-
1.
Circadian regulation of microglia function: Potential targets for treatment of Parkinson's Disease.
Kou, L, Chi, X, Sun, Y, Yin, S, Wu, J, Zou, W, Wang, Y, Jin, Z, Huang, J, Xiong, N, et al
Ageing research reviews. 2024;:102232
Abstract
Circadian rhythms are involved in the regulation of many aspects of the body, including cell function, physical activity and disease. Circadian disturbance often predates the typical symptoms of neurodegenerative diseases and is not only a non-motor symptom, but also one of the causes of their occurrence and progression. Glial cells possess circadian clocks that regulate their function to maintain brain development and homeostasis. Emerging evidence suggests that the microglial circadian clock is involved in the regulation of many physiological processes, such as cytokine release, phagocytosis, and nutritional and metabolic support, and that disruption of the microglia clock may affect multiple aspects of Parkinson's disease, especially neuroinflammation and α-synuclein processes. Herein, we review recent advances in the circadian control of microglia function in health and disease, and discuss novel pharmacological interventions for microglial clocks in neurodegenerative disorders.
-
2.
Effect of probiotic supplementation on in-hospital mortality in patients with acute myocardial infarction: a study protocol for an open-label, randomized, controlled, superiority clinical trial.
Chen, Y, Chen, R, Wang, X, Zhou, Y, Hong, L, Xiong, N, Zhu, J, Ye, S, Tan, X
Trials. 2023;(1):429
Abstract
BACKGROUND Recent studies have demonstrated a correlation between intestinal flora and the severity of myocardial infarction as well as post-myocardial infarction repair. However, few studies have investigated whether probiotics reduce mortality and improve cardiovascular outcomes in patients with acute myocardial infarction. In this study, we will conduct a randomized controlled trial (RCT) to evaluate the effect of probiotics on in-hospital mortality and the incidence of major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). METHODS This is an open-label, randomized, controlled, superiority clinical trial involving 2594 adult patients who were diagnosed with acute myocardial infarction. Patients will be randomized to (1) receive bifidobacteria triple viable capsule (Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis) 840 mg, twice a day, plus standard treatment strategy during the hospital stay, for a maximum of 30 days, or (2) receive the standard treatment strategy and will not take the bifidobacterium triple live capsule. The primary outcome was in-hospital all-cause mortality. DISCUSSION The purpose of this clinical trial is to determine whether probiotics can reduce in-hospital mortality and improve prognosis in patients with AMI, and the results will provide evidence for probiotics as a complementary treatment for AMI. TRIAL REGISTRATION Chinese Clinical Trials Registry ChiCTR2000038797. Registered on 2 October 2020.
-
3.
Evaluation of Treatment With Talazoparib and Avelumab in Patients With Recurrent Mismatch Repair Proficient Endometrial Cancer.
Konstantinopoulos, PA, Gockley, AA, Xiong, N, Krasner, C, Horowitz, N, Campos, S, Wright, AA, Liu, JF, Shea, M, Yeku, O, et al
JAMA oncology. 2022;(9):1317-1322
-
-
Free full text
-
Abstract
IMPORTANCE Although the activity of pembrolizumab and lenvatinib (the only US Food and Drug Administration-approved immunotherapy for mismatch repair proficient endometrial cancer [MMRP EC]) is compelling, there are no biomarkers of response and most patients do not tolerate, do not respond to, or develop resistance to this regimen, highlighting the need for additional, potentially biomarker-driven therapeutic approaches for patients with recurrent MMRP EC. OBJECTIVE To assess the potential positive outcomes and safety of the combination of the polyadenosine diphosphate-ribose polymerase inhibitor talazoparib and the programmed cell death ligand 1 (PD-L1) inhibitor avelumab in recurrent MMRP EC. DESIGN, SETTINGS, AND PARTICIPANTS This investigator-initiated, open-label, single-arm, 2-stage, phase 2 study nonrandomized controlled trial patients at 4 institutions in the US. Key eligibility criteria included measurable disease, unlimited prior therapies, and all endometrial cancer histologies. INTERVENTIONS Talazoparib, 1 mg, orally, daily, and avelumab, 10 mg/kg, intravenously, every 2 weeks, were administered until disease progression or unacceptable toxic effects. MAIN OUTCOMES AND MEASURES Statistical considerations were developed for 2 coprimary objectives of objective response rate and rate of progression-free survival at 6 months, with a 2-stage design that allowed for early discontinuation for futility. Prespecified exploratory objectives included the association of immunogenomic features (determined by targeted-panel next-generation sequencing and immunohistochemistry) with activity. RESULTS Thirty-five female patients (mean [SD] age, 67.9 [8.41] years) received protocol therapy; 9 (25.7%) derived clinical benefit after meeting at least 1 of the 2 coprimary end points. Four patients (11.4%) exhibited confirmed objective response rates (4 partial responses), and 8 (22.9%) survived progression free at 6 months. The most common grade 3 and 4 treatment-related toxic effects were anemia (16 [46%]), thrombocytopenia (10 [29%]), and neutropenia (4 [11%]); no patient discontinued receipt of therapy because of toxic effects. Tumors with homologous recombination repair alterations were associated with clinical benefit from treatment with avelumab and talazoparib. Tumor mutational burden, tumor-infiltrating lymphocytes, and PD-L1 status were not associated with clinical benefit. CONCLUSIONS AND RELEVANCE The results of this nonrandomized controlled trial suggest that treatment with avelumab and talazoparib demonstrated a favorable toxic effect profile and met the predetermined criteria to be considered worthy of further evaluation in MMRP EC. Immunogenomic profiling provided insights that may inform ongoing and future studies of polyadenosine diphosphate-ribose polymerase and PD-L1 inhibitor combinations in endometrial cancer. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02912572.
