Publications by authors named "Jiong Shi"

134 Publications

Does Informant-Based Reporting of Cognitive Decline Correlate with Age-Adjusted Hippocampal Volume in Mild Cognitive Impairment and Alzheimer's Disease?

J Alzheimers Dis Rep 2021 Mar 11;5(1):207-211. Epub 2021 Mar 11.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA.

Background: Informant-based measures are effective screening tools for cognitive impairment. The Alzheimer's Questionnaire (AQ) is a subjective, informant-based measure that detects amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) with high sensitivity and specificity and has been shown to predict amyloid burden.

Objective: To determine whether informant-based report of cognitive decline correlates with hippocampal volume changes in MCI and AD.

Methods: Retrospective chart review of 139 clinically referred patients with clinical diagnoses of aMCI or mild dementia due to AD was conducted. Diagnostic status (clinical diagnosis made by a neurologist), NeuroQuant measured MRI brain with percentile rank hippocampal volume, Montreal Cognitive Assessment (MoCA) total, AQ-Total score, and demographic variables were extracted from medical records. Spearman correlation was used to assess the relationship between hippocampal volume and AQ-Total. The AQ was used to assign diagnostic status. Thus, the relationship between the AQ and diagnostic status was excluded.

Results: The sample include 88 female and 51 male participants. The mean age was 74.37±9.45, mean MOCA was 22.65±4.18, mean education was 14.80±3.35, and mean AQ score was 10.54±5.22. Hippocampal volume and the AQ correlation was  = -0.33 [95%CI -0.47 to -0.17],  < 0.0001.

Conclusion: In a mixed-clinical sample of patients presenting to an outpatient memory disorders center, higher endorseme-nts of functional impairments by caregivers were significantly associated with smaller hippocampal volumes. When used in conjunction with other available measures, these findings further support the role of the AQ in clinical decision-making and demonstrate an additional relationship between clinical measures and volumetric MRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/ADR-200260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075551PMC
March 2021

Dementia with Lewy bodies: emerging drug targets and therapeutics.

Expert Opin Investig Drugs 2021 Apr 26:1-7. Epub 2021 Apr 26.

Lou Ruvo Center for Brain Health, Cleveland Clinic Nevada, Las Vegas, NV, USA.

Dementia with Lewy bodies (DLB) is characterized by the toxic accumulation of α-synuclein protein inside neural cells; this results in neurodegeneration which is clinically accompanied by behavioral and psychological changes. DLB shares features with Parkinson's disease (PD) and Parkinson's disease dementia (PDD), but also overlaps neurochemically and pathologically with Alzheimer's disease. Symptomatic treatments for LBD differ in their effectiveness while disease-modifying and curative approaches are much needed. We explore emerging therapeutics for DLB through the lens of repurposing approved drugs and survey their potential for disease modifying actions in DLB. Given the complexity of DLB with multiple pathologies, potential therapeutic targets that could affect Lewy body pathology, or metabolism or neurotransmitters or immunomodulation were surveyed. We queried PubMed and ClinicalTrials.gov searches 2017-2020. DLB is not simply aredux ofAD or PD; hence, treatments should not be exclusively duplicative ofAD or PD directed treatments. This opens amyriad of possibilities for therapeutic approaches that are disease specific or repurposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13543784.2021.1916913DOI Listing
April 2021

Tumor-associated macrophages are associated with response to neoadjuvant chemotherapy and poor outcomes in patients with triple-negative breast cancer.

J Cancer 2021 15;12(10):2886-2892. Epub 2021 Mar 15.

Dept. of General Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, China.

Tumor-associated macrophages (TAMs) play an essential role in tumor progression and metastasis. However, the role of TAMs in neoadjuvant chemotherapy (NAC) is unclear and need to be identified. The main subject of this study was to investigate whether TAMs are related to the chemotherapeutic response with triple-negative breast cancers (TNBC). We retrospectively analyzed pretreatment tissue from patients who received NAC and followed by a mastectomy or breast-conservation for stage II-III TNBC in this study. The association between TAMs and the pathological complete response (pCR) rate of TNBC to NAC was analyzed. In addition, the correlation of the TAMs with recurrence-free survival (RFS) in patients with TNBC was also evaluated. Of the 91 patients, 31 (34.1%) patients experienced pathological complete response (pCR) after completion of NAC. Regarding the chemotheraptic response, patients with low infiltration of CD163 macrophages achieved a significantly higher rate of pCR. Importantly, Kaplan-Meier survival shown that patients with high infiltration of CD163 macrophages and non-pCR had poor OS and RFS. our data showed that TAMs may predict chemotherapeutic response and can be used as a promising prognostic candidate for poor survival in TNBC patients treated with NAC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7150/jca.47566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8040876PMC
March 2021

Early loss of cerebellar Purkinje cells in human and a transgenic mouse model of Alzheimer's disease.

Neurol Res 2021 Mar 10:1-12. Epub 2021 Mar 10.

Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX USA.

Background: The cerebellum's involvement in AD has been under-appreciated by historically labeling as a normal control in AD research.

Methods: We determined the involvement of the cerebellum in AD progression. Postmortem human and APPswe/PSEN1dE9 mice cerebellums were used to assess the cerebellar Purkinje cells (PC) by immunohistochemistry. The locomotor and spatial cognitive functions were assessed in 4- to 5-month-old APPswe/PSEN1dE9 mice. Aβ plaque and APP processing were determined in APPswe/PSEN1dE9 mice at different age groups by immunohistochemistry and Western blot.

Results: We observed loss of cerebellar PC in mild cognitive impairment and AD patients compared with cognitively normal controls. A strong trend towards PC loss was found in AD mice as early as 5 months. Impairment of balance beam and rotorod performance, but no spatial learning and memory dysfunction was observed in AD mice at 4-5 months. Aβ plaque in the cerebral cortex was evidenced in AD mice at 2 months and dramatically increased at 6 months. Less and smaller Aβ plaques were observed in the cerebellum than in the cerebrum of AD mice. Similar intracellular APP staining was observed in the cerebellum and cerebrum of AD mice at 2 to 10 months. Similar expression of full-length APP and C-terminal fragments were indicated in the cerebrum and cerebellum of AD mice during aging.

