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1.
Urol Oncol ; 2019 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-31601518

RESUMO

PURPOSE: To develop a risk model with combined clinical characteristics and multiparametric MRI parameters for prediction of cribriform morphology in intermediate-risk prostate cancer (CaP) patients. METHODS: We retrospectively included 215 CaP patients received multiparametric MRIexamination, targeted biopsy (TB) combined with systematic biopsy (SB), radical prostatectomy and final Gleason group 2 or 3. Cribriform status was confirmed on both biopsy slices and whole-mount sections. Characteristics were stratified by cribriform status. Mann Whitney U test was performed for continuous variables and the χ2 test for categorical variables. Univariate and multivariate logistic regression analyses were performed for significant predictors, followed by cribriform-risk nomogram construction. Receiver operating characteristic analysis was used for internal discrimination validation with corresponding area under the curve. Calibration curves were plotted and decision curve analysis was performed for clinical benefit exploration. RESULTS: Cribriform morphology was identified in 51.2% (110/215) patients. Cribriform-positive CaP demonstrated significantly higher prostate-specific antigen level, higher prostate-specific antigen density , larger lesion dimension on MRI, higher Prostate Imaging Reporting and Data System score, larger tumor dimension, higher Gleason score, higher pT stage, higher pN stage and more positive surgical margin (all P < 0.01). Sensitivities of TB, SB, TB + SB for detecting cribriform morphology were 28.2% (31/110), 22.7% (25/110), and 36.4% (40/110), respectively. Further, prostate-specific antigen density (P = 0.003), Prostate Imaging Reporting and Data System score (P < 0.001), and maximal biopsy Gleason score (P = 0.004) were independent predictors for positive cribriform morphology. Cribriform-risk nomogram was constructed with the 3 parameters and demonstrated considerable discrimination (area under the curve = 0.887, sensitivity 79.2%, specificity 84.0%) and calibration (mean absolute error 0.021), harboring net benefits with threshold probabilities range from 0 to 0.88. CONCLUSION: A cribriform-risk nomogram was developed and well predicted aggressive cribriform morphology in intermediate-risk CaP patients.

2.
Aging (Albany NY) ; 11(13): 4579-4586, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31280254

RESUMO

BACKGROUND: Apolipoprotein E4 (ApoE4) is the major genetic risk factor of Alzheimer's disease (AD). ApoE4 carriers have cerebral hypometabolism which is thought as a harbinger of AD. Our previous studies indicated ketones improved mitochondria energy metabolism via sirtuin 3 (Sirt3). However, it is unclear whether ketones upregulate Sirt3 and improve ApoE4-related learning and memory deficits. RESULTS: Ketones improved learning and memory abilities of ApoE4 mice but not ApoE3 mice. Sirt3, synaptic proteins, the NAD+/ NADH ratio, and ATP production were significantly increased in the hippocampus and the cortex from ketone treatment. METHODS: Human ApoE3 and ApoE4 transgenic mice (9-month-old) were treated with either ketones or normal saline by daily subcutaneous injections for 3 months (ketones, beta-hydroxybutyrate (BHB): 600 mg/kg/day; acetoacetate (ACA): 150 mg/kg/day). Learning and memory ability of these mice were assessed. Sirt3 protein, synaptic proteins (PSD95, Synaptophysin), the NAD+/ NADH ratio, and ATP levels were measured in the hippocampus and the cortex. CONCLUSION: Our current studies suggest that ketones improve learning and memory abilities of ApoE4 transgenic mice. Sirt3 may mediate the neuroprotection of ketones by increasing neuronal energy metabolism in ApoE4 transgenic mice. This provides the foundation for Sirt3's potential role in the prevention and treatment of AD.

