Incremental value of amyloid PET in a tertiary memory clinic setting in China.

INTRODUCTION: The objective of this study is to investigate the incremental value of amyloid positron emission tomography (Aß-PET) in a tertiary memory clinic setting in China. METHODS: A total of 1073 patients were offered Aß-PET using 18F-florbetapir. The neurologists determined a suspected etiology (Alzheimer's disease [AD] or non-AD) with a percentage estimate of their confidence and medication prescription both before and after receiving the Aß-PET results. RESULTS: After disclosure of the Aß-PET results, etiological diagnoses changed in 19.3% of patients, and diagnostic confidence increased from 69.3% to 85.6%. Amyloid PET results led to a change of treatment plan in 36.5% of patients. Compared to the late-onset group, the early-onset group had a more frequent change in diagnoses and a higher increase in diagnostic confidence. DISCUSSION: Aß-PET has significant impacts on the changes of diagnoses and management in Chinese population. Early-onset cases are more likely to benefit from Aß-PET than late-onset cases. HIGHLIGHTS: Amyloid PET contributes to diagnostic changes and its confidence in Chinese patients. Amyloid PET leads to a change of treatment plans in Chinese patients. Early-onset cases are more likely to benefit from amyloid PET than late-onset cases.

Multipredictor risk models for predicting individual risk of Alzheimer's disease.

BACKGROUND: Early prevention of Alzheimer's disease (AD) is a feasible way to delay AD onset and progression. Information on AD prediction at the individual patient level will be useful in AD prevention. In this study, we aim to develop risk models for predicting AD onset at individual level using optimal set of predictors from multiple features. METHODS: A total of 487 cognitively normal (CN) individuals and 796 mild cognitive impairment (MCI) patients were included from Alzheimer's Disease Neuroimaging Initiative. All the participants were assessed for clinical, cognitive, magnetic resonance imaging and cerebrospinal fluid (CSF) markers and followed for mean periods of 5.6 years for CN individuals and 4.6 years for MCI patients to ascertain progression from CN to incident prodromal stage of AD or from MCI to AD dementia. Least Absolute Shrinkage and Selection Operator Cox regression was applied for predictors selection and model construction. RESULTS: During the follow-up periods, 139 CN participants had progressed to prodromal AD (CDR ≥ 0.5) and 321 MCI patients had progressed to AD dementia. In the prediction of individual risk of incident prodromal stage of AD in CN individuals, the AUC of the final CN model was 0.81 within 5 years. The final MCI model predicted individual risk of AD dementia in MCI patients with an AUC of 0.92 within 5 years. The models were also associated with longitudinal change of Mini-Mental State Examination (p < 0.001 for CN and MCI models). An Alzheimer's continuum model was developed which could predict the Alzheimer's continuum for individuals with normal AD biomarkers within 3 years with high accuracy (AUC = 0.91). CONCLUSIONS: The risk models were able to provide personalized risk for AD onset at each year after evaluation. The models may be useful for better prevention of AD.

Plasma Glial Fibrillary Acidic Protein in the Alzheimer Disease Continuum: Relationship to Other Biomarkers, Differential Diagnosis, and Prediction of Clinical Progression.

BACKGROUND: Plasma glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker in neurological disorders, but further evidence is required in relation to its usefulness for diagnosis and prediction of Alzheimer disease (AD). METHODS: Plasma GFAP was measured in participants with AD, non-AD neurodegenerative disorders, and controls. Its diagnostic and predictive value were analyzed alone or combined with other indicators. RESULTS: A total of 818 participants were recruited (210 followed). Plasma GFAP was significantly higher in AD than in non-AD dementia and non-demented individuals. It increased in a stepwise pattern from preclinical AD, through prodromal AD to AD dementia. It effectively distinguished AD from controls [area under the curve (AUC) > 0.97] and non-AD dementia (AUC > 0.80) and distinguished preclinical (AUC > 0.89) and prodromal AD (AUC > 0.85) from Aß-normal controls. Adjusted or combined with other indicators, higher levels of plasma GFAP displayed predictive value for risk of AD progression (adjusted hazard radio= 4.49, 95%CI, 1.18-16.97, P = 0.027 based on the comparison of those above vs below average at baseline) and cognitive decline (standard-ß=0.34, P = 0.002). Additionally, it strongly correlated with AD-related cerebrospinal fluid (CSF)/neuroimaging markers. CONCLUSIONS: Plasma GFAP effectively distinguished AD dementia from multiple neurodegenerative diseases, gradually increased across the AD continuum, predicted the individual risk of AD progression, and strongly correlated with AD CSF/neuroimaging biomarkers. Plasma GFAP could serve as both a diagnostic and predictive biomarker for AD.

