BBT-877, a Novel Autotaxin Inhibitor, Abrogates Drug Resistance in Epithelial Ovarian Cancer Stem Cells.

BACKGROUND/AIM: Cancer stem cells (CSCs) contribute significantly to the poor prognosis of patients with epithelial ovarian cancer (EOC) due to their roles in drug resistance and tumor metastasis. Autotaxin (ATX) plays a pivotal role in the maintenance of the CSC-like properties of EOC tumors. BBT-877 is a novel ATX inhibitor used in clinical treatment of idiopathic pulmonary fibrosis. However, the effects of BBT-877 on drug resistance and metastasis in ovarian CSCs remain unknown. In this study, we aimed to investigate the effects of BBT-877 on drug resistance and intraperitoneal metastasis of EOC. MATERIALS AND METHODS: Spheroid-forming CSCs, which were isolated from two EOC cell lines, A2780 and SKOV3, were investigated by cell viability, western blot, PCR, Spheroid-forming assay, and in vivo experiments. RESULTS: Spheroid-forming CSCs exhibited increased CSC-like properties and paclitaxel (PTX) resistance. BBT-877 treatment inhibited the viability of spheroid-forming CSCs more potently than that of adherent ovarian cancer cell lines. Combinatorial treatment with BBT-877 and PTX significantly attenuated the viability of spheroid-forming CSCs. In a SKOV3 cells-derived intraperitoneal metastasis model, BBT-877 treatment reduced the number of metastatic tumor nodes, while combinatorial treatment with BBT-877 and PTX more potently attenuated the formation of metastatic nodes and accumulation of ascitic fluid. CONCLUSION: These results suggest that BBT-877 can be combined with conventional anticancer drugs for the treatment of patients with recurrent or drug-resistant EOC.

Learning potential and visuospatial memory could predict amyloid-beta positron emission tomography positivity in amnestic mild cognitive impairment.

We investigate the role of neuropsychological tests, including the learning potential, in predicting amyloid-beta positron emission tomography (Aß-PET) status in amnestic mild cognitive impairment (aMCI). This cross-sectional study included 64 patients with aMCI (31 Aß-PET (-) and 33 (+)) who visited a memory impairment clinic at Pusan National University Hospital between 2014 and 2019. Patients underwent Aß-PET scans using 18F-florbetaben and the Seoul Neuropsychological Screening Battery. Learning potential was determined based on the difference in scores between the first and third trials of the Seoul Verbal Learning test (SVLT). Binary logistic regression was used to demonstrate the association between Aß-PET status and cognitive tests. Predictive ability of cognitive tests for Aß deposition was investigated using receiver operating characteristic curves analysis. From logistic regression models, the SVLT learning potential and Rey-Osterrieth Complex Figure Test (RCFT) delayed recall were found to predict Aß-PET positivity. The areas under the curve (AUC) of the SVLT learning potential and RCFT delayed recall were significantly different from 0.5. Our findings of an association between Aß deposition status and learning potential and visuospatial memory suggest that these cognitive tests could be used to screen patients with aMCI for Aß deposition status.

CD109 Promotes Drug Resistance in A2780 Ovarian Cancer Cells by Regulating the STAT3-NOTCH1 Signaling Axis.

Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy owing to relapse caused by resistance to chemotherapy. We previously reported that cluster of differentiation 109 (CD109) expression is positively correlated with poor prognosis and chemoresistance in patients with EOC. To further explore the role of CD109 in EOC, we explored the signaling mechanism of CD109-induced drug resistance. We found that CD109 expression was upregulated in doxorubicin-resistant EOC cells (A2780-R) compared with that in their parental cells. In EOC cells (A2780 and A2780-R), the expression level of CD109 was positively correlated with the expression level of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, and paclitaxel (PTX) resistance. Using a xenograft mouse model, it was confirmed that PTX administration in xenografts of CD109-silenced A2780-R cells significantly attenuated in vivo tumor growth. The treatment of CD109-overexpressed A2780 cells with cryptotanshinone (CPT), a signal transducer and activator of transcription 3 (STAT3) inhibitor, inhibited the CD109 overexpression-induced activation of STAT3 and neurogenic locus notch homolog protein 1 (NOTCH1), suggesting a STAT3-NOTCH1 signaling axis. The combined treatment of CD109-overexpressed A2780 cells with CPT and N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT), a NOTCH inhibitor, markedly abrogated PTX resistance. These results suggest that CD109 plays a key role in the acquisition of drug resistance by activating the STAT3-NOTCH1 signaling axis in patients with EOC.