3.
PLoS One ; 14(6): e0217566, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31237877

RESUMO

BACKGROUND: Neuropathology has demonstrated a high rate of comorbid pathology in dementia due to Alzheimer's disease (ADD). The most common major comorbidity is Lewy body disease (LBD), either as dementia with Lewy bodies (AD-DLB) or Alzheimer's disease with Lewy bodies (AD-LB), the latter representing subjects with ADD and LBD not meeting neuropathological distribution and density thresholds for DLB. Although it has been established that ADD subjects with undifferentiated LBD have a more rapid cognitive decline than those with ADD alone, it is still unknown whether AD-LB subjects, who represent the majority of LBD and approximately one-third of all those with ADD, have a different clinical course. METHODS: Subjects with dementia included those with "pure" ADD (n = 137), AD-DLB (n = 64) and AD-LB (n = 114), all with two or more complete Mini Mental State Examinations (MMSE) and a full neuropathological examination. RESULTS: Linear mixed models assessing MMSE change showed that the AD-LB group had significantly greater decline compared to the ADD group (ß = -0.69, 95% CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not (ß = -0.30, 95% CI: -0.73, 0.14, p = 0.18). Of those with AD-DLB and AD-LB, only 66% and 2.1%, respectively, had been diagnosed with LBD at any point during their clinical course. Compared with clinically-diagnosed AD-DLB subjects, those that were clinically undetected had significantly lower prevalences of parkinsonism (p = 0.046), visual hallucinations (p = 0.0008) and dream enactment behavior (0.013). CONCLUSIONS: The probable cause of LBD clinical detection failure is the lack of a sufficient set of characteristic core clinical features. Core DLB clinical features were not more common in AD-LB as compared to ADD. Clinical identification of ADD with LBD would allow stratified analyses of ADD clinical trials, potentially improving the probability of trial success.

4.
Cell Adh Migr ; 13(1): 229-235, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31208274

RESUMO

We studied the role of Sirtuin 3 (SIRT3) in microglial cell migration in ischemic stroke. We used a middle cerebral artery occlusion (MCAO) model of focal ischemia. We then applied lentivirus-packaged SIRT3 overexpression and knock down in microglial N9 cells to investigate the underlying mechanism driving microglial cell migration. More microglial cells appeared in the ischemic lesion side after MCAO. The levels of SIRT3 were increased in macrophages, the main source of microglia, after ischemia. CX3CR1 levels were increased with SIRT3 overexpression. SIRT3 promoted microglial N9 cells migration by upregulating CX3CR1 in both normal and glucose deprived culture media. These effects were G protein-dependent. Our study for the first time shows that SIRT3 promotes microglia migration by upregulating CX3CR1.

5.
Eur J Nucl Med Mol Imaging ; 46(7): 1531-1541, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31025048

RESUMO

PURPOSE: To explore the diagnostic performance of 68Ga-PSMA PET/CT for identification of pathological cribriform morphology in prostate cancer (PCa). METHODS: The study retrospectively enrolled 49 PCa patients who had undergone preoperative multiparametric MRI (mpMRI) and 68Ga-PSMA PET/CT, and who had Gleason pattern (GP) 4 and absence of GP 5 on radical prostatectomy specimens. Lesions with GP 4 were outlined and stratified according to their cribriform status. Volumes of interest were drawn on matched mpMRI and PET images, and parameters including average apparent diffusion coefficient (ADCmean), tenth percentile ADC (ADC10%) and maximum standardized uptake value (SUVmax) were derived. The Mann-Whitney U test was used for continuous variables and the chi-squared test for categorical variables. Receiver operating characteristic analysis was used to compare imaging parameters in identifying cribriform morphology. The associations between cribriform-positive PCa and imaging variables were evaluated in a univariate analysis using a logistic regression model. RESULTS: A total of 62 lesions were identified in 49 patients with GP 4. Of these lesions, 37 (59.7%) in 34 patients (69.4%) showed cribriform morphology. ADCmean and ADC10% were similar between cribriform-positive and non-cribriform groups (P > 0.05), while SUVmax was significantly different (median SUVmax 18.3 vs. 9.4 per patient, P = 0.003, 18.2 vs. 7.2 per lesion, P < 0.001), yielding sensitivities and specificities of 76% and 86% in a per-patient analysis, and 77% and 88% in a per-lesion analysis, respectively. Further, PSMA was significantly overexpressed in cribriform-positive PCa (P = 0.003). SUVmax was a significant predictor of cribriform morphology in PCa (odds ratio 8.61, 95% confidence interval 4.96-25.27, per patient; odds ratio 11.93, 95% confidence interval 6.49-33.74, per lesion; both P < 0.001). CONCLUSION: 68Ga-PSMA PET/CT effectively identifies the aggressive cribriform morphology in PCa.