18F-Florzolotau PET imaging captures the distribution patterns and regional vulnerability of tau pathology in progressive supranuclear palsy.

PURPOSE: Human post mortem studies have described the topographical patterns of tau pathology in progressive supranuclear palsy (PSP). Recent advances in tau PET tracers are expected to herald the next era of PSP investigation for early detection of tau pathology in living brains. This study aimed to investigate whether 18F-Florzolotau PET imaging may capture the distribution patterns and regional vulnerability of tau pathology in PSP, and to devise a novel image-based staging system. METHODS: The study cohort consisted of 148 consecutive patients with PSP who had undergone 18F-Florzolotau PET imaging. The PSP rating scale (PSPrs) was used to measure disease severity. Similarities and differences of tau deposition among different clinical phenotypes were examined at the regional and voxel levels. An 18F-Florzolotau pathological staging system was devised according to the scheme originally developed for post mortem data. In light of conditional probabilities for the sequence of events, an 18F-Florzolotau modified staging system by integrating clusters at the regional level was further developed. The ability of 18F-Florzolotau staging systems to reflect disease severity in terms of PSPrs score was assessed by analysis of variance. RESULTS: The distribution patterns of 18F-Florzolotau accumulation in living brains of PSP showed a remarkable similarity to those reported in post mortem studies, with the binding intensity being markedly higher in Richardson's syndrome. Moreover, 18F-Florzolotau PET imaging allowed detecting regional vulnerability and tracking tau accumulation in an earlier fashion compared with post mortem immunostaining. The 18F-Florzolotau staging systems were positively correlated with clinical severity as reflected by PSPrs scores. CONCLUSIONS: 18F-Florzolotau PET imaging can effectively capture the distribution patterns and regional vulnerability of tau pathology in PSP. The 18F-Florzolotau modified staging system holds promise for early tracking of tau deposition in living brains.

Plasma Biomarkers and Positron Emission Tomography Tau Pathology in Progressive Supranuclear Palsy.

BACKGROUND: Development of disease-modifying therapeutic trials of progressive supranuclear palsy (PSP) urges the need for sensitive fluid biomarkers. OBJECTIVES: The objectives of this study were to explore the utility of plasma biomarkers in the diagnosis, differential diagnosis, and assessment of disease severity, brain atrophy, and tau deposition in PSP. METHODS: Plasma biomarkers were measured using a single-molecule array in a cohort composed of patients with PSP, Parkinson's disease (PD), multiple system atrophy with predominant parkinsonism (MSA-P), and healthy controls (HCs). RESULTS: Plasma neurofilament light chain (NfL) outperformed other plasma makers (ie, glial fibrillary acidic protein [GFAP], phosphorylated-tau 181 [p-tau181], amyloid-ß 1-40, amyloid-ß 1-42) in identifying PSP from HC (area under the curve [AUC] = 0.904) and from MSA-P (AUC = 0.711). Plasma GFAP aided in distinguishing PSP from HC (AUC = 0.774) and from MSA-P (AUC = 0.832). It correlated with brainstem atrophy and higher regional tau accumulation. However, plasma p-tau181 neither helped in diagnosis nor was it associated with clinical or neuroimaging measures. CONCLUSIONS: Plasma NfL and GFAP showed different values in differentiating PSP from HC or controls with other forms of neurodegenerative parkinsonism and detecting disease severity, brain atrophy, or tau deposition in PSP. © 2023 International Parkinson and Movement Disorder Society.

In Vivo 18 F-APN-1607 Tau Positron Emission Tomography Imaging in MAPT Mutations: Cross-Sectional and Longitudinal Findings.