Neuropsychological, neuroimaging and autopsy findings of butane encephalopathy.

BACKGROUND: Butane is an aliphatic hydrocarbon used in various commercial products. While numerous reports of sudden cardiac-related deaths from butane inhalation have been described, butane-associated acute encephalopathy has rarely been reported. CASE PRESENTATION: A 38-year-old man presented with cognitive dysfunction after butane gas inhalation. Neuropsychological test results showed impairments in verbal and visual memory, and frontal executive function. Diffusion weighted MRI revealed symmetric high-signal changes in the bilateral hippocampus and globus pallidus. FDG-PET demonstrated decreased glucose metabolism in the bilateral precuneus and occipital areas and the left temporal region. At the 8-month follow-up, he showed still significant deficits in memory and frontal functions. Diffuse cortical atrophy with white matter hyperintensities and extensive glucose hypometabolism were detected on follow-up MRI and FDG-PET, respectively. Brain autopsy demonstrated necrosis and cavitary lesions in the globus pallidus. CONCLUSIONS: Only a few cases of butane encephalopathy have been reported to date. Brain lesions associated with butane encephalopathy include lesions in the bilateral thalamus, insula, putamen, and cerebellum. To the best of our knowledge, this is the first report on bilateral hippocampal and globus pallidal involvement in acute butane encephalopathy. The pathophysiology of central nervous system complications induced by butane intoxication is not yet fully understood. However, the direct toxic effects of butane or anoxic injury secondary to cardiac arrest or respiratory depression have been suggested as possible mechanisms of edematous changes in the brain after butane intoxication.

TRRAP Enhances Cancer Stem Cell Characteristics by Regulating NANOG Protein Stability in Colon Cancer Cells.

NANOG, a stemness-associated transcription factor, is highly expressed in many cancers and plays a critical role in regulating tumorigenicity. Transformation/transcription domain-associated protein (TRRAP) has been reported to stimulate the tumorigenic potential of cancer cells and induce the gene transcription of NANOG. This study aimed to investigate the role of the TRRAP-NANOG signaling pathway in the tumorigenicity of cancer stem cells. We found that TRRAP overexpression specifically increases NANOG protein stability by interfering with NANOG ubiquitination mediated by FBXW8, an E3 ubiquitin ligase. Mapping of NANOG-binding sites using deletion mutants of TRRAP revealed that a domain of TRRAP (amino acids 1898-2400) is responsible for binding to NANOG and that the overexpression of this TRRAP domain abrogated the FBXW8-mediated ubiquitination of NANOG. TRRAP knockdown decreased the expression of CD44, a cancer stem cell marker, and increased the expression of P53, a tumor suppressor gene, in HCT-15 colon cancer cells. TRRAP depletion attenuated spheroid-forming ability and cisplatin resistance in HCT-15 cells, which could be rescued by NANOG overexpression. Furthermore, TRRAP knockdown significantly reduced tumor growth in a murine xenograft transplantation model, which could be reversed by NANOG overexpression. Together, these results suggest that TRRAP plays a pivotal role in the regulation of the tumorigenic potential of colon cancer cells by modulating NANOG protein stability.

Eccrine Hidradenoma of the Nasal Vestibule: A Rare Clinical Entity.

Eccrine hidradenoma is a relatively rare benign tumor of sweat gland origin but with possible malignant transformation. It usually consists of solitary, well-demarcated papules or nodules covered with normal skin. Common sites of involvement are the scalp, face, limbs, and anterior trunk. Although the lining of the nasal vestibule includes hair follicles, sebaceous glands, and sweat glands, an eccrine hidradenoma originating in the nasal vestibule has yet to be reported. Herein, we describe a rare clinical presentation of nasal eccrine hidradenoma, treated successfully using a transnasal endoscopic approach.