Discussion: Our study in post-mortem human brains and transgenic AD mice provided neuropathological and functional evidence that cerebellar dysfunction may occur at the early stage of AD and likely independent of Aβ plaque.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01616412.2021.1893566DOI Listing
March 2021

Integrated clinicopathologic and immunohistochemical analysis of gastric adenocarcinoma with hepatoid differentiation: an exploration of histogenesis, molecular characteristics and prognostic markers.

Hum Pathol 2021 Feb 23. Epub 2021 Feb 23.

Department of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu 210008, China. Electronic address:

In addition to hepatoid adenocarcinoma (HAC), gastric adenocarcinoma with enteroblastic differentiation (GAED) and common adenocarcinoma (COM) could also show hepatoid differentiation, which present a poor prognosis. To elucidate the histogenesis and development of gastric cancer with hepatoid differentiation, we identified 55 cases by histological morphology and a panel of markers including α-fetoprotein (AFP), Glypican 3 (GPC3) and SALL4, then clinicopathologic parameters, pathomorphological characteristics, mucin phenotypes, molecular features, Immunoscore and survival analysis were assessed. A mixture of 3 types (COM+GAED+HAC) was most commonly observed in a same case, and typical transition between each histological subtype were frequently seen. Hyaline globule and pink amorphous substance were often present. HER2 was amplified in 21.8% cases. All the tumors showed intestinal phenotype (69.1%) and mixed gastric/intestinal phenotype (30.9%), and were all defined to chromosomal instable (CIN)/genomically stable (GS) group. Considering that 83.6% cases presented TP53 gene mutation phenotype and 61.8% cases showed ≥10% aberrant E-cadherin expression, the precise molecule classification is ambiguous. Survival analysis showed that patients with high SALL4 expression or low Immunoscore had a significantly poor overall survival (OS). Moreover, SALL4, HER2 and Immunoscore had an independent influence on OS. In conclusion, we suggest that the development of gastric adenocarcinoma with hepatoid differentiation might a continuously progressive profile: from intestinal type COM adenocarcinoma to GAED and then HAC. CIN/GS subtypes might be where they belonged, and SALL4, HER2 and Immunoscore may be potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humpath.2021.02.003DOI Listing
February 2021

Therapeutic considerations for APOE and TOMM40 in Alzheimers disease: A tribute to Allen Roses MD.

Expert Opin Investig Drugs 2021 Jan 2;30(1):39-44. Epub 2020 Dec 2.

Cleveland Clinic, Lou Ruvo Center for Brain Health , Las Vegas, NV, USA.

: Four years ago this Autumn, pioneering neurologist Prof. Allen. D. Roses passed away. Hence, we have taken time to reflect on his work and legacy in Alzheimer's disease (AD) research. Prof. Roses rejected the widely accepted amyloid hypothesis, which identifies amyloid beta (Aβ) protein accumulation within the brain as the cause of AD. Instead, he proposed that the epsilon type 4 allele of apolipoprotein (APOE- Ɛ4) and translocase of outer mitochondrial membrane 40 homolog (TOMM40) were preeminent factors in the pathogenesis and progression of AD, particularly in late-onset AD (LOAD). This rejection of the amyloid hypothesis has generated new investigations into APOE and TOMM40 as risk factors for AD. : We discuss the contributions of Prof. Roses to AD research, describe how APOE-Ɛ4 and TOMM40 have been posited to trigger neuropathological changes leading to AD, and explore paths to future clinical applications built on the foundations of his research. : The unconventional methodology of targeting APOE and TOMM40 offers great potential for the development of effective preventive and disease-modifying AD interventions. Future preclinical and clinical investigations will greatly benefit from the groundbreaking scientific discoveries of Prof. Roses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/13543784.2021.1849138DOI Listing
January 2021

The Host Cell Metabolite Inositol Hexakisphosphate Promotes Efficient Endogenous HIV-1 Reverse Transcription by Stabilizing the Viral Capsid.

mBio 2020 12 1;11(6). Epub 2020 Dec 1.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

A defining activity of retroviruses is reverse transcription, the process by which the viral genomic RNA is converted into the double-stranded DNA required for virus replication. Reverse transcriptase (RT), the viral enzyme responsible for this process, was identified in 1970 by assaying permeabilized retrovirus particles for DNA synthesis Such reactions are inefficient, with only a small fraction of viral genomes being converted to full-length double-stranded DNA molecules, possibly owing to disruption of the structure of the viral core. Here, we show that reverse transcription in purified HIV-1 cores is enhanced by the addition of the capsid-binding host cell metabolite inositol hexakisphosphate (IP6). IP6 potently enhanced full-length minus-strand synthesis, as did hexacarboxybenzene (HCB), which also stabilizes the HIV-1 capsid. Both IP6 and HCB stabilized the association of the viral CA and RT proteins with HIV-1 cores. In contrast to the wild type, cores isolated from mutant HIV-1 particles containing intrinsically hyperstable capsids exhibited relatively efficient reverse transcription in the absence of IP6, further indicating that the compound promotes reverse transcription by stabilizing the viral capsid. We also observed that the capsid-destabilizing antiviral compound PF74 inhibited endogenous reverse transcription with a potency that mirrors its ability to inhibit reverse transcription during infection. Our results show that the stabilization of the HIV-1 capsid permits efficient reverse transcription in HIV-1 cores, providing a sensitive experimental system for analyzing the functions of viral and host cell molecules and the role of capsid disassembly (uncoating) in the process. HIV-1 infection requires reverse transcription of the viral genome. While much is known about the biochemistry of reverse transcription from simplified biochemical reactions, reverse transcription during infection takes place within a viral core. However, endogenous reverse transcription reactions using permeabilized HIV-1 virions or purified viral cores have been inefficient. Using viral cores purified from infectious HIV-1 particles, we show that efficient reverse transcription is achieved by addition of the capsid-stabilizing metabolite inositol hexakisphosphate. The enhancement of reverse transcription was linked to the capsid-stabilizing effect of the compound, consistent with the known requirement for an intact or semi-intact viral capsid for HIV-1 infection. Our results establish a biologically relevant system for dissecting the function of the viral capsid and its disassembly during reverse transcription. The system should also prove useful for mechanistic studies of capsid-targeting antiviral drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.02820-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7733946PMC
December 2020

Isoflurane activates AMP-activated protein kinase to inhibit proliferation, and promote apoptosis and autophagy in cervical carcinoma both and .

