Faculty Bibliography

The increasing aging population and aging-associated diseases have become a global issue for decades. People over 65 show an increased prevalence and greater severity of periodontitis, which poses threats to overall health. Studies have demonstrated a significant association between aging and the dysfunction of neutrophils, critical cells in the early stages of periodontitis, and their crosstalk with macrophages and T and B lymphocytes to establish the periodontal lesion. Neutrophils differentiate and mature in the bone marrow before entering the circulation; during an infection, they are recruited to infected tissues guided by the signal from chemokines and cytokines to eliminate invading pathogens. Neutrophils are crucial in maintaining a balanced response between host and microbes to prevent periodontal diseases in periodontal tissues. The impacts of aging on neutrophils' chemotaxis, anti-microbial function, cell activation, and lifespan result in impaired neutrophil functions and excessive neutrophil activation, which could influence periodontitis course. We summarize the roles of neutrophils in periodontal diseases and the aging-related impacts on neutrophil functional responses. We also explore the underlying mechanisms that can contribute to periodontitis manifestation in aging. This review could help us better understand the pathogenesis of periodontitis, which could offer novel therapeutic targets for periodontitis.

The mycobiome plays a key role in the host immune responses in homeostasis and inflammation. Recent studies suggest that an imbalance in the gut's fungi contributes to chronic, noninfectious diseases such as obesity, metabolic disorders, and cancers. Pathogenic fungi can colonize specific organs, and the gut mycobiome has been linked to the development and progression of various cancers, including colorectal, breast, head and neck, and pancreatic cancers. Some fungal species can promote tumorigenesis by triggering the complement system. However, in immunocompromised patients, fungi can also inhibit this activation and establish life-threatening infections. Interestingly, the interaction of the fungi and bacteria can also induce unique host immune responses. Recent breakthroughs and advancements in high-throughput sequencing of the gut and tumor mycobiomes are highlighting novel diagnostic and therapeutic opportunities for cancer. We discuss the latest developments in the field of cancer and the mycobiome and the potential benefits and challenges of antifungal therapies.

BACKGROUND:We evaluated the feasibility of completing 6 cycles of nab-paclitaxel (nab-P) and carboplatin (C) in a single arm prospective clinical trial for advanced/recurrent EC and safety and efficacy of day (D) 1, 8 nab-P in combination with D1 C q3weeks. METHODS:IV q21D. The trial tested the null hypothesis that subjects completing 6 cycles was ≤0.50 versus the alternative that the proportion is ≥0.75 in a single stage design with alpha = 0.05 and power = 80% with 23 subjects. Patients who completed 6 cycles (primary outcome), objective response rate (ORR) and clinical benefit rate (CBR) were estimated with exact 95% Clopper-Pearson confidence intervals. Progression free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier methods. RESULTS:From 08/2016-03/2018, 23 patients were enrolled. Nineteen patients (82.6%, 95% CI: 61.2%, 95.0%) completed 6 cycles, thus we could reject our null. Twelve patients (52.2%) experienced ≥1 grade 3/4 treatment-related adverse events including: anemia, 6 (26.1%); neutropenia, 5 (21.7%); diarrhea, 3 (13.0%). Fourteen patients (60.1%) reported grade 1 neuropathy. Of 9 patients with measurable target lesions, the ORR was 33.3% (95% CI: 7.5%, 70.1%) and CBR was 55.6% (95% CI: 21.2%, 86.3%). Median PFS in the advanced/recurrent patients was 23.2 (95% CI: 12.1, NR) months. CONCLUSIONS:The nab-P/C D1, 8 regimen met pre-specified feasibility criteria with acceptable toxicity and efficacy. Use of nab-P decreases need for steroid pre-medications, and this carboplatin doublet may prove advantageous for trials assessing combinations with immune checkpoint inhibitors in advanced EC.