Serum progranulin is not associated with rs5848 polymorphism in Korean patients with neurodegenerative diseases.

Low serum progranulin (PGRN) is known to be associated with granulin (GRN) gene mutation and T alleles of GRN rs5848 polymorphism. However, there have been only a few Asian studies exploring these. We investigated the serum PGRN levels, rs5848 genotypes, and their relations with cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in the Korean population. Serum PGRN levels, GRN rs5848 polymorphism, and GRN mutations were evaluated in 239 participants (22 cognitively unimpaired participants and 217 patients with neurodegenerative diseases). CSF AD biomarkers were also evaluated in 214 participants. There was no significant difference in the serum PGRN levels among the diagnostic groups. We could not find any GRN mutation carrier in our sample. The differences in the frequencies of the rs5848 genotypes among the clinical groups or the effects of the rs5848 genotypes on serum PGRN were not observed. There was no correlation between the serum PGRN level or rs5848 genotype and CSF AD biomarkers. Neither the T allele nor the TT genotype had an effect on the development of AD. Our results showed that serum PGRN levels were not associated with rs5848 genotypes, indicating that multiple single nucleotide polymorphisms might affect PGRN concentrations in an ethnicity-specific manner.

The Role of Decreased Cortical Thickness and Volume of Medial Temporal Lobe Structures in Predicting Incident Psychosis in Patients With Alzheimer's Disease: A Prospective Longitudinal MRI Study.

OBJECTIVE: To investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD. DESIGN, SETTING, AND PARTICIPANTS: This hospital-based prospective longitudinal study enrolled 109 patients with AD. All patients with AD were evaluated at 3-month intervals to investigate the effect of decreased cortical thickness or volume of medial temporal lobe structures on the risk of incident psychosis in patients with AD. OUTCOME MEASURE: The main outcome measure was time-to-progression from AD to incident psychosis. The thickness or volume of medial temporal lobe structures (i.e., the hippocampus, entorhinal cortex, and parahippocampus) were measured using magnetic resonance imaging and the Freesurfer automated segmentation pipeline at baseline. RESULTS: Multivariate Cox proportional hazards regression analysis revealed that a decreased cortical thickness or volume of medial temporal region was associated with a higher risk of incident psychosis in patients with AD. The hazard ratios for decreased cortical thickness of the left entorhinal cortex and decreased cortical volume of the right hippocampus were 4.291 (95% confidence interval [CI], 1.196-15.384) and 2.680 [(CI, 1.003-1.196]), respectively. CONCLUSION: Our study revealed that decreased cortical thickness or volume of medial temporal sub-regions is a risk factor for incident psychosis in patients with AD. A careful assessment of the thickness or volume of the medial temporal lobe structures in AD may improve early detection and intervention of psychosis in AD.

Atypical Young-onset Dementia in Cerebral Thromboangiitis Obliterans: A Case Report.

Young-onset dementia (YOD, age at onset below 45 y) has a broad differential diagnosis. We describe a 41-year-old man with atypical manifestations of YOD syndrome in cerebral thromoboangiitis obliterans (CTAO). Extensive antemortem workup including clinical assessment, laboratory investigations, neuroimaging, and genetic testing did not elucidate a diagnosis. Postmortem neuropathologic examination revealed cortical sickle-shaped granular atrophy, resulting from numerous remote infarcts and cortical microinfarcts that mainly affected the bilateral frontal and parietal lobe, confirming CTAO. Although CTAO is a rare cause of vascular dementia, it should be considered as one of the differentials in patients with YOD with a history of heavy smoking and presence of symmetric damages of watershed-territory on neuroimaging.

The Relationship of Plasma Transthyretin Level with Global or Regional Amyloid Beta Burden in Subjects with Amnestic Mild Cognitive Impairment: Cross-Sectional Amyloid PET Study.