J Recept Signal Transduct Res 2020 Oct 12:1-8. Epub 2020 Oct 12.

Department of Anesthesiology, HanDan Central Hospital, Handan, China.

Objective: Isoflurane is an extensively used inhalational anesthesia, and its carcinogenic or anti-cancerous effect has been identified recently. However, the specific role of isoflurane in cervical cancer remains unclear.

Aim: This study aimed to investigate the function of isoflurane in cervical cancer as well as the underlying mechanism.

Methods: After isoflurane treatment, HeLa cell viability, percentage of apoptotic cells, expression of active caspase-3/9 were examined by CCK-8 assay, Annexin V-FITC/PI double staining, and Western blot analysis, respectively. ROS generation, ratio of NAD/NADH, and ATP level after isoflurane stimulation were determined using commercial assay kits. Afterwards, activation of AMPK and autophagy was assessed through Western blot analysis and immunofluorescence. Whether AMPK mediated the isoflurane-induced apoptosis and autophagy was explored by adding an AMPK inhibitor (Compound C). The function of isoflurane was finally investigated on a HeLa cell model.

Results: Isoflurane inhibited cell viability and induced apoptosis evidenced by upregulation of active caspase-3/9 in HeLa cells. Oxidative stress was triggered by isoflurane, as isoflurane elevated ROS level, and lowered ratio of NAD/NADH and ATP level. Further results showed isoflurane activated the AMPK/mTOR pathway and induced autophagy. In addition, inhibition of AMPK led to ameliorated effects of isoflurane on apoptosis and autophagy. experiments proved isoflurane could repress tumorigenesis, activate AMPK, and induce autophagy in mouse.

Conclusions: Isoflurane activated AMPK to inhibit proliferation and promote apoptosis and autophagy both and .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10799893.2020.1831535DOI Listing
October 2020

Alzheimer's disease beyond amyloid: strategies for future therapeutic interventions.

BMJ 2020 10 9;371:m3684. Epub 2020 Oct 9.

Centre of Excellence in Neurodegeneration, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m3684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541037PMC
October 2020

Screening for cognitive impairment with the montreal cognitive assessment at six months after stroke and transient ischemic attack.

Neurol Res 2021 Jan 23;43(1):15-21. Epub 2020 Sep 23.

Department of Neurology, Beijing Tiantan Hospital, Capital Medical University , Beijing, China.

Objective: Cognitive impairment usually occurs in the acute phase after stroke, but most stroke survivors experience some form of long-term cognitive deficit. The aim of this study was to establish the cutoff point of the Montreal Cognitive Assessment (MoCA-Beijing) in screening for cognitive impairment (CI) at 6 months of ischemic stroke or transient ischemic attack (TIA).

Methods: A total of 301 stroke patients and 15 TIA patients were recruited. Patients were assessed at six months by the MoCA-Beijing and a formal neuropsychological battery. The 1.5 SD below the level of the norm on several tests indicated cognitive impairment (CI).

Results: Most stroke and TIA patients were in their 60s (61.23 ± 10.60 years old). The optimal cutoff point for MoCA-Beijing in discriminating patients with CI from those with no cognitive impairment (NCI) was 24/25 (sensitivity 63.28%, specificity 71.22%, PPV = 73.68%, NPV = 60.37%, classification accuracy = 66.72%). The predominant cognitive deficits were visuospatial ability (84.85%), and then attention/executive function (79.27%).

Conclusion: The MoCA-Beijing cutoff score for differentiating CI from NCI after stroke and TIA at six months was at 24/25, and it is important for routine clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/01616412.2020.1819070DOI Listing
January 2021

PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE)-a population-based prospective cohort study: rationale, design and baseline participant characteristics.

Stroke Vasc Neurol 2021 Mar 30;6(1):145-151. Epub 2020 Aug 30.

Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

Background And Purpose: Cardiovascular diseases and dementia are two major diseases in the elderly. Atherosclerosis is associated with future vascular events and cognitive impairment. The PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study is a population-based prospective cohort study with comprehensive evaluation of multiterritorial artery stenosis and plaque using advanced vascular imaging techniques and prospective collection of vascular events and cognitive assessments.

Methods: Between May 2017 and September 2019, the PRECISE study enrolled 3067 community-dwelling adults with ages between 50 and 75 years cluster sampled from six villages and four communities of Lishui city in China. Data are collected in face-to-face interviews at baseline, 2-year and 4-year follow-up visits. Brain MRI including high-resolution sequences for intracranial and carotidal arteries and CT angiography for thoracoabdominal arteries were performed at baseline and will be rescanned after 4 years. Cardiovascular/cerebrovascular events and cognitive assessment will be prospectively collected after the enrollment. Blood and urine samples were collected and biomarkers were tested at baseline.

Results: A total of 3067 subjects were enrolled, among which 53.5% were female with an average age of 61.2±6.7 years. Among them, 2.8%, 8.1%, 43.1% and 21.6% had a history of stroke, coronary heart diseases, hypertension and diabetes mellitus, respectively.

Conclusions: The PRECISE study is a population-based prospective cohort study with comprehensive evaluation of atherosclerotic stenosis and plaque using advanced vascular imaging techniques. Data from this cohort provide us an opportunity to precisely evaluate polyvascular atherosclerosis and its association with future vascular events and cognitive impairment.