BACKGROUND: Frontotemporal lobar degeneration with tauopathy caused by MAPT (microtubule-associated protein tau) mutations is a highly heterogenous disorder. The ability to visualize and longitudinally monitor tau deposits may be beneficial to understand disease pathophysiology and predict clinical trajectories. OBJECTIVE: The aim of this study was to investigate the cross-sectional and longitudinal 18 F-APN-1607 positron emission tomography/computed tomography (PET/CT) imaging findings in MAPT mutation carriers. METHODS: Seven carriers of MAPT mutations (six within exon 10 and one outside of exon 10) and 15 healthy control subjects were included. All participants underwent 18 F-APN-1607 PET/CT at baseline. Three carriers of exon 10 mutations received follow-up 18 F-APN-1607 PET/CT scans. Standardized uptake value ratio (SUVR) maps were obtained using the cerebellar gray matter as the reference region. SUVR values observed in MAPT mutation carriers were normalized to data from healthy control subjects. A regional SUVR z score ≥ 2 was used as the criterion to define positive 18 F-APN-1607 PET/CT findings. RESULTS: Although the seven study patients had heterogenous clinical phenotypes, all showed a significant 18 F-APN-1607 uptake characterized by high-contrast signals. However, the anatomical localization of tau deposits differed in patients with distinct clinical symptoms. Follow-up imaging data, which were available for three patients, demonstrated worsening trends in patterns of tau accumulation over time, which were paralleled by a significant clinical deterioration. CONCLUSIONS: Our data represent a promising step in understanding the usefulness of 18 F-APN-1607 PET/CT imaging for detecting tau accumulation in MAPT mutation carriers. Our preliminary follow-up data also suggest the potential value of 18 F-APN-1607 PET/CT for monitoring the longitudinal trajectories of frontotemporal lobar degeneration caused by MAPT mutations. © 2021 International Parkinson and Movement Disorder Society.

Dopamine transporter imaging in progressive supranuclear palsy: Severe but nonspecific to subtypes.

BACKGROUND: Previous studies with a limited sample size suggested more severe dopaminergic transporter (DAT) lesions in the striatum of progressive supranuclear palsy (PSP) than those in Parkinson's disease (PD) and multiple system atrophy-parkinsonism (MSA-P). However, few studies had taken various subtypes of PSP into consideration, making the reanalysis of DAT imaging in larger PSP cohort with various subtypes in need. OBJECTIVES: To compare the dopaminergic lesion patterns of PSP with MSA-P and PD, and to explore the specific striatal subregional patterns of different PSP subtypes. METHODS: 11 C-CFT positron emission tomography (PET) imaging was conducted in 83 PSP patients consisting of different subtypes, 61 patients with PD, 41 patients with MSA-P, and 43 healthy volunteers. Demographic and clinical data were compared by the chi-squared test or one-way analysis of variance. A generalized linear model was used to examine intergroup differences in tracer uptake values after adjusting for age, disease duration, and disease severity. Areas under the receiver operating characteristic curve were calculated to assess the diagnostic accuracy of subregional DAT binding patterns. RESULTS: The patients with PSP presented more severe DAT loss in the striatum than in PD and MSA-P, especially in caudate. In PSP, the subregional lesion was still more severe in putamen than in caudate, similar to that in PD and MSA-P. Among detailed subtypes, no significant difference was detected. CONCLUSION: The dopaminergic lesions were more severe in PSP, and no difference was detected among subtypes.

Striatal asymmetry index and its correlation with the Hoehn & Yahr stage in Parkinson's disease.

