Faculty Bibliography

Aging involves the accumulation of various forms of molecular and cellular damage over time. Key features of aging, such as mitochondrial dysfunction, dysbiosis, and oxidative stress, are closely linked and largely driven by inflammation. This study examines the role of succinate, a key metabolite produced and utilized by cells of both host and microbes, and its receptor, succinate receptor 1 (SUCNR1), in age-related oral dysbiosis and inflammation. We examined young and aged wild-type (WT) and SUCNR1 knockout (KO) mice for this analysis. Our findings revealed significant aging-associated alveolar bone loss and succinate elevation in aged WT mice, along with notable changes in the oral microbiome. Conversely, aged KO mice showed reduced bone loss, lower succinate levels, less inflammation, and better-maintained microbial function. These results suggest that SUCNR1 is crucial in influencing aging-related succinate elevation, oral dysbiosis, and inflammation. Analysis of gene families and pathways in the oral microbiome demonstrated distinct aging-related changes between WT and KO mice, with the functional potential being preserved in the KO-aged group. This study underscores the importance of succinate elevation and signaling through SUCNR1 in regulating inflammation, alveolar bone loss, and shifts in the oral microbiome, offering potential targets for therapeutic interventions in age-related oral health issues.

BACKGROUND:Immunocompromised patients with B lymphocyte deficiency and hypogammaglobulinemia after anti-CD19 chimeric antigen receptor (CAR) T cell therapy for relapsed/refractory follicular lymphoma (FL) are at high risk of severe coronavirus disease 2019 (COVID-19) infection. CASE DESCRIPTION/METHODS:In our study, two patients with refractory FL had persistent COVID-19 infection after their anti-CD19 CAR T cell therapy. The patients were diagnosed with post-COVID-19 syndrome or COVID-19 with interstitial inflammation and persistent hypoxemia. The patients received molnupiravir and Paxlovid, along with methylprednisolone therapy when their interleukin (IL)-6 levels were high. No response was observed in interstitial inflammation, persistent hypoxemia, or persistent positive expression of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); however, the level of IL-6 decreased after these therapies. These two patients subsequently received low-dose ruxolitinib (5 mg, twice daily) as salvage therapy in combination with a gradually reduced dosage of methylprednisolone. After 1-2 months of ruxolitinib therapy, persistent hypoxemia was relieved, and interstitial inflammation was significantly absorbed. At the same time, the SARS-CoV-2 detection was found to be negative. CONCLUSIONS:Ruxolitinib might be a safe and effective alternative salvage therapy for patients with COVID-19 having interstitial inflammation and persistent hypoxemia without high cytokine levels and no response to corticosteroids.

Mounting evidence shows that gut microbiota communities and the human immune system coexist and influence each other, and there are a number of reports of a correlation between specific changes in gut microbiota and the occurrence of autoimmune diseases. B lymphocytes play a central role in the regulation of both gut microbiota communities and in autoimmune diseases. Here, we summarize evidence of the influence of gut microbiota-B cell pathways on autoimmune diseases and how B cells regulate microorganisms, which provides mechanistic insights with relevance for identification of potential therapeutic targets and related fields.

AIMS/OBJECTIVE:Neurological diseases like Alzheimer's disease (AD) with cognitive deficits show impaired theta, gamma, and ripple bands. Restoring these oscillations may be crucial for rescuing cognitive functions. Low-intensity transcranial ultrasound stimulation (TUS), a noninvasive neuromodulation method, offers high spatial resolution and deep penetration. However, it remains unclear how 40 Hz and 200 Hz TUS may improve memory in AD by regulating hippocampal oscillations. METHODS:We applied 40 Hz and 200 Hz TUS to the CA1 region of AD mice, performing memory assessments and CA1 electrophysiology recordings simultaneously. RESULTS:Our results showed that both 40 Hz and 200 Hz TUS significantly improved memory performance in AD mice by targeting the dorsal hippocampus and increasing power in corresponding frequency bands. Specifically, 40 Hz TUS enhanced gamma and ripple bands, while 200 Hz TUS strongly affected both. This enhancement increased during stimulation and persisted 5 days poststimulation. Improved coupling between theta and gamma oscillations indicated better hippocampal coordination with other brain regions. Additionally, 40 Hz TUS raised sharp wave ripple (SPW-Rs) incidence, and 200 Hz TUS increased both SPW-R incidence and duration, contributing to memory improvement. Behavioral performance significantly improved with TUS at both frequencies. CONCLUSION/CONCLUSIONS:Ultrasound-induced synchronized neural activities at 40 Hz and 200 Hz entrained corresponding oscillations and improved memory in Alzheimer's disease.

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.