bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microglial Activation, Tau Pathology, and Neurodegeneration Biomarkers Predict Longitudinal Cognitive Decline in Alzheimer’s Disease Continuum
Authors: Chen Yi-He , Lin Rong-Rong , Huang Hui-Feng , Xue Yan-Yan , Tao Qing-Qing 
Published: June 2022

PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer’s disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.Patients and MethodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 &lt; 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.
Mediation of the APOE Associations With Cognition Through Cerebral Blood Flow: The CIBL Study
Authors: Wang Yan-Li , Sun Mengfan , Wang Fang-Ze , Wang Xiaohong , Jia Ziyan , Zhang Yuan , Li Runzhi , Jiang Jiwei , Wang Linlin , Li Wenyi , Sun Yongan , Chen Jinglong , Zhang Cuicui , Shi Baolin , Liu Jianjian , Liu Xiangrong , Xu Jun 
Published: June 2022

BackgroundThe ε4 allele of the apolipoprotein E (APOE) gene is a strong genetic risk factor for aging-related cognitive decline. However, the causal connection between ε4 alleles and cognition is not well understood. The objective of this study was to identify the roles of cerebral blood flow (CBF) in cognitive-related brain areas in mediating the associations of APOE with cognition.MethodsThe multiple linear regression analyses were conducted on 369 subjects (mean age of 68.8 years; 62.9% of women; 29.3% of APOE ε4 allele carriers). Causal mediation analyses with 5,000 bootstrapped iterations were conducted to explore the mediation effects.ResultAPOE ε4 allele was negatively associated with cognition (P &lt; 0.05) and CBF in the amygdala, hippocampus, middle temporal gyrus, posterior cingulate, and precuneus (all P &lt; 0.05). The effect of the APOE genotype on cognition was partly mediated by the above CBF (all P &lt; 0.05).ConclusionCBF partially mediates the potential links between APOE genotype and cognition. Overall, the APOE ε4 allele may lead to a dysregulation of the vascular structure and function with reduced cerebral perfusion, which in turn leads to cognitive impairment.
Brain Somatic Variant in Ras-Like Small GTPase RALA Causes Focal Cortical Dysplasia Type II
Authors: Xu Han , Gao Kai , Liu Qingzhu , Wang Tianshuang , Zhang Zhongbin , Cai Lixin , Wu Ye , Jiang Yuwu 
Published: June 2022

PurposeIn our group’s previous study, we performed deep whole-exome sequencing and targeted amplicon sequencing in the postoperative brain tissue of epilepsy patients with focal cortical dysplasia type II (FCD II). We identified the first somatic variant of RALA in the brain tissue of a child with FCD type IIb. RALA encodes a small GTPase of the Ras superfamily. To date, the role of RALA in brain development is not yet known. In this study, we reported that the RALA somatic variant led to FCD type II through activation of the mammalian target of rapamycin (mTOR) pathways.Materials and MethodsHEK293T cells were transfected in vitro to analyze the expression of the RalA protein, as well as phosphorylated S6 (P-S6), one of the major markers of mTOR pathway activation, RalA GTPase activity, and the interaction between RalA and its downstream binding effectors. In vivo, wild-type, and mutant RALA plasmids were transfected into the local cortex of mice using in utero electroporation to evaluate the effect of RALA c.G482A on neuronal migration.ResultsThe RALA c.G482A mutation increased RalA protein expression, the abnormal activation of the mTOR pathways, RalA GTPase activity, and binding to downstream effectors. RALA c.G482A local transfection in the embryonic brain in utero induced abnormal cortical neuron migration in mice.ConclusionThis study demonstrated for the first time that the somatic gain-of-function variant of RALA activates the mTOR pathway and leads to neuronal migration disorders in the brain, facilitating the development of FCD II. Therefore, RALA brain somatic mutation may be one of the pathogenic mechanisms leading to FCD II, which is always related to drug-resistant epilepsy in children. However, more somatic variations of this gene are required to be confirmed in more FCD II patient brain samples.
OnabotulinumtoxinA Dosing, Disease Severity, and Treatment Benefit in Patients With Cervical Dystonia: A Cohort Analysis From CD PROBE
Authors: Agarwal Pinky , Barbano Richard , Moore Henry , Schwartz Marc , Zuzek Aleksej , Sadeghi Marjan , Patel Atul 
Published: June 2022