PURPOSE: Striatal asymmetry is a common feature in Parkinson's disease (PD), which changes with the progression of the disease. However, the correlation between the striatal asymmetry and severity of PD remains unclear. The present study aimed to investigate the characteristics of asymmetry in PD, and analyze the correlation between the striatal asymmetry index (SAI) and disease severity. MATERIALS AND METHODS: This retrospective study enrolled 63 patients with idiopathic PD. The severity of PD was classified according to the Hoehn & Yahr (H&Y) staging system. The SAI in the subregions of the striatum was measured using 11C-N-2-carbomethoxy-3-(4-fluorophenyl)-tropane (11C-CFT) positron emission tomography (PET). RESULTS: There was a significant difference in the SAI of the posterior putamen among the three groups (H&Y stage I, H&Y stage II, and H&Y stage III-IV; p = 0.001). However, there was no difference in the SAI of the anterior putamen (p = 0.340) or SAI of the caudate nucleus (p = 0.342) among the three groups. The SAI of the posterior putamen in patients with PD was significantly higher than that in patients with multiple system atrophy or progressive supranuclear palsy (p = 0.008). CONCLUSION: The SAI of the posterior putamen is associated with the severity of PD, and may be correlated to the loss of dopamine cells in the pars compacta of the ventrolateral substantia nigra projecting to the posterior putamen. The SAI may be a potential indicator for evaluating the severity of PD, and distinguishing PD from other degenerative diseases.

Characterization of a novel glucocorticoid-resistant human B-cell acute lymphoblastic leukemia cell line, with AMPK, mTOR and fatty acid synthesis pathway inhibition.

BACKGROUND: Acquired glucocorticoid (GC) resistance remains the main obstacle in acute lymphoblastic leukemia (ALL) therapy. The aim of the present study was to establish a novel GC-resistant B-ALL cell line and investigate its biological characteristics. METHODS: A cell culture technique was used to establish the GC-resistant cell line from the parental cell, NALM-6. Molecular and cellular biological techniques including flow cytometry, MTT assay, western blotting, DNA fingerprinting analysis and whole transcriptome sequencing (WTS) were used to characterize the GC-resistant cell lines. Nude mice were used for xenograft studies. RESULTS: The GC-resistant cell line, NALM-6/HDR, was established by culturing NALM-6 cells under hypoxia for 5 weeks with a single dexamethasone (Dex) treatment. We subcloned the NALM-6/HDR cell lines, and got 6 monoclone Dex-resistant cell lines, NALM-6/HDR-C1, C3, C4, C5, C6 and C9 with resistance index (RI) ranging from 20,000-50,000. NALM-6/HDR and its monoclone cell line, NALM-6/HDR-C5, exhibited moderate (RI 5-15) to high resistance (RI > 20) to Ara-c; low or no cross-resistance to L-Asp, VCR, DNR, and MTX (RI < 5). STR analysis confirmed that NALM-6/HDR and NALM-6/H were all derived from NALM-6. All these cells derived from NALM-6 showed similar morphology, growth curves, immunophenotype, chromosomal karyotype and tumorigenicity. WTS analysis revealed that the main metabolic differences between NALM-6 or NALM-6/H (GC-sensitive) and NALM-6/HDR (GC-resistant) were lipid and carbohydrates metabolism. Western blotting analysis showed that NALM-6/HDR cells had a low expression of GR and p-GR. Moreover, AMPK, mTORC1, glycolysis and de novo fatty acid synthesis (FAS) pathway were inhibited in NALM-6/HDR when compared with NALM-6. CONCLUSIONS: NALM-6/HDR cell line may represent a subtype of B-ALL cells in patients who acquired GC and Ara-c resistance during the treatment. These patients may get little benefit from the available therapy target of AMPK, mTORC1, glycolysis and FAS pathway.

Screening for Early-Stage Parkinson's Disease: Swallow Tail Sign on MRI Susceptibility Map-Weighted Images Compared With PET.