6.
Retrovirology ; 16(1): 10, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947724

RESUMO

BACKGROUND: Efficient HIV-1 replication depends on interaction of the viral capsid with the host protein cyclophilin A (CypA). CypA, a peptidylprolyl isomerase, binds to an exposed loop in the viral CA protein via the enzyme's active site. Recent structural analysis of CypA in complex with CA tubes in conjunction with molecular dynamics simulations identified a secondary CA binding site on CypA that allows a bridging interaction with two hexameric subunits of the assembled CA lattice, leading to capsid stabilization (Liu et al. in Nat Commun 7:10714, 2016). RESULTS: We performed mutational analysis of residues that have been proposed to mediate CA binding at the secondary binding site on CypA (A25, K27, P29 and K30) and tested the effects of the amino acid substitutions using interaction assays and HIV-1 infection assays in cells. The binding of recombinant CypA to self-assembled CA tubes or native HIV-1 capsids was measured in vitro using a quantitative fluorescence microscopy binding assay revealing that affinity and stoichiometry of CypA to the CA lattice was not affected by the substitutions. To test for functionality of the CypA secondary CA-binding site in HIV-1 infection, mutant CypA proteins were expressed in cells in which endogenous CypA was deleted, and the effects on HIV-1 infection were assayed. In normal HeLa-P4 cells, infection with HIV-1 bearing the A92E substitution in CA is inhibited by endogenous CypA and was inhibited to the same extent by expression of CypA mutants in CypA-null HeLa-P4 cells. Expression of the mutant CypA proteins in CypA-null Jurkat cells restored their permissiveness to infection by wild type HIV-1. CONCLUSIONS: The amino acid changes at A25, K27, P29 and K30 did not affect the affinity of CypA for the CA lattice and did not impair CypA function in infection assays suggesting that these residues are not part of a secondary CA binding site on CypA.


Assuntos
Capsídeo/metabolismo , Ciclofilina A/química , HIV-1/fisiologia , Interações entre Hospedeiro e Microrganismos , Replicação Viral , Aminoácidos , Sítios de Ligação , Proteínas do Capsídeo/metabolismo , Ciclofilina A/genética , Células HeLa , Humanos , Células Jurkat , Ligação Proteica , Vírion/fisiologia
7.
J Alzheimers Dis ; 69(2): 355-362, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30958373

RESUMO

BACKGROUND: Emerging evidence shows tau acetylation has been observed in Alzheimer's disease (AD) brain at early Braak stages and is involved in regulating tau early accumulation. However, the effects of deacetylase Sirtuin 3 (Sirt3) on tau acetylation and its aggregations are unclear. OBJECTIVE: We studied the effects of Sirt3 on tau acetylation and its aggregations. METHODS: We investigated the protein levels of Sirt3 and tangle tau in human postmortem brains slices from AD, mild cognitive impairment, and age- and education-matched cognitively normal subjects, and AD model mice. We also measured tau acetylation levels in hippocampal HT22 cells after Sirt3 knockdown or overexpression. RESULTS: The level of Sirt3 was inversely related with tau protein in brain slices from both human being and AD model mice. Mechanistically, tau acetylation decreased dramatically with Sirt3 overexpression, while tau acetylation increased after Sirt3 knockdown in hippocampal HT22 cells. CONCLUSIONS: Sirt3 may play a role in tau acetylation and could be a potential target for novel therapy to alleviate tau accumulation.