-
4.
Effect of a genetically engineered interferon-alpha versus traditional interferon-alpha in the treatment of moderate-to-severe COVID-19: a randomised clinical trial.
Li, C, Luo, F, Liu, C, Xiong, N, Xu, Z, Zhang, W, Yang, M, Wang, Y, Liu, D, Yu, C, et al
Annals of medicine. 2021;(1):391-401
-
-
Free full text
-
Abstract
BACKGROUND There are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. To compare the effectiveness of a novel genetically engineered recombinant super-compound interferon (rSIFN-co) with traditional interferon-alpha added to baseline antiviral agents (lopinavir-ritonavir or umifenovir) for the treatment of moderate-to-severe COVID-19. METHOD In this multicenter randomized (1:1) trial, patients hospitalized with moderate-to-severe COVID-19 received either rSIFN-co nebulization or interferon-alpha nebulization added to baseline antiviral agents for no more than 28 days. The primary endpoint was the time to clinical improvement. Secondary endpoints included the overall rate of clinical improvement assessed on day 28, the time to radiological improvement and virus nucleic acid negative conversion. RESULTS A total of 94 patients were included in the safety set (46 patients assigned to rSIFN-co group, 48 to interferon-alpha group). The time to clinical improvement was 11.5 days versus 14.0 days (95% CI 1.10 to 2.81, p = .019); the overall rate of clinical improvement on day 28 was 93.5% versus 77.1% (difference, 16.4%; 95% CI 3% to 30%); the time to radiological improvement was 8.0 days versus 10.0 days (p = .002), the time to virus nucleic acid negative conversion was 7.0 days versus 10.0 days (p = .018) in the rSIFN-co and interferon alpha arms, respectively. Adverse events were balanced with no deaths among groups. CONCLUSIONS AND RELEVANCE rSIFN-co was associated with a shorter time of clinical improvement than traditional interferon-alpha in the treatment of moderate-to-severe COVID-19 when combined with baseline antiviral agents. rSIFN-co therapy alone or combined with other antiviral therapy is worth to be further studied.Key messagesThere are few effective therapies for coronavirus disease 2019 (COVID-19) upon the outbreak of the pandemic. Interferon alphas, by inducing both innate and adaptive immune responses, have shown clinical efficacy in treating severe acute respiratory syndrome coronavirus and Middle East respiratory syndrome coronavirus.In this multicenter, head-to-head, randomized, clinical trial which included 94 participants with moderate-to-severe COVID-19, the rSIFN-co plus antiviral agents (lopinavir-ritonavir or umifenovir) was associated with a shorter time of clinical improvement than interferon-alpha plus antiviral agents.
-
5.
Fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes: a multi-centre retrospective study.
Wang, S, Ma, P, Zhang, S, Song, S, Wang, Z, Ma, Y, Xu, J, Wu, F, Duan, L, Yin, Z, et al
Diabetologia. 2020;63(10):2102-2111
-
-
-
Free full text
-
Plain language summary
Hyperglycaemia was a risk factor for mortality from severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) and is an independent risk factor for lower respiratory tract infection and poor prognosis. The aim of this retrospective study of 605 patients without previously diagnosed diabetes was to examine the association between fasting blood glucose (FBG) on admission and the 28-day in hospital mortality of COVID-19 patients. Patients with a FBG level of 7.0mmol/l or over had more than double the risk of dying than those with a level of 6.0mmol/l or less. Other risk factors for mortality included age, being male, and severity of pneumonia at admission. Compared with patients whose FBG was 6.0mmol/l or lower at admission, patients with FBG of 7.0 mmol/l and above had a 3.99 times higher risk of in-hospital complications, whilst those with FBG of 6.1–6.9 mmol/l had a 2.61 times higher risk of complications. The authors conclude that glycaemic testing and control are important to all COVID-19 patients even where they have no pre-existing diabetes.