BACKGROUND: Swallow tail sign (STS) on MRI is presumed to be an imaging biomarker of nigrosome-1, which may exhibit a similar role as positron emission tomography (PET), indicating dopaminergic degeneration. PURPOSE: To investigate whether an alteration of STS could serve as an alternative screening sign compared with PET in the diagnosis of early-stage Parkinson's disease (esPD). STUDY TYPE: Prospective. POPULATION: Thirty-seven patients with esPD and 27 age- and sex-matched healthy controls (HCs). FIELD STRENGTH/SEQUENCE: Quantitative susceptibility mapping images were collected on 3T MRI and [18 F]9-fluoropropyl-(+)-dihydrotetra-benazine PET images were acquired using a 64 rings PET/CT scanner. ASSESSMENT: Alterations of STS and striatal uptake in each hemisphere were visually rated on a 0-2 points scale. Point 2: normal appearance of STS/normal striatal uptake; Point 1: partial loss of STS/uptake reduction confined to the putamen; Point 0: total loss of STS/uptake reduction extended to the caudate nucleus. The concordance rate of STS rating and ipsilateral striatal binding was calculated at the nuclei level. At the participant level, an evaluation rating was calculated by adding the STS ratings from both hemispheres to distinguish esPD from HCs. STATISTICAL TESTS: The intra- and interobserver agreement were tested using Cohen's kappa and the intraclass correlation coefficient. Hotelling's T-squared test was used to compare the difference of rating points. Receiver operating characteristic analysis was performed to evaluate the diagnostic power. RESULTS: The intra- and interobserver agreement for STS and striatal uptake rating was over 0.75. There was no significant difference of rating point distribution (P = 0.084). The concordance rate was 94.3% for the right side and 91.4% for the left. Using bilateral partial loss of STS as the threshold, the achieved sensitivity and specificity for discriminating esPD from HCs were 94.59% and 92.49%, respectively. DATA CONCLUSION: STS alterations corresponded well with striatal uptake on PET in esPD, and our proposed evaluation scale of STS had satisfactory diagnostic performance in discriminating the disease. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Oral administration of MnCl2 attenuated hyperlipidemia-related cardiac remodeling in ApoE-/- mice.

Manganese chloride (MnCl2) has been shown to inhibit the Yes-associated protein (YAP) in high-fat diet-fed ApoE-/- mice. Although YAP has been implicated in atherogenesis, there are limited data on the effects of MnCl2 on cardiac remodeling. In this study, we discovered, by electrocardiography, that hyperlipidemia led to spontaneous supraventricular arrhythmia (SVA) in ApoE-/- (KO) mice, with 3 of 9 KO + MnCl2 mice (33%) exhibiting lower incidence of spontaneous SVA than KO mice (6 of 10 mice, 60%). Echocardiography revealed that reduced systolic function in KO mice was reversed by MnCl2 treatment. Oil Red O staining of the aortas and biochemical analysis of lipid levels showed that MnCl2 inhibited plaque formation in a lipid metabolism-independent manner. MnCl2 inhibited inflammatory cell infiltration and reduced fibrosis, as evidenced by hematoxylin and eosin, immunohistochemical and Masson's trichrome staining, respectively. Our findings demonstrate that spontaneous SVA and reduced systolic function were blocked by MnCl2. Our findings show that MnCl2 was useful in delaying cardiac remodeling and reducing susceptibility to spontaneous SVA in a mouse model of hyperlipidemia.

Clinical characteristics of cognitive impairment in patients with Parkinson's disease and its related pattern in 18 F-FDG PET imaging.

This study aimed to characterize the clinical features and the related cerebral glucose metabolism pattern of cognitive impairments in Parkinson's disease (PD) with positron emission tomography (PET) imaging. We recruited 168 PD patients and 100 age-matched healthy controls of similar education and gender distribution. All of those enrolled underwent clinical assessment including the unified Parkinson's disease rating scale motor score, Hoehn and Yahr scale, and comprehensive neuropsychological tests including domains of executive function, attention, memory, visuospatial function, and language. Demographics and the results of cognitive measures were compared between patients and healthy controls. Cognition status was classified as PD patients with dementia (PD-D), PD patients with mild cognitive impairment (PD-MCI), or PD patients with normal cognition (PD-NC). In 53 PD patients who underwent 18 F-fluorodeoxyglucose (18 F-FDG) PET imaging, correlations between Z-score values of the different cognitive domains and cerebral 18 F-FDG uptake were assessed using statistical parametric mapping (SPM8) corrected for age and motor severity. A total of 23.2% of PD patients were PD-MCI and 8.9% were PD-D. In the group of PD-MCI, 96.3% showed multiple-domain deficits, with executive function and attention impairment most predominantly involved. All the cognitive domain scores with the exception of language correlated with 18 F-FDG metabolisms, primarily in posterior temporo-parieto-occipital association cortical areas. This study found that cognitive impairment in PD particularly encompasses frontal/executive deficits. Posterior cortical areas, containing multiple neurotransmitters and neural circuits, may play an important role in the pathogenesis of cognitive impairment in PD.