8.
Acta Neurol Scand ; 139(4): 389-394, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30676642

RESUMO

OBJECT: We characterize idiopathic normal pressure hydrocephalus (NPH) following treatment with lumbar puncture (LP) and shunt placement through clinical evaluation and quantitative ProtoKinetics Zeno walkway assessments. We evaluate the symptomology by determining gait characteristics altered by treatment. METHODS: Patients at Barrow Neurological Institute (BNI) who underwent a LP, removing 30-32 mL cerebrospinal fluid) followed by ventriculoperitoneal shunt placement in February 2015 to February 2017 were analyzed for gait impairments. Inclusion in the study required a diagnosis of NPH, no conflicting comorbidities, and pre-LP, post-LP, and 6-month post-shunt assessments. Analyses of gait and balance data recorded by physical therapists and the ProtoKinetics Zeno Walkway at pre-LP, post-LP, and post-shunt were performed. RESULTS: A total of 28 patients were included and one-way analysis of variance and Tukey-Kramer HSD was performed. Among the 15 clinical assessments, nine were significantly altered. Using the ProtoKinetics Zeno Walkway, 7 out of 10 characteristics recorded were considered significantly different among the three data sets. Furthermore, there were more significant differences between pre-LP assessments and post-shunt assessments in comparison to differences between pre-LP assessments and post-LP assessments. CONCLUSIONS: Our results indicate that certain gait characteristics better fit NPH than others. By focusing on the features that are caused by NPH and alleviated by LP and/or shunt placement, a more definitive NPH diagnosis can be attained. Additionally, our findings confirm a cumulative effect of continuous drainage via shunt placement may lead to increased improvement in NPH symptoms over LP results.


Assuntos
Transtornos Neurológicos da Marcha/etiologia , Hidrocefalia de Pressão Normal/diagnóstico , Idoso , Feminino , Humanos , Hidrocefalia de Pressão Normal/complicações , Hidrocefalia de Pressão Normal/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Punção Espinal , Derivação Ventriculoperitoneal
9.
Aging (Albany NY) ; 10(10): 2874-2883, 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30362958

RESUMO

Alzheimer's disease (AD) is manifested by regional cerebral hypometabolism. Sirtuin 3 (Sirt3) is localized in mitochondria and regulates cellular metabolism, but the role of Sirt3 in AD-related hypometabolism remains elusive. We used expression profiling and weighted gene co-expression network analysis (WGCNA) to analyze cortical neurons from a transgenic mouse model of AD (APPSwInd). Based on WGCNA results, we measured NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and its deacetylation activity, and ATP production across both in vivo and in vitro models. To investigate the effect of Sirt3 on amyloid-ß (Aß)-induced mitochondria damage, we knocked down and over-expressed Sirt3 in hippocampal cells. WGCNA revealed Sirt3 as a key player in Aß-related hypometabolism. In APP mice, the NAD+ level, NAD+/ NADH ratio, Sirt3 protein level and activity, and ATP production were all reduced compared to the control. As a result, learning and memory performance were impaired in 9-month-old APP mice compared to wild type controls. Using hippocampal HT22 cells model, Sirt3 overexpression increased Sirt3 deacetylation activity, rescued mitochondria function, and salvaged ATP production, which were damaged by Aß. Sirt3 plays an important role in regulating Aß-induced cerebral hypometabolism. This study suggests a potential direction for AD therapy.