Background: To investigate the relationships of plasma transthyretin levels with amyloid beta deposition and medial temporal atrophy in amnestic mild cognitive impairment. Methods: This is a cross-sectional study of association of subjects with amnestic mild cognitive impairment. Plasma transthyretin levels, brain magnetic resonance imaging, and 18F-florbetaben positron emission tomography were simultaneously measured in subjects with amnestic mild cognitive impairment. Results: Plasma transthyretin levels were positively associated with amyloid beta deposition in global (r = 0.394, P = .009), frontal cortex (r = 0.316, P = .039), parietal cortex (r = 0.346, P = .023), temporal cortex (r = 0.372, P = .014), occipital cortex (r = 0.310, P = .043), right posterior cingulate (r = 0.350, P = .021), left precuneus (r = 0.314, P = .040), and right precuneus (r = 0.398, P = .008). No association between plasma transthyretin level and medial temporal sub-regional atrophies was found. Conclusions: Our findings of positive association of plasma transthyretin levels with global and regional amyloid beta burden suggest upregulation of transthyretin level as a reactive response to amyloid beta deposition during the early stages of the Alzheimer's disease process.

Reduced Thickness of the Anterior Cingulate Cortex as a Predictor of Amnestic-Mild Cognitive Impairment Conversion to Alzheimer's Disease with Psychosis.

BACKGROUND: A long-term follow-up study in patients with amnestic mild cognitive impairment (aMCI) is needed to elucidate the association between regional brain volume and psychopathological mechanisms of Alzheimer's disease with psychosis (AD + P). OBJECTIVE: The purpose of this study was to investigate the effect of the thickness of the angular cingulate cortex (ACC) on the risk of AD + P conversion in patients with aMCI. METHODS: This was a hospital-based prospective longitudinal study including 174 patients with aMCI. The main outcome measure was time-to-progression from aMCI to AD + P. Subregions of the ACC (rostral ACC, rACC; caudal ACC, cACC) and hippocampus (HC) were measured as regions of interest with magnetic resonance imaging and the Freesurfer analysis at baseline. Survival analysis with time to incident AD + P as an event variable was calculated with Cox proportional hazards models using the subregions of the ACC and HC as a continuous variable. RESULTS: Cox proportional hazard analyses showed that the risk of AD + P was associated with sub-regional ACC thickness but not HC volume: reduced cortical thickness of the left cACC (HR [95%CI], 0.224 [0.087-0.575], p = 0.002), right cACC (HR [95%CI], 0.318 [0.132-0.768], p = 0.011). This association of the cACC with the risk of AD also remained significant when adjusted for HC volume. CONCLUSION: We found that reduced cortical thickness of the cACC is a predictor of aMCI conversion to AD + P, independent of HC, suggesting that the ACC plays a vital role in the underlying pathogenesis of AD + P.

Whole-Exome Sequencing in Papillary Microcarcinoma: Potential Early Biomarkers of Lateral Lymph Node Metastasis.

BACKGROUND: Early identification of patients with high-risk papillary thyroid microcarcinoma (PTMC) that is likely to progress has become a critical challenge. We aimed to identify somatic mutations associated with lateral neck lymph node (LN) metastasis (N1b) in patients with PTMC. METHODS: Whole-exome sequencing (WES) of 14 PTMCs with no LN metastasis (N0) and 13 N1b PTMCs was performed using primary tumors and matched normal thyroid tissues. RESULTS: The mutational burden was comparable in N0 and N1b tumors, as the median number of mutations was 23 (range, 12 to 46) in N0 and 24 (range, 12 to 50) in N1b PTMC (P=0.918). The most frequent mutations were detected in PGS1, SLC4A8, DAAM2, and HELZ in N1b PTMCs alone, and the K158Q mutation in PGS1 (four patients, Fisher's exact test P=0.041) was significantly enriched in N1b PTMCs. Based on pathway analysis, somatic mutations belonging to the receptor tyrosine kinase-RAS and NOTCH pathways were most frequently affected in N1b PTMCs. We identified four mutations that are predicted to be pathogenic in four genes based on Clinvar and Combined Annotation-Dependent Depletion score: BRAF, USH2A, CFTR, and PHIP. A missense mutation in CFTR and a nonsense mutation in PHIP were detected in N1b PTMCs only, although in one case each. BRAF mutation was detected in both N0 and N1b PTMCs. CONCLUSION: This first comprehensive WES analysis of the mutational landscape of N0 and N1b PTMCs identified pathogenic genes that affect biological functions associated with the aggressive phenotype of PTMC.