A Novel Inhibitor of Homodimerization Targeting MyD88 Ameliorates Renal Interstitial Fibrosis by Counteracting TGF-ß1-Induced EMT in Vivo and in Vitro.

BACKGROUND/AIMS: The TLR/MyD88/NF-κB signaling pathway has been successfully used to treat renal interstitial fibrosis (RIF). However, the exact therapeutic mechanism is still unknown. Here, we assessed the therapeutic efficacy of TJ-M2010-2, a small molecular compound that inhibits MyD88 homodimerization, in RIF induced by ischemia reperfusion injury (IRI). METHODS: In vivo, RIF was induced in mice by IRI, and the mice were prophylactically treated with TJ-M2010-2. In vitro, HK-2 cells were incubated with TGF-ß1 to induce EMT, and the cells were pretreated with TJ-M2010-2. RESULTS: We found that, compared with the IRI group, the TJ-M2010-2 group showed marked attenuation of RIF and renal function injury; decreased expression of TGF-ß1, α-SMA, vimentin, MMP2 and MMP9; and increased E-cadherin expression. Furthermore, TGF-ß1-induced EMT was blocked by TJ-M2010-2 in HK-2 cells, as evidenced by blocked morphologic transformation, restored E-cadherin expression and inhibited α-SMA expression. In addition, compared to the TGF-ß1 group, the TJ-M2010-2 group showed profound inhibition of the expression of TRAF6, p65 and Snail and upregulation of the expression of IκBα. CONCLUSION: This MyD88 inhibitor may be a potential therapeutic agent to ameliorate RIF.

Effect of neoadjuvant chemoradiotherapy on perioperative immune function of patients with locally advanced esophageal cancer.

This study aims to evaluate the effect of neoadjuvant chemoradiotherapy (NCRT) on perioperative immune function during surgery to treat resectable locally advanced esophageal cancer. Records were retrospectively analyzed for 220 patients with locally advanced esophageal cancer, of whom 112 received surgery alone and 98 received neoadjuvant NCRT plus surgery. The two groups were compared in terms of proportions of CD3+, CD4+, CD8+, and natural kill (NK) cells, as well as the ratio of CD4+ to CD8+ cells. These measurements were made using flow cytometry on preoperative day 1 and on postoperative days 1 and 7. Subgroup analysis were performed in terms of degrees of pathological response of NCRT. When the entire NCRT and no-NCRT (surgery alone) cohorts were compared, no significant differences in propocrtions of CD3+, CD4+, CD8+, or NK cells or in the CD4+/CD8+ ratio occurred at any of the three time points. Similar results were obtained using the subgroup of NCRT patients who were NCRT-sensitive, but the subgroup of NCRT-insensitive patients showed significantly lower CD4+ and NK proportions and lower CD4+/CD8+ ratio than the no-NCRT group. Our findings suggest that NCRT does not affect perioperative immune function in patients who are NCRT-sensitive, but it does significantly reduce such function in patients who are NCRT-insensitive.

Atorvastatin attenuates experimental contrast-induced acute kidney injury: a role for TLR4/MyD88 signaling pathway.

OBJECTIVES: To investigate the protective effect of different atorvastatin doses on contrast-induced acute kidney injury and the related mechanism. METHODS: Healthy male Sprague-Dawley (SD) rats were randomly divided into the blank control group, experimental control group and different-dose atorvastatin groups. A rat model of contrast-induced acute kidney injury was established. We detected changes in serum creatinine (Scr) and blood urea nitrogen (BUN) before and after model establishment, observed and scored renal tubular injury, analyzed rat renal cell apoptosis, and measure the expression of signal pathway proteins and downstream inflammatory factors. RESULTS: After contrast agent injection, the Scr and BUN levels of the experimental control group were significantly increased, the different doses applied in the atorvastatin group significantly reduced the Scr and BUN levels (p < .05) and ameliorated the contrast-induced acute kidney injury (p < .05) and significantly reduced Toll-like receptor 4 (TLR4), Myeloid differentiation factor 88 (Myd88), and Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein expression and relative mRNA expression levels (p < .05) and significantly decreased expression levels of downstream inflammatory factors (p < .05). CONCLUSION: Different atorvastatin doses have protective effects on contrast-induced acute renal tubular injury in rats, possibly by targeting TLR4, suppressing TLR4 expression, regulating the TLR4/Myd88 signaling pathway, and inhibiting the expression of downstream inflammatory factors.