STUDY DESIGN/METHODS:A retrospective observational study. OBJECTIVE:To assess whether the six-minute walk test (6MWT) can predict cardiopulmonary function in children with idiopathic scoliosis (IS) as an alternative to the cardiopulmonary exercise test (CPET). SUMMARY OF BACKGROUND DATA/BACKGROUND:Cardiopulmonary functional impairment in the setting of IS is a common health problem. A simple and convenient assessment method is needed. MATERIALS AND METHODS/METHODS:We recruited 65 children (eight male, 57 female) aged 10.70 to 14.84 years old with IS. Radiographic characteristics of the cohort were measured, including Risser's sign and Cobb angle. We measured cardiopulmonary exercise tolerance using both the 6MWT and CPET and their corresponding indicators, including six-minute walking distance (6MWD) and peak oxygen uptake (peak VO 2 ), respectively. Pearson correlation analysis was used to determine the relationship between 6MWT indicators and IS parameters. Linear regression models were used to explore the relationship between 6MWT and CPET response indicators. RESULTS:Over a third of the cohort (35.4%) had a Risser's sign grade of 0, with 21.5% in grade 2 and 3, respectively. The cohort's mean Cobb angle was 26.02°. 6MWD was significantly positively correlated with Risser's sign ( R =0.258; P =0.038) and change in respiratory rate positively correlated with vertebral rotation ( R =0.264; P =0.034). 6MWD positively correlated with peak VO 2 , peak VO 2 /heart rate (HR), and metabolic equivalents, and negatively correlated with the ventilation equivalent of the carbon dioxide slope (VE/VCO 2 slope) ( P <0.05). These four CPET indicators were found to be predicted from 6MWD in the linear regression model ( P <0.05). CONCLUSIONS:CPET response indicators, especially peak VO 2 , can be predicted using 6MWD, among other factors. The 6MWT can therefore be used to rapidly and efficiently predict the cardiorespiratory tolerance of children with IS. LEVEL OF EVIDENCE/METHODS:3.

Type 2 diabetes (T2D) is a chronic metabolic disorder in which insulin resistance and impaired insulin secretion result in altered metabolite balance, specifically elevated levels of circulating glucose and succinate, which increases the risk of many pathologies, including periodontitis. Succinate, a tricarboxylic acid (TCA) cycle intermediate, can be produced and metabolized by both host cells and host microbiota, where elevated levels serve as an inflammation and pathogen threat signal through activating the succinate G protein-coupled receptor, SUCNR1. Modulating succinate-induced SUCNR1 signaling remains a promising therapeutic approach for pathologies resulting in elevated levels of succinate, such as T2D and periodontitis. Here, we demonstrate hyperglycemia and elevated intracellular succinate in a T2D mouse model and determine gut microbiome composition. Drawing on previous work demonstrating the ability of a novel SUCNR1 antagonist, compound 7a, to block inflammation and alleviate dysbiosis in a mouse model, we examined if compound 7a has an impact on the growth and virulence gene expression of bacterial and fungal human microbiota in vitro, and if 7a could reduce bone loss in a periodontitis-induced mouse model. T2D mice harbored a significantly different gut microbiome, suggesting the altered metabolite profile of T2D causes shifts in host-microbial community structure, with enrichment in succinate producers and consumers and mucin-degrading bacteria. Bacterial and fungal cultures showed that 7a did not influence growth or virulence gene expression, suggesting the therapeutic effects of 7a are a direct result of 7a interacting with host cells and that alterations in microbial community structure are driven by reduced host SUCNR1 signaling. This work further suggests that targeting SUCNR1 signaling is a promising therapeutic approach in metabolic, inflammatory, or immune disorders with elevated succinate levels.

The gastrointestinal ecosystem has received the most attention when examining the contributions of the human microbiome to health and disease. This concentration of effort is logical due to the overwhelming abundance of microbes in the gut coupled with the relative ease of sampling compared with other organs. However, the intestines are intimately connected to multiple extraintestinal organs, providing an opportunity for homeostatic microbial colonisation and pathogenesis in organs traditionally thought to be sterile or only transiently harbouring microbiota. These habitats are challenging to sample, and their low microbial biomass among large amounts of host tissue can make study challenging. Nevertheless, recent findings have shown that many extraintestinal organs that are intimately linked to the gut harbour stable microbiomes, which are colonised from the gut in selective manners and have highlighted not just the influence of the bacteriome but that of the mycobiome and virome on oncogenesis and health.

Diabetes mellitus is a group of chronic diseases characterized by high blood glucose levels. Diabetic patients have a higher risk of sustaining osteoporotic fractures than non-diabetic people. The fracture healing is usually impaired in diabetics, and our understanding of the detrimental effects of hyperglycemia on fracture healing is still inadequate. Metformin is the first-line medicine for type 2 diabetes (T2D). However, its effects on bone in T2D patients remain to be studied. To assess the impacts of metformin on fracture healing, we compared the healing process of closed-wound fixed fracture, non-fixed radial fracture, and femoral drill-hole injury models in the T2D mice with and without metformin treatment. Our results demonstrated that metformin rescued the delayed bone healing and remolding in the T2D mice in all injury models. In vitro analysis indicated that compromised proliferation, osteogenesis, chondrogenesis of the bone marrow stromal cells (BMSCs) derived from the T2D mice were rescued by metformin treatment when compared to WT controls. Furthermore, metformin could effectively rescue the impaired detrimental lineage commitment of BMSCs isolated from the T2D mice in vivo as assessed by subcutaneous ossicle formation of the BMSC implants in recipient T2D mice. Moreover, the Safranin O staining of cartilage formation in the endochondral ossification under hyperglycemic condition significantly increased at day 14 post-fracture in the T2D mice receiving metformin treatment. The chondrocyte transcript factors SOX9 and PGC1α, important to maintain chondrocyte homeostasis, were both significantly upregulated in callus tissue isolated at the fracture site of metformin-treated MKR mice on day 12 post-fracture. Metformin also rescued the chondrocyte disc formation of BMSCs isolated from the T2D mice. Taken together, our study demonstrated that metformin facilitated bone healing, more specifically bone formation and chondrogenesis in T2D mouse models.