Smaller hippocampal volume in APOE ε4 carriers independent of amyloid-ß (Aß) burden.

OBJECTIVE: To investigate the association of the APOE ε4 genotype with hippocampal volume, independent of Aß burden. METHOD: This cross-sectional study included 71 participants with mild cognitive impairment or mild AD. All participants were divided into carriers or non-carriers of the ε4 allele. The main outcome was hippocampal volume measured using structural magnetic resonance imaging; 18F-florbetaben positron emission tomography was additionally performed to investigate the association of APOE ε4 genotype with hippocampal volumes, independently of Aß burden. Analysis of covariance was conducted to compare the differences in hippocampal volumes between carriers and non-carriers of the ε4 allele after controlling for global Aß burden or local hippocampal Aß burden. RESULTS: The APOE ε4 genotype was associated with a smaller right and total hippocampal volume (right: 3160.16 ± 365.71 vs. 3365.24 ± 434.88, p < 0.05; total: 6257.48 ± 790.60 vs. 6599.52 ± 840.58, p < 0.05), independent of Aß burden. CONCLUSION: Our findings on the association of APOEε4 genotype with hippocampal volume independent of Aß burden suggest that the APOEε4 genotype may contribute to hippocampal neurodegeneration through an Aß-independent mechanism.

TRIB2 Stimulates Cancer Stem-Like Properties through Activating the AKT-GSK3ß-ß-Catenin Signaling Axis.

Tribbles homolog 2 (TRIB2) is implicated in tumorigenesis and drug resistance in various types of cancers. However, the role of TRIB2 in the regulation of tumorigenesis and drug resistance of cancer stem cells (CSCs) is still elusive. In the present study, we showed increased expression of TRIB2 in spheroid-forming and aldehyde dehydrogenase-positive CSC populations of A2780 epithelial ovarian cancer cells. Short hairpin RNA-mediated silencing of TRIB2 expression attenuates the spheroid-forming, migratory, tumorigenic, and drug-resistant properties of A2780 cells, whereas overexpression of TRIB2 increases the CSC-like characteristics. TRIB2 overexpression induced GSK3ß inactivation by augmenting AKT-dependent phosphorylation of GSK3ß at Ser9, followed by increasing ß-catenin level via reducing the GSK3ß-mediated phosphorylation of ß-catenin. Treatment of TRIB2-ovexpressed A2780 cells with the phosphoinositide-3-kinase inhibitor LY294002 abrogated TRIB2-stimulated proliferation, migration, drug resistance of A2780 cells. These results suggest a critical role for TRIB2 in the regulation of CSC-like properties by increasing the stability of ß-catenin protein via the AKT-GSK3ß-dependent pathways.

Association of Temporolimbic Volumes with Treatment Response to Antipsychotic Medication for Delusion in Patients with Alzheimer's Disease.

Objective: This study investigated the association between gray matter volume and the treatment response to antipsychotic medication in patients with Alzheimer's disease (AD). Methods: We included 26 AD patients with delusions from the Memory Impairment Center of the Pusan National University Hospital in South Korea. All participants underwent baseline brain magnetic resonance imaging and took risperidone as an antipsychotic medication for 6 weeks. Gray matter volumes were measured using voxel-based morphometry at baseline. Treatment response with respect to delusional symptoms was defined as the change in delusion item scores in the Korean version of the Neuropsychiatry Inventory (K-NPI), from baseline to 6 weeks later. A voxel-based multiple linear regression model integrated with statistical parametric mapping was used to investigate the association between gray matter volume and treatment response after controlling for covariates. Results: The treatment response was significantly positively correlated with gray matter volume in the temporal lobe (both the fusiform gyri and the left superior and inferior temporal gyri) and the limbic system (the left parahippocampal gyrus and left amygdala) after controlling for age, sex, education level, total intracranial volume, risperidone dosage, baseline Korean version of the Mini-Mental Status Examination scores, and baseline K-NPI scores for the delusion and non-delusion domains (P < .001, uncorrected, KE > 100 voxels). Conclusion: Our findings suggest that specific gray matter volumes, including those of the temporal region and the limbic system, may affect treatment response to antipsychotic medication in terms of delusional symptoms in patients with AD.