Short-term MyD88 inhibition ameliorates cardiac graft rejection and promotes donor-specific hyporesponsiveness of skin grafts in mice.

Recognition of evolutionarily conserved ligands by Toll-like receptors (TLRs) triggers signaling cascades in innate immune cells to amplify adaptive immune responses. Nearly all TLRs require MyD88 to transduce downstream signaling. MyD88 deficiency has been shown to promote the allograft acceptance in mice. However, direct evidence for therapeutic potential of MyD88 inhibitors remains lacking. Herein, we used a MyD88 inhibitor, namely ST2825, to explore its therapeutic potential and mechanisms in fully allogeneic skin and heart transplant models. Phenotypic maturation of dendritic cells stimulated by TLR ligands was alleviated by ST2825 in parallel with reduced T-cell proliferation in vitro. A short-course treatment with ST2825 significantly prolonged cardiac graft survival (mean survival time = 18.5 ± 0.92 days vs. 7.25 ± 0.46 days). ST2825-treated group had significantly reduced proinflammatory cytokines in allografts compared with control group. ST2825 combined with anti-CD154 induced long-term skin allograft acceptance in about one-third of recipients (>100 days). 'Skin-tolerant' recipients showed attenuated donor-specific IFN-γ responses, intact IL-4 responses, and compromised alloantibody responses. We conclude that MyD88 inhibitor ST2825 attenuates acute cardiac rejection and promotes donor-specific hyporesponsiveness in stringent skin transplant models. The direct evidence suggests that pharmacological inhibition of MyD88 hold promising potential for transplant rejection.

Targeting mTOR/p70S6K/glycolysis signaling pathway restores glucocorticoid sensitivity to 4E-BP1 null Burkitt Lymphoma.

BACKGROUND: Increasing evidence indicates that rapamycin could be used as a potential glucocorticoid (GC) sensitizer in lymphoblastic malignancies via genetic prevention of 4E-BP1 phosphorylation. Interestingly, we found that combined rapamycin with dexamethasone can effectively reverse GC resistance in 4E-BP1 null lymphoma cells. In this study, we investigated the potential link between mTOR/p70S6K signaling pathway, glycolysis, autophagy and GC resistance. METHODS: Antitumor effects of the combination of rapamycin and dexamethasone were evaluated on cell viability by MTT assay and in vivo studies, on cell cycle and apoptosis by flow cytometry, on autophagy by western blot, MDC staining and transmission electron microscopy and on cell signaling by western blot. Moreover, to test whether inhibiting glycolysis is the core mechanism in rapamycin restoring GC sensitivity, we took glycolysis inhibitor 2-deoxyglucose to replace rapamycin and then evaluated the antitumor effects in vitro. RESULTS: Raji cells are resistant to rapamycin (IC50 > 1000 nM) or dexamethasone (IC50 > 100 µM) treatment alone. The combination of rapamycin and dexamethasone synergistically inhibited the viability of Raji cells in vitro and in vivo by inducing caspase-dependent and -independent cell death and G0/G1 cell cycle arrest. These effects were achieved by the inhibition of mTOR/p70S6K signaling pathway, which led to the inhibition of glycolysis and the induction of autophagy. Pretreatment with pan-caspase inhibitor z-VAD-fmk or autophagy inhibitor 3-MA failed to protect the cells from combined treatment-induced death. Glycolysis inhibitor combined with dexamethasone produced a similar antitumor effects in vitro. CONCLUSIONS: Inhibition of mTOR/p70S6K/glycolysis signaling pathway is the key point of therapy in reversing GC resistant in Burkitt lymphoma patients.

[Controlled clinical study on compound Decumbent Corydalis Rhizome and diclofenac in treatment of knee osteoarthritis].