Abstract
AIMS/HYPOTHESIS Hyperglycaemia is associated with an elevated risk of mortality in community-acquired pneumonia, stroke, acute myocardial infarction, trauma and surgery, among other conditions. In this study, we examined the relationship between fasting blood glucose (FBG) and 28-day mortality in coronavirus disease 2019 (COVID-19) patients not previously diagnosed as having diabetes. METHODS We conducted a retrospective study involving all consecutive COVID-19 patients with a definitive 28-day outcome and FBG measurement at admission from 24 January 2020 to 10 February 2020 in two hospitals based in Wuhan, China. Demographic and clinical data, 28-day outcomes, in-hospital complications and CRB-65 scores of COVID-19 patients in the two hospitals were analysed. CRB-65 is an effective measure for assessing the severity of pneumonia and is based on four indicators, i.e. confusion, respiratory rate (>30/min), systolic blood pressure (≤90 mmHg) or diastolic blood pressure (≤60 mmHg), and age (≥65 years). RESULTS Six hundred and five COVID-19 patients were enrolled, including 114 who died in hospital. Multivariable Cox regression analysis showed that age (HR 1.02 [95% CI 1.00, 1.04]), male sex (HR 1.75 [95% CI 1.17, 2.60]), CRB-65 score 1-2 (HR 2.68 [95% CI 1.56, 4.59]), CRB-65 score 3-4 (HR 5.25 [95% CI 2.05, 13.43]) and FBG ≥7.0 mmol/l (HR 2.30 [95% CI 1.49, 3.55]) were independent predictors for 28-day mortality. The OR for 28-day in-hospital complications in those with FBG ≥7.0 mmol/l and 6.1-6.9 mmol/l vs <6.1 mmol/l was 3.99 (95% CI 2.71, 5.88) or 2.61 (95% CI 1.64, 4.41), respectively. CONCLUSIONS/INTERPRETATION FBG ≥7.0 mmol/l at admission is an independent predictor for 28-day mortality in patients with COVID-19 without previous diagnosis of diabetes. Glycaemic testing and control are important to all COVID-19 patients even where they have no pre-existing diabetes, as most COVID-19 patients are prone to glucose metabolic disorders. Graphical abstract.
-
6.
Dysregulated Microbial Fermentation of Soluble Fiber Induces Cholestatic Liver Cancer.
Singh, V, Yeoh, BS, Chassaing, B, Xiao, X, Saha, P, Aguilera Olvera, R, Lapek, JD, Zhang, L, Wang, WB, Hao, S, et al
Cell. 2018;175(3):679-694.e22
Abstract
Dietary soluble fibers are fermented by gut bacteria into short-chain fatty acids (SCFA), which are considered broadly health-promoting. Accordingly, consumption of such fibers ameliorates metabolic syndrome. However, incorporating soluble fiber inulin, but not insoluble fiber, into a compositionally defined diet, induced icteric hepatocellular carcinoma (HCC). Such HCC was microbiota-dependent and observed in multiple strains of dysbiotic mice but not in germ-free nor antibiotics-treated mice. Furthermore, consumption of an inulin-enriched high-fat diet induced both dysbiosis and HCC in wild-type (WT) mice. Inulin-induced HCC progressed via early onset of cholestasis, hepatocyte death, followed by neutrophilic inflammation in liver. Pharmacologic inhibition of fermentation or depletion of fermenting bacteria markedly reduced intestinal SCFA and prevented HCC. Intervening with cholestyramine to prevent reabsorption of bile acids also conferred protection against such HCC. Thus, its benefits notwithstanding, enrichment of foods with fermentable fiber should be approached with great caution as it may increase risk of HCC.
-
7.
Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management.
Guo, S, Huang, J, Jiang, H, Han, C, Li, J, Xu, X, Zhang, G, Lin, Z, Xiong, N, Wang, T
Frontiers in aging neuroscience. 2017;:171
Abstract
Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs) in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non-pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and α2δ agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered.
-
8.
Protein-Restricted Diets for Ameliorating Motor Fluctuations in Parkinson's Disease.
Wang, L, Xiong, N, Huang, J, Guo, S, Liu, L, Han, C, Zhang, G, Jiang, H, Ma, K, Xia, Y, et al
Frontiers in aging neuroscience. 2017;:206
Abstract
Levodopa is considered to be the most effective symptomatic drug for Parkinson's disease (PD). As the disease progresses, however, the patients are likely to experience a reduced response to levodopa and develop motor fluctuations (i.e., end-of-dose wearing off and unpredictable "on-off"). Protein-rich diets and elevated plasma concentrations of large neutral amino acids have been proved to impair the therapeutic effect of levodopa by reducing its absorption and influx into the brain. On the other hand, the protein-restricted diets including low-protein diet (LPD), protein-redistribution diet (PRD) and PRD with use of low-protein products can all improve the efficacy of levodopa in patients with motor fluctuations. However, it should be noted that protein-restricted diets may also contribute to several side effects, including dyskinesia, weight loss, and malnutrition (e.g., protein and calcium insufficiency). Together, protein-restricted diets are an effective approach to improve motor fluctuations in PD patients, while long-term adherence to these diets requires monitoring for side effects.