10.
BMC Neurol ; 18(1): 155, 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30257642

RESUMO

BACKGROUND: Peripheral diagnostics for Alzheimer's disease (AD) continue to be developed. Diagnostics capable of detecting AD before the onset of symptoms are particularly desirable, and, given the fact that early detection is imperative for alleviating long-term symptoms of the disease, methods which enable detection in the earliest stages are urgently needed. Saliva testing is non-invasive, and saliva is easy to acquire. A simple, non-invasive saliva test can potentially be used as an adjunct to diagnose AD during its earliest stages. METHODS: Salivary levels of beta amyloid 42 (Aß42) were quantitated with enzyme-linked immunosorbent-type assays. Fifteen AD patients (7 men, mean age 77.8 ± 1.8 years, mean Mini-Mental State Examination [MMSE] score 19.0 ± 1.3) and 7 normal controls (2 men, mean age 60.4 ± 4.7 years, mean MMSE 29.0 ± 0.4) were enrolled. RESULTS: Salivary Aß42 levels were significantly higher in AD patients than in controls (51.7 ± 1.6 pg/mL for AD and 21.1 ± 0.3 pg/mL for controls, p < 0.001). Based on these results, saliva testing appears to be a promising method for detecting AD during its critical early stages.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/análise , Biomarcadores/análise , Diagnóstico Precoce , Saliva/química , Idoso , Idoso de 80 Anos ou mais , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Oncotarget ; 9(53): 30025-30033, 2018 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-30046385

RESUMO

Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is a downstream target gene of the Wnt/ß-catenin signaling pathway and identified as a marker of cancer stem-like cells of colorectal carcinoma (CRC). Here, the heterogeneous expression pattern of Lgr5 and its clinical significance were studied by the method of immunohistochemistry in 204 CRC tumors at various pTNM stages. Lgr5 expression was found in 82.4% (168/204) cases, significantly more common in neoplastic cells at the infiltrative front (n = 59.5%, 110/185) or at the expanding front (n = 36.4%, 59/162) than at the tumor center (n = 16.7%, 34/204; P < 0.01). Tumor budding (TB) was discovered with significantly higher Lgr5 expression (n = 39.3%, 57/145, P = 0.03) and significantly positively correlated between Lgr5 expression and TB grade (r = 0.19, P = 0.02). Additionally, both positive Lgr5 expression and a high TB grade were significantly correlated to the depth of tumor invasion, lymph node metastasis, pTNM stage, and perineural invasion (P < 0.01). The study results suggest that heterogeneous expression of Lgr5 may be a risk factor for local invasion and distant metastasis of CRC.

12.
Artigo em Inglês | MEDLINE | ID: mdl-30010112

RESUMO

OBJECTIVE: To compare the enhancement pattern of hepatic angiomyolipoma (HAML) on contrast enhanced ultrasound (CEUS) and magnetic resonance (MR). METHODS: The data of seven patients (females; age 28-52 years; mean, 42 years) with histologically proven HAMLs were retrospectively reviewed. All patients underwent CEUS and MR examination. The images were analyzed by two experienced doctors who blinded to the clinical and pathological information of cases. RESULTS: The mean diameter of the nodule was 5.7 cm (range: 3.2-10 cm). Histopathologic results revealed 4 nodules to be myomatous type and 3 nodules to be mixed type. All nodules showed hyperenhanced during arterial phase on both CEUS and MRI. During portal and delayed phase, washout was more showed on MRI (5/7, 71.4% ) than on CEUS (2/7, 28.6% ). CONCLUSIONS: There is discrepancy of enhancement pattern between CEUS and MRI. The quick wash-in and sustained hyperenhancement on CEUS may be helpful for the diagnosis of HAML.

13.
HPB (Oxford) ; 20(12): 1163-1171, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30030081

RESUMO

BACKGROUND: To compare the diagnostic performance of CT criteria and to establish a new model in evaluating portal venous invasion by hilar cholangiocarcinoma. METHODS: CT images of 67 patients with hilar cholangiocarcinoma were retrospectively reviewed. Modified Loyer's, Lu's and Li's standard introduced from pancreatic cancer were used to evaluate portal venous invasion with the reference of intraoperative findings and/or postoperative pathological diagnosis. A new model was constructed with modified Lu's standard and contact length between portal vein and tumor. RESULTS: The modified Loyer's standard, modified Lu's standard and Li's standard showed a sensitivity of 86.7%, 83.3%, 70.0%, a specificity of 89.4%, 95.7%, 95.7% and an accuracy of 88.6%, 92.0%, 88.1%, respectively. CT criteria performed better in evaluating left branch. The new model performed significantly better than any CT criterion or contact length, with a sensitivity of 95.0%, a specificity of 96.5% and an accuracy of 96.0%. CONCLUSIONS: Modified Lu's standard performed best in evaluating portal venous invasion by hilar cholangiocarcinoma among three CT criteria. The left branch invasion could be evaluated by CT criteria better than the right branch and the trunk of portal vein. The new mode significantly improved the diagnostic performance of portal venous invasion by hilar cholangiocarcinoma.