BACKGROUND:Children with idiopathic scoliosis (IS) have a high risk of osteoporosis and IS with low bone mineral density (BMD) are susceptible to curve progression. This review aims to explore the risk factors of low BMD in children with IS. METHODS:Studies were retrieved from 5 databases that were published up to January 2022. Search terms are keywords in titles or abstracts, including subject headings related to "Scoliosis", "Bone Mineral Density", and "Risk Factors". Observational studies on risk factors of low BMD in children with IS were enrolled in this review. The number of studies, sample size, outcome measures, research type, endocrine, and lifestyle-related factors, gene/signal pathway, and other contents were extracted for qualitative analysis. RESULTS:A total of 56 studies were included in this scoping review. Thirty studies involved genetic factors that may affect BMD, including the Vitamin-D receptor gene, RANK/RANKL signal pathway, the function of mesenchymal stem cells, Runx2, Interleukin-6 (IL-6), and miR-145/β-catenin pathway. Eight studies mentioned the influence of endocrine factors on BMD, and the results showed that serum levels of IL-6, leptin and its metabolites, and ghrelin in children with IS were different from the age-matched controls. In addition, there were 18 articles on lifestyle-related factors related to low BMD in children with IS, consisting of physical activity, calcium intake, Vitamin D level, and body composition. CONCLUSIONS:Genetic, endocrine, and lifestyle-related factors might relate to low BMD and even osteoporosis in IS. To prevent osteoporosis, the effectiveness of regular screening for low BMD risk factors in children with IS needs to be investigated. Additionally, clear risk factors suggest strategies for bone intervention. Future studies should consider the effectiveness of calcium and vitamin D supplements and physical activity in BMD improvement.

PURPOSE/OBJECTIVE:Osteoporosis is a risk factor for idiopathic scoliosis (IS) progression, but it is still unclear whether IS patients have bone mineral density (BMD) loss and a higher risk of osteoporosis than asymptomatic people. This systematic review aims to explore the differences in BMD and prevalence of osteoporosis between the IS group and the control group. METHODS:We searched 5 health science-related databases. Studies that were published up to February 2022 and written in English and Chinese languages were included. The primary outcome measures consisted of BMD z score, the prevalence of osteoporosis and osteopenia, and areal and volumetric BMD. Bone morphometry, trabecular microarchitecture, and quantitative ultrasound measures were included in the secondary outcome measures. The odds ratio (OR) and the weighted mean difference (WMD) with a 95% confidence interval (CI) were used to pool the data. RESULTS:A total of 32 case-control studies were included. The pooled analysis revealed significant differences between the IS group and the control group in BMD z score (WMD -1.191; 95% CI  - 1.651 to -0.732, p  <  0.001). Subgroup analysis showed significance in both female (WMD -1.031; 95% CI -1.496 to -0.566, p  <  0.001) and male participants (WMD -1.516; 95% CI -2.401 to -0.632, p  =  0.001). The prevalence of osteoporosis and osteopenia in the group with IS was significantly higher than in the control group (OR  =  6.813, 95% CI 2.815-16.489, p  <  0.001; OR 1.879; 95% CI 1.548-2.281, p  <  0.000). BMD measures by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography showed a significant decrease in the IS group (all p  <  0.05), but no significant difference was found in the speed of sound measured by quantitative ultrasound between the two groups (p > 0.05). CONCLUSION/CONCLUSIONS:Both the male and female IS patients had a generalized lower BMD and an increased prevalence of osteopenia and osteoporosis than the control group. Future research should focus on the validity of quantitative ultrasound in BMD screening. To control the risk of progression in IS patients, regular BMD scans and targeted intervention are necessary for IS patients during clinical practice.

Distinct fungal communities or "mycobiomes" have been found in individual tumor types and are known to contribute to carcinogenesis. Two new studies present a comprehensive picture of the tumor-associated mycobiomes from a variety of human cancers. These studies reveal that fungi, although in low abundance, are ubiquitous across all major human cancers and that specific mycobiome types can be predictive of survival.