Comparison of Amyloid in Cerebrospinal Fluid, Brain Imaging, and Autopsy in a Case of Progressive Supranuclear Palsy.

Cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aß1-42) and amyloid positron emission tomography (PET) are the 2 main Alzheimer disease amyloid biomarkers that have been validated in neuropathologically confirmed Alzheimer disease cases. Although many studies have shown concordance of amyloid positivity or negativity between CSF Aß1-42 and amyloid PET, several studies also reported discrepancies between these 2 Aß biomarkers. We conducted a comparison of CSF Aß1-42 level, amyloid PET, and autopsy findings in a case with progressive supranuclear palsy in which biomarker acquisition and postmortem pathologic examination were conducted almost at the same time. Our case with antemortem CSF Aß1-42 (+)/amyloid PET (-) who was pathologically confirmed with Aß pathology in the cerebral cortex may indicate CSF Aß1-42 is more sensitive for assessing in vivo Aß than amyloid PET.

Comparative Analysis of Adipose-Derived Stromal Cells and Their Secretome for Auricular Cartilage Regeneration.

Adipose-derived stromal cells (ADSCs) can repair auricular cartilage defects. Furthermore, stem cell secretome may also be a promising biological therapeutic option, which is equal to or even superior to the stem cell. We explored the therapeutic efficacies of ADSCs and their secretome in terms of rabbit auricular cartilage regeneration. ADSCs and their secretome were placed into surgically created auricular cartilage defects. After 4 and 8 weeks, the resected auricles were histopathologically and immunohistochemically examined. We used real-time PCR to determine the levels of genes expressing collagen type II, transforming growth factor-ß1 (TGF-ß1), and insulin-like growth factor-1 (IGF-1). ADSCs significantly improved auricular cartilage regeneration at 4 and 8 weeks, compared to the secretome and PBS groups, as revealed by gross examination, histopathologically and immunohistochemically. ADSCs upregulated the expression of collagen type II, TGF-ß1, and IGF-1 more so than did the secretome or PBS. The expression levels of collagen type II and IGF-1 were significantly higher at 8 weeks than at 4 weeks after ADSC injection. Although ADSCs thus significantly enhanced new cartilage formation, their secretome did not. Therefore, ADSCs may be more effective than their secretome in the repair of auricular cartilage defect.

Comparison of Diagnostic Performances Between Cerebrospinal Fluid Biomarkers and Amyloid PET in a Clinical Setting.

The diagnostic performances of cerebrospinal fluid (CSF) biomarkers and amyloid positron emission tomography (PET) were compared by examining the association and concordance or discordance between CSF Aß1-42 and amyloid PET, after determining our own cut-off values for CSF Alzheimer's disease (AD) biomarkers. Furthermore, we evaluated the ability of CSF biomarkers and amyloid PET to predict clinical progression. CSF Aß1-42, t-tau, and p-tau levels were analyzed in 203 individuals [27 normal controls, 38 mild cognitive impairment (MCI), 62 AD dementia, and 76 patients with other neurodegenerative diseases] consecutively recruited from two dementia clinics. We used both visual and standardized uptake value ratio (SUVR)-based amyloid PET assessments for analyses. The association of CSF biomarkers with amyloid PET SUVR, hippocampal atrophy, and cognitive function were investigated by linear regression analysis, and the risk of conversion from MCI to AD dementia was assessed using a Cox proportional hazards model. CSF p-tau/Aß1-42 and t-tau/Aß1-42 exhibited the best diagnostic accuracies among the CSF AD biomarkers examined. Correlations were observed between CSF biomarkers and global SUVR, hippocampal volume, and cognitive function. Overall concordance and discordance between CSF Aß1-42 and amyloid PET was 77% and 23%, respectively. Baseline positive CSF Aß1-42 for MCI demonstrated a 5.6-fold greater conversion risk than negative CSF Aß1-42 .  However, amyloid PET findings failed to exhibit significant prognostic value. Therefore, despite presence of a significant correlation between the CSF Aß1-42 level and SUVR of amyloid PET, and a relevant concordance between CSF Aß1-42 and amyloid PET, baseline CSF Aß1-42 better predicted AD conversion.