14.
Mod Pathol ; 31(10): 1599-1607, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29802360

RESUMO

Clinical decision-making on endoscopic vs. surgical resection of early gastric cardiac carcinoma remains challenging because of uncertainty on risk of lymph node metastasis. The aim of this multicenter study was to investigate risk factors of lymph node metastasis in early gastric cardiac carcinoma. Guided with the World Health Organization diagnostic criteria, we studied 2101 radical resections of early gastric carcinoma for risk factors associated with lymph node metastasis, including tumor location, gross pattern, size, histology type, differentiation, invasion depth, lymphovascular, and perineural invasion. We found that the risk of lymph node metastasis was significantly lower in early gastric cardiac carcinomas (6.7%, 33/495), compared with early gastric non-cardiac carcinomas (17.1%, 275/1606) (p < 0.0001). In early gastric cardiac carcinoma, no lymph node metastasis was identified in intramucosal carcinoma (0/193) and uncommon types of carcinomas (0/24), irrespective of the gross pattern, size, histologic type, differentiation, and invasion depth. Ulceration, size > 3 cm, and submucosal invasion were not significant independent risk factors for lymph node metastasis. In 33 early gastric cardiac carcinomas with lymph node metastasis, either lymphovascular invasion or poor differentiation was present in 16 (48.5%) cases and together in six cases. By multivariate analysis, independent risk factors of lymph node metastasis in early gastric cardiac carcinoma included lymphovascular invasion (Odds Ratio (OR): 7.6, 95% Confidence Interval (CI): 2.8-20.2) (p < 0.0001) and poor differentiation (OR: 6.0, 95% CI: 1.4-25.9) (p < 0.05). In conclusion, lymph node metastasis was not identified in early gastric cardiac intramucosal carcinoma and uncommon types of carcinoma. The risk of lymph node metastasis was also significantly lower in tumors with submucosal invasion, especially for cases without lymphovascular invasion or poor differentiation. These results lend support to the role of endoscopic therapy in the treatment of patients with early gastric cardiac carcinoma.

15.
JAMA Neurol ; 75(9): 1114-1123, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29799984

RESUMO

Importance: Patients with amnestic mild cognitive impairment (aMCI) may progress to clinical Alzheimer disease (AD), remain stable, or revert to normal. Earlier progression to AD among patients who were ß-amyloid positive vs those who were ß-amyloid negative has been previously observed. Current research now accepts that a combination of biomarkers could provide greater refinement in the assessment of risk for clinical progression. Objective: To evaluate the ability of flutemetamol F 18 and other biomarkers to assess the risk of progression from aMCI to probable AD. Design, Setting, and Participants: In this multicenter cohort study, from November 11, 2009, to January 16, 2014, patients with aMCI underwent positron emission tomography (PET) at baseline followed by local clinical assessments every 6 months for up to 3 years. Patients with aMCI (365 screened; 232 were eligible) were recruited from 28 clinical centers in Europe and the United States. Physicians remained strictly blinded to the results of PET, and the standard of truth was an independent clinical adjudication committee that confirmed or refuted local assessments. Flutemetamol F 18-labeled PET scans were read centrally as either negative or positive by 5 blinded readers with no knowledge of clinical status. Statistical analysis was conducted from February 19, 2014, to January 26, 2018. Interventions: Flutemetamol F 18-labeled PET at baseline followed by up to 6 clinical visits every 6 months, as well as magnetic resonance imaging and multiple cognitive measures. Main Outcomes and Measures: Time from PET to probable AD or last follow-up was plotted as a Kaplan-Meier survival curve; PET scan results, age, hippocampal volume, and aMCI stage were entered into Cox proportional hazards logistic regression analyses to identify variables associated with progression to probable AD. Results: Of 232 patients with aMCI (118 women and 114 men; mean [SD] age, 71.1 [8.6] years), 98 (42.2%) had positive results detected on PET scan. By 36 months, the rates of progression to probable AD were 36.2% overall (81 of 224 patients), 53.6% (52 of 97) for patients with positive results detected on PET scan, and 22.8% (29 of 127) for patients with negative results detected on PET scan. Hazard ratios for association with progression were 2.51 (95% CI, 1.57-3.99; P < .001) for a positive ß-amyloid scan alone (primary outcome measure), 5.60 (95% CI, 3.14-9.98; P < .001) with additional low hippocampal volume, and 8.45 (95% CI, 4.40-16.24; P < .001) when poorer cognitive status was added to the model. Conclusions and Relevance: A combination of positive results of flutemetamol F 18-labeled PET, low hippocampal volume, and cognitive status corresponded with a high probability of risk of progression from aMCI to probable AD within 36 months.