To evaluate the efficacy and safety of compound Decumbent Corydalis Rhizome (DCR) in treating patients with knee osteoarthritis (OA). Totally 79 patients with knee osteoarthritis were selected from out-patient and inpatient departments of West China Hospital and randomly divided into the test group and the control group. The test group (n = 41) was given Compound DCR with the dosage of 1.8 g · d(-1), while the control group (n = 38) was administered with diclofenac sodium with the dosage of 75 mg · d(-1). After 12 weeks of treatment, the total efficacy rates based on patients/physicians evaluation for experimental and control groups were 68.29%, 63.41% and 71.05%, 63.16%, respectively, without significant difference between the two groups. Both of the two groups showed significant improvements in the main efficacy indexes (pain on walking 20 m) and minor indexes (tenderness on palpation, Western Ontario and McMaster Universities OA index (WOMAC) and Short-Form Health Survey (SF-36 ), but without significant difference in efficacy between them. The incidence of related adverse events was 24.39% in the test group and 47.37% in the control group, respectively, with significant differences between the two groups (P < 0.05). In the controlled study, compound DCR is as efficient as diclofenac sodium but more tolerable, with a good clinical application prospect.

Double positive CD4+CD8+ T cells: key suppressive role in the production of autoantibodies in systemic lupus erythematosus.

BACKGROUND & OBJECTIVES: The presence of CD4+CD8+ (double positive) T cells (DPT) in the target organs of several autoimmune diseases has been reported. The aim of this study was to investigate the pathogenic role of DPT in systemic lupus erythematosus (SLE). METHODS: A total of 175 SLE cases and 125 matched healthy controls were investigated for CD3+, CD4+, CD8+ lymphocytes and DPT by flow cytometry. Serum samples from SLE patients and controls were tested for antinuclear antibody (ANA), anti-double strain deoxyribonucleic acid (anti-dsDNA), anti-U1 ribonucleoprotein (anti-U1 RNP), anti-sjogren syndrome A (anti-SSA), anti-ribosomal P protein (anti-rib-P), anti-Smith (anti-Sm), anti-Sjogren syndrome B (anti-SSB), complement 3 (C3) and complement 4 (C4). RESULTS: The DPT median and 5-95 per cent range of SLE cases and healthy controls were 0.50 [0.10-2.60] and 0.80 [0.20-2.74] respectively (P<0.001). SLE patients were divided into a ≥1:1000 subgroup and a <1:1000 subgroup according to the ANA titre. The DPT of the former subgroup was significantly lower than that of the latter (P=0.032). The DPT medians of positive subgroups with anti-dsDNA (P<0.001), anti-U1RNP (P=0.018), anti-SSA (P=0.021) or anti-rib-P (P=0.039) were also significantly lower than the negative subgroups. Likewise, DPT was significantly lower in SLE subgroups with low concentration of C3 or C4 than those with high concentration (P<0.006). INTERPRETATION & CONCLUSIONS: Our findings show that the DPT cells may play a key suppressive role in the production of autoantibodies in SLE. Direct evidence that DPT regulates the pathogenesis of SLE needs to be investigated in future work.

Treatment of primary chronic glomerulonephritis with Rehmannia glutinosa acteosides in combination with the angiotensin receptor blocker irbesartan: a randomized controlled trial.

This study aims to assess the efficacy and safety of Rehmannia glutinosa acteosides used in combination with the angiotensin receptor blocker irbesartan to treat primary chronic glomerulonephritis. A total of 479 patients diagnosed with primary chronic glomerulonephritis were recruited from outpatient clinics and were randomly assigned to the treatment group (Rehmannia glutinosa acteosides, two 200-mg capsules, bid; and irbesartan, one 150-mg tablet, qd) or the control group (irbesartan, one 150-mg tablet, qd). The primary outcome was 24-h urinary protein. Secondary outcome measures included blood pressure, estimated glomerular filtration rate, erythrocyturia, serum alanine aminotransferase, aspartate transaminase and electrolytes. After 8 weeks of treatment, the treatment group showed a mean reduction in 24-h proteinuria of 36.42% compared to baseline, which was significantly higher than the mean reduction from baseline of 27.97% in the control group (P = 0.0278).Adverse drug reactions occurred at a similarly low rate in the treatment group (0.4%) and control group (1.2%, P = 0.3724). In the treatment of chronic glomerulonephritis, the combination of Rehmannia glutinosa acteosides and irbesartan can reduce proteinuria more effectively than irbesartan alone.