Trial Registration Number: ClinicalTrials.gov Registry (NCT03178448).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/svn-2020-000411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005894PMC
March 2021

Clinicopathological features to distinguish malignant solitary fibrous tumors of the prostate from prostatic stromal tumors.

Virchows Arch 2021 Apr 20;478(4):619-626. Epub 2020 Aug 20.

The Department of Pathology, Duke University School of Medicine, Durham, NC, 27710, USA.

Mesenchymal tumors of the prostate are rare but encompass a wide differential diagnosis. In our study, we aimed to investigate the clinicopathological features that can be used to differentiate malignant solitary fibrous tumors (mSFTs) occurring in the prostate from prostatic stromal tumors. A total of 15 patients with mesenchymal tumors of the prostate were identified in Nanjing Drum Tower Hospital from 2009 to 2019, including 3 mSFTs, 9 stromal tumors of uncertain malignant potential (STUMPs), and 3 prostatic stromal sarcomas (PSSs). Immunohistochemical stains for signal transducer and activator of transcription 6 (STAT6), aldehyde dehydrogenase 1 (ALDH1), CD34, desmin, smooth muscle actin (SMA), progesterone receptor (PR), CD117, and cytokeratin (CK) were performed on representative sections from each tumor, and the clinical features, histology, and immunophenotype of these three groups were analyzed. There was no significant difference in mean patient age of patients diagnosed with mSFTs, STUMPs, and PSSs. mSFTs and PSSs showed significantly increased tumor size (p < 0.05), Ki-67 proliferation index (p < 0.0001), and mitotic activity (p < 0.05) when compared with STUMPs. mSFTs showed significantly higher expression of STAT6 compared with both PSSs and STUMPs (p < 0.0001, p < 0.0001). PR showed significantly more expression in STUMPs than in mSFTs or PSSs (p < 0.0001, p < 0.0001). Desmin and SMA showed significantly more expression in STUMPs than in mSFTs (p < 0.05). ALDH1, CD117, CK, and CD34 showed no significant difference in staining between mSFTs, STUMPs, and PSSs. Therefore, a limited panel of STAT6, PR, and Ki-67 may be useful in distinguishing between mSFTs, STUMPs, and PSSs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00428-020-02909-2DOI Listing
April 2021

Diagnostic performance of a nomogram incorporating cribriform morphology for the prediction of adverse pathology in prostate cancer at radical prostatectomy.

Oncol Lett 2020 Sep 10;20(3):2797-2805. Epub 2020 Jul 10.

Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu 210008, P.R. China.

The aim of the present study was to develop a novel nomogram that incorporated clinical factors, imaging parameters and biopsy pathological factors (including cribriform morphology) to predict adverse pathology in prostate cancer (PCa). A total of 223 patients with PCa, who had undergone preoperative multi-parametric magnetic resonance imaging and had a biopsy of Gleason pattern (GP) 4, absence of GP 5 and pure Grade Group (GG) 3 [Gleason score (GS) 3+4, GS 4+3, GS 4+4], were retrospectively enrolled onto the study. The contribution of GG to the biopsy and Prostate Imaging Reporting and Data System (PI-RADS) score for PCa harboring adverse pathology were analyzed. Univariate and multivariate logistic regression analyses were performed to determine significant pathology predictors of adverse pathology for nomogram development. The nomogram was internally validated using bootstrapping with 1,000 iterations. The diagnostic performance of the nomogram was analyzed by receiver operating characteristics (ROC) analysis and decision curve analysis (DCA). A higher biopsy GG and PI-RADS score were associated with an increased likelihood of adverse pathology. Prostate specific antigen density (PSAD), biopsy GG, cribriform morphology on biopsy and PI-RADS score were significant predictors and were included in the nomogram. The ROC area under the curve of the nomogram was 0.88 (95% confidence interval, 0.84-0.91), with a high specificity (0.91) and moderate sensitivity (0.72). The novel nomogram was shown to have a higher net benefit for the prediction of adverse pathology in PCa, compared with any individual factors determined by DCA. Overall, a novel nomogram incorporating PSAD, PI-RADS score, biopsy GG and cribriform morphology on biopsy was shown to perform well in the prediction of PCa harboring adverse pathology at the time of radical prostatectomy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3892/ol.2020.11861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400272PMC
September 2020

Intrinsic curvature of the HIV-1 CA hexamer underlies capsid topology and interaction with cyclophilin A.

Nat Struct Mol Biol 2020 09 3;27(9):855-862. Epub 2020 Aug 3.

Division of Structural Biology, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK.

The mature retrovirus capsid consists of a variably curved lattice of capsid protein (CA) hexamers and pentamers. High-resolution structures of the curved assembly, or in complex with host factors, have not been available. By devising cryo-EM methodologies for exceedingly flexible and pleomorphic assemblies, we have determined cryo-EM structures of apo-CA hexamers and in complex with cyclophilin A (CypA) at near-atomic resolutions. The CA hexamers are intrinsically curved, flexible and asymmetric, revealing the capsomere and not the previously touted dimer or trimer interfaces as the key contributor to capsid curvature. CypA recognizes specific geometries of the curved lattice, simultaneously interacting with three CA protomers from adjacent hexamers via two noncanonical interfaces, thus stabilizing the capsid. By determining multiple structures from various helical symmetries, we further revealed the essential plasticity of the CA molecule, which allows formation of continuously curved conical capsids and the mechanism of capsid pattern sensing by CypA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41594-020-0467-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064030PMC
September 2020

Impairment of cognition and sleep after acute ischaemic stroke or transient ischaemic attack in Chinese patients: design, rationale and baseline patient characteristics of a nationwide multicentre prospective registry.

Stroke Vasc Neurol 2021 Mar 13;6(1):139-144. Epub 2020 Jul 13.

Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Background And Aim: Cognitive impairment and sleep disorder are both common poststroke conditions and are closely related to the prognosis of patients who had a stroke. The Impairment of CognitiON and Sleep after acute ischemic stroke or transient ischemic attack in Chinese patients (ICONS) study is a nationwide multicentre prospective registry to investigate the occurrence and associated factors of cognitive impairment and sleep disorder after acute ischaemic stroke (AIS) or transient ischaemic attack (TIA).

Methods: Consecutive AIS or TIA in-hospital patients within 7 days after onset were enrolled from 40 participating sites in China. Comprehensive baseline clinical and imaging data were collected prospectively. Blood and urine samples were also collected on admission and follow-up visits. Patients were interviewed face to face for cognition and sleep related outcomes at 2 weeks, 3, 6 and 12 months after AIS/TIA and followed up for clinical outcomes by telephone annually over 5 years.

Results: Between August 2015 and January 2018, a total of 2625 patients were enrolled. 92.65% patients had AIS and 7.35% patients had TIA. Overall, the average age was 61.04 years, and 72.38% patients were male. Median National Institutes of Health Stroke Scale score was 3 in AIS patients.

Conclusions: The ICONS study is a large-scale nationwide prospective registry to investigate occurrence and the longitudinal changes of cognitive impairment and sleep disorder after AIS or TIA. Data from this registry may also provide opportunity to evaluate associated factors of cognitive impairment or sleep disorder after AIS or TIA and their impact on clinical outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/svn-2020-000359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005906PMC
March 2021

Comprehensive evaluation of Ga-PSMA-11 PET/CT parameters for discriminating pathological characteristics in primary clear-cell renal cell carcinoma.

Eur J Nucl Med Mol Imaging 2021 Feb 4;48(2):561-569. Epub 2020 Jul 4.

Department of Urology, Nanjing Drum Tower Hospital, Institute of Urology Nanjing University, The Affiliated Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing, 210008, Jiangsu Province, China.

Purpose: To evaluate parameters derived from Ga-PSMA-11 PET/CT images for discriminating pathological characteristics in primary clear-cell renal cell carcinoma (ccRCC).

Methods: The study retrospectively examined data for 36 ccRCC patients with preoperative Ga-PSMA-11 PET/CT scan and surgical specimens. Radiological parameters including maximal tumor diameter, mean CT value, and maximal standard uptake value (SUV) were derived from PET/CT images. Pathological characteristics included WHO/ISUP grade and adverse pathology (tumor necrosis or sarcomatoid or rhabdoid feature). Values of radiological parameters were compared within subgroups of pathological characteristics. Receiver operating characteristic (ROC) curve analysis was used for the effectiveness of radiological parameters in differentiating pathological characteristics, estimating area under the ROC curve (AUC) and 95% confidence intervals (CIs).

Results: The WHO/ISUP grade distribution for 36 tumors was grade 1, 9 (25.0%); grade 2, 12 (33.3%); grade 3, 9 (25.0%); and grade 4, 6 (16.7%). Adverse pathology was positive for 15 (41.7%). Radiological tumor diameter and SUVmax significantly differed by WHO/ISUP grade, pT stage, and adverse pathology (all P < 0.05), with no difference by CT value. Tumor diameter demonstrated sensitivity 86% and specificity 88% for pT stage, with cutoff 6.70 and AUC 0.91 (95% CI, 0.79-1.00, P < 0.001). SUV could effectively differentiate WHO/ISUP grade (3-4 vs. 1-2) and adverse pathology (positive vs. negative), with AUC 0.89 (95% CI, 0.81-0.98, P < 0.001), cutoff 16.4, sensitivity 100%, and specificity 71% and AUC 0.92 (95% CI, 0.85-0.99, P < 0.001), cutoff 18.5, sensitivity 94%, and specificity 87%, respectively.

Conclusion: Ga-PSMA-11 PET/CT could effectively identify aggressive pathological features of ccRCC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00259-020-04916-6DOI Listing
February 2021

MiR-125b Loss Activated HIF1α/pAKT Loop, Leading to Transarterial Chemoembolization Resistance in Hepatocellular Carcinoma.

Hepatology 2021 Apr 7;73(4):1381-1398. Epub 2020 Nov 7.

MOE Key Laboratory of Biosystems Homeostasis & Protection, Life Sciences Institute, Zhejiang University, Hangzhou, China.

Background And Aims: Transarterial chemoembolization (TACE) is a standard locoregional therapy for patients with hepatocellular carcinoma (HCC) patients with a variable overall response in efficacy. We aimed to identify key molecular signatures and related pathways leading to HCC resistance to TACE, with the hope of developing effective approaches in preselecting patients with survival benefit from TACE.

Approach And Results: Four independent HCC cohorts with 680 patients were used. MicroRNA (miRNA) transcriptome analysis in patients with HCC revealed a 41-miRNA signature related to HCC recurrence after adjuvant TACE, and miR-125b was the top reduced miRNA in patients with HCC recurrence. Consistently, patients with HCC with low miR-125b expression in tumor had significantly shorter time to recurrence following adjuvant TACE in two independent cohorts. Loss of miR-125b in HCC noticeably activated the hypoxia inducible factor 1 alpha subunit (HIF1α)/pAKT loop in vitro and in vivo. miR-125b directly attenuated HIF1α translation through binding to HIF1A internal ribosome entry site region and targeting YB-1, and blocked an autocrine HIF1α/platelet-derived growth factor β (PDGFβ)/pAKT/HIF1α loop of HIF1α translation by targeting the PDGFβ receptor. The miR-125b-loss/HIF1α axis induced the expression of CD24 and erythropoietin (EPO) and enriched a TACE-resistant CD24-positive cancer stem cell population. Consistently, patients with high CD24 or EPO in HCC had poor prognosis following adjuvant TACE therapy. Additionally, in patients with HCC having TACE as their first-line therapy, high EPO in blood before TACE was also noticeably related to poor response to TACE.