16.
Mol Neurobiol ; 55(11): 8592-8601, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29574628

RESUMO

Increasing evidence indicates that sirtuin 3 (Sirt3) has neuroprotective effects in regulating oxidative stress and energy metabolism, both of which are involved in the pathogenesis of Alzheimer's disease (AD). However, it is unclear whether Sirt3 is associated with cognitive performance and pathological changes in AD. We conducted a case-control study of the postmortem brains of AD (n = 16), mild cognitive impairment (n = 13), and age- and education-matched cognitively normal (CN, n = 11) subjects. We measured the mRNA and protein levels of Sirt3 and assessed their association with cognitive performance and AD pathology. In an ex vivo model of cortical neurons from transgenic mice that carry human tau protein, we modified Sirt3 expression by genetic knockdown and knock-in to investigate the cause-effect relationship between Sirt3 and tau. Sirt3 levels were reduced in the entorhinal cortex, the middle temporal gyrus, and the superior frontal gyrus of AD subjects compared to those of CN. This reduction was associated with poorer test scores of neuropsychological evaluation and the severity of tau pathology. Further study with genetic manipulation of Sirt3 revealed that amyloid-ß increased levels of total tau acetylated tau through its modulation of Sirt3. These data suggest that reduction of Sirt3 is critically involved in pathogenesis of AD.

17.
Hum Pathol ; 76: 100-109, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29514108

RESUMO

Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer rarely curable by surgery that is increasing rapidly in incidence. Chromosomal translocations and amplifications of the fibroblast growth factor receptor 2 (FGFR2) locus are present in several kinds of tumors including ICC, but their incidence has not been assessed in Chinese patients. Using break-apart probes and by determining the ratios of FGFR2/chromosome enumeration probe (CEP) 10 double-color probes, we evaluated 122 ICCs for the presence of FGFR2 translocations and amplifications, respectively, by fluorescence in situ hybridization. We further determined FGFR2 protein expression by immunohistochemistry and analyzed the clinicopathologic records of the patients. Eight tumors (6.6%) had FGFR2 translocations, whereas 15 (12.3%) had low-level FGFR2 amplification. Interestingly, the tumors that showed both translocation and low-level amplification frequently were of the mass-forming type. Compared with the ICCs with normal FGFR2s, tumors with amplifications secreted less mucus (P = .017) and typically were accompanied by hepatitis B virus infection (P = .004). Tumors with low-level amplification generally were of lower stage (P = .013) and associated with better overall survival (P = .017). As tumors with FGFR2 amplification exhibit different biology from lesions with a normal gene, low-level amplification of FGFR2 may play an important role in tumor progression and may be a marker for targeted therapy.

