscape of tumors, and to patient-specific immune changes that should be taken into account as combination immunotherapy becomes available for pancreatic cancer., Competing Interests: Competing interests: The authors have declared that no conflict of interest exists.

Background: The cumulative effect of too much sedentary behavior may contribute to weight gain and obesity., Objective: The aim of this study was to conduct a systematic review and meta-analysis of prospective cohorts and randomized controlled studies to determine the association between sedentary behavior and body weight and obesity in adults., Data Sources and Study Selection: Relevant studies were identified from searches of the MEDLINE, Embase, AMED and PubMed databases up to May 2017, and by manual searches of in-text citations. Studies that evaluated the association in adults between sedentary behavior and body weight or obesity, while controlling for physical activity, were included. Overall, 31 publications met the eligibility criteria, including 23 prospective cohort studies with data that could be extracted for a quantitative meta-analysis, and a single randomized controlled trial., Results: There were no significant associations between sedentary behavior and any measure of body weight or obesity, with the exception of waist circumference. For the latter outcome, over a 5-year follow-up period, each 1 h per day increase-from baseline to follow-up-in sedentary behavior was associated with a 0.02 mm [95% confidence interval (CI) 0.01-0.04; p = 0.001) increase in waist circumference. The odds ratio of becoming overweight or obese was 1.33 (95% CI 1.11-1.60; p = 0.001) in the highest compared with lowest categories of sedentary behavior., Conclusions: Meta-analysis of data from prospective cohort studies showed small, inconsistent and non-significant associations between sedentary behavior and body weight.