Conclusions: MiR-125b loss activated the HIF1α/pAKT loop, contributing to HCC resistance to TACE and the key nodes in this axis hold the potential in assisting patients with HCC to choose TACE therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/hep.31448DOI Listing
April 2021

Effect of ApoE isoforms on mitochondria in Alzheimer disease.

Neurology 2020 06 26;94(23):e2404-e2411. Epub 2020 May 26.

From the Barrow Neurological Institute (J.Y., M.N.S., M.N., J.S.), St. Joseph Hospital and Medical Center, Phoenix, AZ; Banner Alzheimer's Institute (E.M.R.), Phoenix, AZ; Civin Laboratory for Neuropathology (T.G.B., G.E.S.), Banner Sun Health Research Institute, Sun City, AZ; Cleveland Clinic Lou Ruvo Center for Brain Health (M.N.S.), Las Vegas, NV; School of Life Sciences (M.N.), Arizona State University, Tempe; Department of Neurology (R.J.C.), Mayo Clinic Arizona, Scottsdale; Advanced Innovation Center for Human Brain Protection (J.S.), Capital Medical University, Beijing, China; and China National Clinical Research Center for Neurological Diseases (J.S.), Beijing Tiantan Hospital, Capital Medical University, Beijing.

Objective: To test the hypothesis that ApoE isoforms affect mitochondrial structure and function that are related to cognitive impairment in Alzheimer disease (AD), we systematically investigated the effects of ApoE isoforms on mitochondrial biogenesis and dynamics, oxidative stress, synapses, and cognitive performance in AD.

Methods: We obtained postmortem human brain tissues and measured proteins that are responsible for mitochondrial biogenesis (peroxisome proliferator-activated receptor-gamma coactivator-1α [PGC-1α] and sirtuin 3 [SIRT3]), for mitochondrial dynamics (mitofusin 1 [MFN1], mitofusin 2 [MFN2], and dynamin-like protein 1 [DLP1]), for oxidative stress (superoxide dismutase 2 [SOD2] and forkhead-box protein O3a [Foxo3a]), and for synapses (postsynaptic density protein 95 [PSD95] and synapsin1 [Syn1]). A total of 46 cases were enrolled, including ApoE-ɛ4 carriers (n = 21) and noncarriers (n = 25).

Results: Levels of these proteins were compared between ApoE-ɛ4 carriers and noncarriers. ApoE-ɛ4 was associated with impaired mitochondrial structure and function, oxidative stress, and synaptic integrity in the human brain. Correlation analysis revealed that mitochondrial proteins and the synaptic protein were strongly associated with cognitive performance.

Conclusion: ApoE isoforms influence mitochondrial structure and function, which likely leads to alteration in oxidative stress, synapses, and cognitive function. These mitochondria-related proteins may be a harbinger of cognitive decline in ApoE-ɛ4 carriers and provide novel therapeutic targets for prevention and treatment of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455369PMC
June 2020

The Occurrence and Longitudinal Changes of Cognitive Impairment After Acute Ischemic Stroke.

Neuropsychiatr Dis Treat 2020 26;16:807-814. Epub 2020 Mar 26.

Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People's Republic of China.

Background And Purpose: More and more evidence suggests that cognitive impairment (CI) after stroke is closely related to the quality of life of stroke patients. The primary aim of this study is to investigate the occurrence and longitudinal changes of CI at different stages after acute ischemic stroke (AIS) in Chinese patients.

Methods: The data of this study come from the impairment of cognition and Sleep after acute ischemic stroke or transient ischemic attack in Chinese patients study (ICONS), a nationwide multicenter prospective registry that recruited consecutive AIS or transient ischemic attack in-hospital patients within 7 days after onset. Patients were followed for Montreal Cognitive Assessment (MoCA) scale at 2-week (2w), 3 months (3m) and 12 months (12m). CI was defined as MoCA score≦22. No cognitive impairment (NCI) was defined as MoCA score>22.

Results: A total of 2432 AIS patients were enrolled in this study. Overall, 72.94% of patients were male and the average age was 60.95 years. Median National Institutes of Health Stroke Scale score was 3. The occurrence rate of CI was 52.38%, 35.55% and 34.16% at 2w, 3m and 12m. Among patients with CI at 2w and 3m, 39.9% and 27.9% of patients returned to NCI at next follow-up point. At 3m and 12m follow-up, there were also 9.6% and 12.7% new CI patients. The two cognitive items with the highest abnormal rate were "Delayed recall" (89.35%, 83.33% and 82.80%) and "Visuospatial/executive" (78.91%, 73.42% and 70.08%). The cognitive item with the highest percentage of improved patients was "Orientation" (60.91-76.68%), and the cognitive item with the lowest percentage of improved patients was "Language" (35.85-44.50%).

Conclusion: CI had a relatively high occurrence at 2w to 12m after AIS. CI at 3m and 12m was significantly lower than that at 2w after stroke. The occurrence of abnormalities and recovery probability for different cognitive items also differed greatly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/NDT.S234544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114937PMC
March 2020

Marked thickening of muscularis mucosae and submucosa in the gastric cardia: A histopathological study of 110 surgical resection cases.

J Dig Dis 2020 Apr 27;21(4):205-214. Epub 2020 Apr 27.

Department of Gastroenterology, Nanjing Drum Tower Hospital Affiliated to Nanjing University School of Medicine, Nanjing, Jiangsu Province, China.

Objective: To investigate histopathologic changes of muscularis mucosae (MM) and submucosa in the gastric cardia.

Methods: We performed a histopathology study of 50 distal esophagectomies with proximal gastrectomies for esophageal squamous cell carcinoma as the study (non-cancerous cardiac) group and 60 gastrectomies for early gastric cardiac carcinoma as the cancer group. The gastroesophageal junction was defined as the distal end of squamous epithelium, multilayered epithelium, or deep esophageal glands or ducts. Gastric cardia (n = 110) was defined as the presence of cardiac and cardio-oxyntic mucosae distal to the gastroesophageal junction.