18.
Exp Ther Med ; 15(3): 2837-2843, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29456687

RESUMO

The present study explored the relationship between Girdin protein expression and the survival rate of patients with lung carcinoma. A total of 334 lung cancer specimens, 20 benign lung disease tissue sections and 24 fresh tissues from patients with lung carcinoma were analyzed by immunohistochemistry and western blotting. Girdin protein was expressed in 130/334 (38.93%) of the cases examined. Girdin protein expression was correlated with tumor/node/metastasis stage (P<0.001), lymph node metastasis (P=0.001), distant metastasis (P<0.001) and specimen sites (P=0.034). Girdin expression was also correlated with signal transducer and activator of transcription 3 (STAT3) expression (P<0.001). Patients with high Girdin and STAT3 expression had a significantly poorer prognosis compared with those with low/high, high/low or low/low expression (P<0.001). In summary, Girdin may be a prognostic marker of lung cancer and serve as a biomarker for metastasis.

19.
Int J Neurosci ; 128(2): 151-154, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28911255

RESUMO

Purpose/Aim of the study: To study finger displacement in patients with Parkinson disease dementia (PDD) and in patients with Alzheimer disease (AD). METHODS: We examined 56 patients with PDD and 35 with AD. Patients were examined during their regular outpatient clinic visit. Finger displacement was measured by observers not actively involved in the study using a creative grid ruler for all PDD and AD patients. Finger displacement was examined by asking patients to point their index fingers toward the grid ruler with the nails facing upward. Patients were asked to maintain the pointing position for 15 s. After 15 s, patients were asked to close their eyes for another 15 s while maintaining the same position. A positive result was downward index finger displacement of ≥5 cm within the 15-second time window with eyes closed. RESULTS: Of the 56 PDD patients, 53 had bilateral finger displacement of >5 cm. In comparison, of the 35 AD patients, only 1 patient had minimal displacement. CONCLUSIONS: Results of the non-invasive finger displacement test may provide insight, on an outpatient basis, of the integrity of subcortical-cortical circuits. Downward finger displacement, especially bilateral downward displacement, may signal the extensive disruption of subcortical-cortical circuits that occurs in PDD patients. ABBREVIATIONS: AChE: acetylcholinesterase; AD: Alzheimer disease; DLB: dementia with Lewy bodies; ET: essential tremor; MDS-UPDRS: Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale; MMSE: Mini-Mental State Examination; PD: Parkinson disease; PDD: Parkinson disease dementia.


Assuntos
Doença de Alzheimer/diagnóstico , Demência/diagnóstico , Doença de Parkinson/complicações , Idoso , Idoso de 80 Anos ou mais , Demência/etiologia , Diagnóstico Diferencial , Feminino , Dedos , Humanos , Masculino , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico
20.
Int J Biol Sci ; 13(11): 1438-1449, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29209147

RESUMO

Intronic miRNAs, residing in intronic regions of host genes, are thought to be co-transcribed from their host genes and present consistent expression patterns with host genes. Recent studies reported a few intronic miRNAs with discordant expression with their host genes. We therefore aimed to understand the expression pattern of intronic miRNAs and their host genes in hepatocellular carcinoma (HCC) and reveal possible associated molecular mechanisms. Our genome wide integration analysis of miRNA and mRNA transcriptomes, in three dataset from 550 patients with HCC, found that a large amount of miRNA-host gene pairs were discordantly expressed. Consistent results were also revealed in 775 breast cancer patients. Further, most of HCC-related intronic miRNAs were predicted to have distinct upstream regulators and independent proximal promoter signals from host genes. The discordant expression of representative pairs, miR-26s/CTDSPs, was validated experimentally. We have also identified the independent transcriptional start site, promoter signal, and transcriptional factor of miR-26b from its host gene. Collectively, discordant expression of intronic miRNAs and their host genes was relatively ubiquitous and the intronic miRNA "independent transcription" may partially contribute to such a phenotype.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , MicroRNAs/genética , Transcriptoma/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Perfilação da Expressão Gênica/métodos , Humanos
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