Results: The average thickness of MM and submucosa in the cardia was 1.04 and 1.41 mm, respectively, which was significantly thicker than that in distal stomach (n = 34) (0.22 and 0.99 mm) or distal esophagus (n = 92) (0.60 and 1.15 mm). In the cardia, thickened MM displayed frayed muscle fibers (93.3%) with a significantly higher prevalence of entrapped glands, cysts, and lymphoid follicles than in the distal stomach or distal esophagus. In the submucosa fatty changes, cysts, and abnormal arteries were significantly more common in the cardia than in the distal stomach or distal esophagus. Compared with the study group, the cardia in the cancer group showed significantly thicker MM (average 1.31 vs 0.72 mm) and submucosa (average 1.61 vs 1.16 mm), more frequent frayed MM (93.3% vs 60.0%), prolapse-like changes (50.0% vs 2.0%), and cysts (26.7% vs 4.0%).

Conclusion: MM and submucosa of the cardia were significantly thickened, especially in early gastric cardiac carcinomas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/1751-2980.12860DOI Listing
April 2020

Integration of immunogenic activation and immunosuppressive reversion using mitochondrial-respiration-inhibited platelet-mimicking nanoparticles.

Biomaterials 2020 02 19;232:119699. Epub 2019 Dec 19.

Jiangsu Key Laboratory of Molecular and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, 210009, China. Electronic address:

Here, we developed platelet membranes (PM) as nano-carriers to co-encapsulate metformin (Met) and IR780 (PM-IR780-Met NPs). The resulting nano-carrier ensured a longer circulation lifetime and facilitated the greater accumulation of IR780 and Met in tumors owing to the active adhesion between PM and tumor cells. As a photodynamic therapy (PDT) agent, IR780 could effectively kill the tumor by producing toxic reactive singlet oxygen species (ROS), while the introduction of Met inhibited mitochondrial respiration and reduced tumor oxygen consumption, thereby evoking an oxygen-boosted PDT and propelling the immunogenic cell death (ICD)-based immunogenic pathway. Meanwhile, the reversed tumor hypoxia also impeded the myeloid derived suppressor cell (MDSC)-regulated immunosuppressive pathway. Finally, tremendous T cells were recruited and activated, providing a promising platform to eliminate the primary tumors and synchronously opening a new avenue for the effective ablation of tumor metastasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biomaterials.2019.119699DOI Listing
February 2020

Apolipoprotein E regulates mitochondrial function through the PGC-1α-sirtuin 3 pathway.

Aging (Albany NY) 2019 12 6;11(23):11148-11156. Epub 2019 Dec 6.

China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.

Cerebral hypometabolism is a pathophysiological hallmark of Alzheimer's disease (AD). Our previous studies found that a mitochondrial protein, sirtuin3 (Sirt3), was down-regulated in human AD postmortem brains. Sirt3 protected neurons against oligo-amyloid β-42 induced hypometabolism in human Apolipoprotein E4 (ApoE4) transgenic mice. However, how ApoE affects mitochondrial function and its proteins such as Sirt3 remains unclear.We characterized and compared levels of Sirt3 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α, a Sirt3 activator), oxidative stress proteins, synaptic proteins, cognitive task performance and ATP production in 12-month old human ApoE4 and ApoE3 transgenic mice, and assessed changes in Sirt3 expression on cellular metabolism in primary neurons from ApoE4 and ApoE3 transgenic mice.Compared to ApoE3 mice, Sirt3 and PGC-1α levels were significantly lower in ApoE4 mice. Learning and memory, synaptic proteins, the NAD+/ NADH ratios, and ATP production were significantly lower in ApoE4 mice as well. Sirt3 knockdown reduced the oxygen consumption and ATP production in primary neurons with the human ApoE3, while Sirt3 overexpression protected these damages in ApoE4 neurons.Our findings suggest that ApoE4 suppresses mitochondrial function via the PGC-1α- Sirt3 pathway. This discovery provides us novel therapeutic targets for the treatment and prevention of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.102516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6932918PMC
December 2019

Diagnostic Value of Ga-PSMA PET/CT for Detection of Phosphatase and Tensin Homolog Expression in Prostate Cancer: A Pilot Study.

J Nucl Med 2020 06 22;61(6):873-880. Epub 2019 Nov 22.

Department of Urology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Institute of Urology Nanjing University, Jiangsu Province, China

Our purpose was to explore the value of Ga-prostate-specific membrane antigen (PSMA) PET/CT for detection of phosphatase and tensin homolog (PTEN)-loss prostate cancer. We retrospectively enrolled 75 patients who underwent multiparametric MRI and Ga-PSMA PET/CT before radical prostatectomy. Lesions were outlined on pathologic images, and regions of interest were drawn on matched multiparametric MRI and PET/CT images. Imaging parameters, including average apparent diffusion coefficient and SUV, were derived. Immunohistochemical staining was performed to evaluate the PTEN status. The diagnostic performance of imaging parameters was analyzed by receiver-operating-characteristic analysis. Univariate logistic regression analyses were used to evaluate the association between clinical and imaging variables and PTEN status. In total, 103 lesions from 75 patients were analyzed. Of these lesions, 38 of 103 (36.9%) showed PTEN-loss status. Our study showed a strong association between SUV and PTEN-loss tumors both in the per-patient analysis ( < 0.01) and in the per-lesion analysis ( < 0.01), yielding sensitivity and specificity of 0.80 and 0.77, respectively, in the per-patient analysis and 0.83 and 0.74, respectively, in the per-lesion analysis. Meanwhile, higher pathologic PSMA expression was found in the PTEN-deficiency tumors. However, there was no significant difference between PTEN-loss tumors and PTEN-intact tumors using parameters such as average apparent diffusion coefficient ( > 0.05) and score on the Prostate Imaging Reporting and Data System, version 2 ( > 0.05). Surprisingly, SUV was a significant predictor for detection of PTEN-loss tumors (odds ratio of 7.56 and 95% confidence interval of 2.18-26.24 on per-patient analysis; odds ratio of 13.66 and 95% confidence interval of 4.32-43.24 on per-lesion analysis). Ga-PSMA PET/CT could effectively detect aggressive PTEN-loss tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2967/jnumed.119.236059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262223PMC
June 2020

Laennec's approach for laparoscopic anatomic hepatectomy based on Laennec's capsule.

BMC Gastroenterol 2019 Nov 21;19(1):194. Epub 2019 Nov 21.

Hepatobiliary and Pancreatic Center & Liver Transplantation Center, The Affiliated Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing, Jiangsu Province, People's Republic of China.

Background: Although isolating Glissonean pedicles and hepatic veins are critical procedures during anatomical hepatectomy, there is no standardized approach. We propose the novel Laennec's approach for laparoscopic anatomic hepatectomy (LAH) based on Laennec's capsule, which serves as the anatomic landmark for LAH. The aim of this study was to elucidate that the natural gap between Laennec's capsule and the adjacent tissues contributes to standardization of the surgical technique for LAH.

Methods: Eighty-four cases were enrolled in this observable clinical trial. They underwent LAH for liver diseases. Laennec's approach was proposed for LAH based on Laennec's capsule. The liver tissues close to Glissonean pedicle, hepatic veins, naked area, and inferior vena cava were collected for hematoxylin and eosin, resorcinol-fuchsin staining, and immunohistochemistry.

Results: The staining revealed capsule packaging of the whole liver independent of the adjacent tissues and intrahepatic vessels. A natural gap was found between Laennec's capsule and the adjacent tissues at different sites. Laennec's capsule served as the landmark for isolating Glissonean pedicle and hepatic veins, mobilizing the liver, and performing Hanging maneuver. Eighty-four cases underwent LAH for liver diseases using this strategy. The operation time was 277.23 min. The mean of hospital days was 9.8.

Conclusions: Laennec's approach based on Laennec's capsule contributes to standardization of the surgical technique for LAH, and brings innovations that facilitates safe and effective liver resection under laparoscopy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12876-019-1107-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873526PMC
November 2019

Combined clinical characteristics and multiparametric MRI parameters for prediction of cribriform morphology in intermediate-risk prostate cancer patients.

Urol Oncol 2020 04 7;38(4):216-224. Epub 2019 Oct 7.

Department of Radiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China. Electronic address:

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 χ 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.urolonc.2019.09.002DOI Listing
April 2020

Significant benefit of nivolumab combining radiotherapy in metastatic gallbladder cancer patient with strong PD-L1 expression: a case report.

Onco Targets Ther 2019 8;12:5389-5393. Epub 2019 Jul 8.

The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, People's Republic of China.

Background: Gallbladder cancer (GBC) is the main pathological type of biliary tract cancers. Due to its aggressive nature, GBC is usually diagnosed at advanced stages with limited therapeutic options and poor outcome, especially after failure of chemotherapy.

Case Presentation: Herein, we report a recurrent metastatic GBC patient with strong programmed death-ligand 1 (PD-L1) expression (≥50%) who obtained a significant response to radiotherapy combining nivolumab treatment.

Conclusions: To our knowledge this is the first case presenting significant nivolumab response in a Chinese GBC patient. This remarkable response was most likely associated with the strong PD-L1 expression, and indicated that PD-L1 expression could be considered as a biomarker for nivolumab treatment in metastatic gallbladder cancer. However, more studies are needed for validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2147/OTT.S208926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625641PMC
July 2019

Ketones improves Apolipoprotein E4-related memory deficiency via sirtuin 3.

Aging (Albany NY) 2019 07;11(13):4579-4586

Barrow Neurological Institute, St. Joseph Hospital and Medical Center, Dignity Health Organization, Phoenix, AZ 85013, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.18632/aging.102070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660057PMC
July 2019

Faster cognitive decline in dementia due to Alzheimer disease with clinically undiagnosed Lewy body disease.

PLoS One 2019 25;14(6):e0217566. Epub 2019 Jun 25.

Banner Sun Health Research Institute, Sun City, Arizona, United States of America.

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 (β = -0.69, 95% CI: -1.05, -0.33, p<0.001) while the AD-DLB group did not (β = -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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0217566PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6592515PMC
February 2020

Sirtuin 3 promotes microglia migration by upregulating CX3CR1.

Cell Adh Migr 2019 12;13(1):229-235

b Barrow Neurological Institute , St. Joseph Hospital and Medical Center, Dignity Health Organization , Phoenix , AZ , USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/19336918.2019.1629224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601551PMC
December 2019

Does informant-based reporting of cognitive symptoms predict amyloid positivity on positron emission tomography?

Alzheimers Dement (Amst) 2019 Dec 6;11:424-429. Epub 2019 Jun 6.

Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV.

Introduction: Researchers are searching for clinical instruments to predict amyloid positivity for disease classification. Informant-based reports could detect disease status. This study compares subjective memory complaints captured by informant-based reports between positron emission tomography (PET)-positive and PET-negative patients and hypothesizes that amyloid PET positivity associates with increased informant-based cognitive complaints.

Methods: Ninety-eight amnestic mild cognitive impairment or mild dementia subjects were studied. Subjective report was captured by the informant-driven Alzheimer's Questionnaire (AQ) administered before PET. Differences in demographics and AQ score by diagnostic status and amyloid status were measured, and a receiver-operating characteristic curve was calculated.

Results: Sixty-five mild cognitive impairment/Alzheimer's disease amyloid PET-positive and 33 amyloid PET-negative subjects were included. AQ was significantly higher (12.51 ± 4.95) for amyloid PET-positive subjects (9.06 ± 3.65;  = .001).

Conclusions: Amyloid PET-positive subjects with Alzheimer's disease or mild cognitive impairment have more informant-based reports of cognitive decline, indicating utility for a brief informant measure.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.dadm.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558087PMC
December 2019