IntroductionThe Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE) study (ClinicalTrials.gov identifier: NCT00836017), a multicenter, prospective, observational registry, was designed to identify real-world practices and outcomes for patients with cervical dystonia (CD) treated with onabotulinumtoxinA (onabotA). This secondary analysis from CD PROBE aims to determine the impact of presentation subtype on onabotA utilization and CD severity.Materials and MethodsThe study cohort includes those who completed all 3 treatments, 4 office visits, and had data recorded for all assessments. Patient outcomes were assessed with the Cervical Dystonia Impact Profile (CDIP-58), Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), and determination of CD severity. Treatment interval, dose, and adverse events (AEs) were also recorded. Data were stratified according to prior exposure to botulinum toxins (BoNTs) and analyzed with descriptive statistics.ResultsTorticollis was the most common presentation subtype in the study cohort (N = 350); the proportion of patients with torticollis was highest in those with severe disease. At each treatment, between 40.7 and 65.2% of those categorized as severe shifted to moderate or mild severity after treatment. Sustained improvements in CDIP-58 and TWSTRS were observed regardless of prior exposure to BoNTs. Dosing of onabotA generally increased from injection 1 to injection 3 and tended to be lower for patients naïve to BoNT. Median time interval between injections for the study cohort was 94.0 to 97.5 days. The most common AEs (dysphagia, muscular weakness) and injection intervals were similar between naïve vs. non-naïve patients; there were no serious treatment-related AEs.ConclusionsThis secondary cohort analysis from CD PROBE demonstrates that three repeat treatments with onabotA at intervals consistent with labeling attenuated disease severity and neck pain, resulting in sustained improvements in physician- and patient-reported outcomes. No new safety signals were identified.
Malignant Myoepithelioma of the Head and Neck: Demographics, Clinicopathological Characteristics, Treatment, and Prognosis
Authors: Wang Jia-Qi , Deng Rong-Xin , Liu Hui , Luo Yuan , Lu Meng-Meng , Yang Zhi-Cheng 
Published: June 2022

Malignant myoepithelioma of the head and neck (HNMM) is a rare malignancy, and its characteristics and survival rates have not been well-defined. This study aimed to define the epidemiology of HNMM and identify the prognostic factors associated with the disease. Data on all patients diagnosed with HNMM between 1991 and 2016 were gathered from the Surveillance Epidemiology and End Results (SEER) database. The demographics, clinicopathological characteristics, treatment, and prognoses of the patients were described. Cox regression analysis was used to identify the prognostic factors, and the prognostic nomograms for overall survival (OS) and disease-specific survival (DSS) were constructed. A total of 333 cases of HNMM were identified. The average age at diagnosis was 60.6 years, and 50.1% of the patients were men. After diagnosis, 46.2% of patients underwent surgery alone, 43.5% of patients underwent surgery and radiotherapy, and 3.6% of patients received only radiotherapy. Survival analysis showed that the 5-year OS and DSS for all HNMM patients were 69.7 and 82.1%, respectively. In the multivariate analysis model, the undifferentiated pathological grade (P &lt;0.05) and M1 in the M category (P &lt;0.01) were independent prognostic factors for poor OS and DSS, whereas the use of surgical resection was an independent favorable prognostic factor for both OS and DSS (P &lt;0.05). The prognostic nomograms for OS and DSS prediction were constructed; the C-index values for OS and DSS prediction were 0.78 (95% CI 0.70–0.86) and 0.79 (95% CI 0.67–0.90), respectively. In conclusion, this SEER data-based study demonstrated that HNMM patients often had a favorable prognosis, and distant metastasis, pathological grade, and the use of surgery contributed to their survival. Furthermore, we developed a prognostic nomogram to predict OS and DSS for HNMM patients to aid physicians in the clinical management of this rare disease.
Retrospective Clinical Evaluation of a Decision-Support Software for Adaptive Radiotherapy of Head and Neck Cancer Patients
Authors: Gros Sebastien A. A. , Santhanam Anand P. , Block Alec M. , Emami Bahman , Lee Brian H. , Joyce Cara 
Published: June 2022

PurposeThis study aimed to evaluate the clinical need for an automated decision-support software platform for adaptive radiation therapy (ART) of head and neck cancer (HNC) patients.MethodsWe tested RTapp (SegAna), a new ART software platform for deciding when a treatment replan is needed, to investigate a set of 27 HNC patients’ data retrospectively. For each fraction, the software estimated key components of ART such as daily dose distribution and cumulative doses received by targets and organs at risk (OARs) from daily 3D imaging in real-time. RTapp also included a prediction algorithm that analyzed dosimetric parameter (DP) trends against user-specified thresholds to proactively trigger adaptive re-planning up to four fractions ahead. The DPs evaluated for ART were based on treatment planning dose constraints. Warning (V95&lt;95%) and adaptation (V95&lt;93%) thresholds were set for PTVs, while OAR adaptation dosimetric endpoints of +10% (DE10) were set for all Dmax and Dmean DPs. Any threshold violation at end of treatment (EOT) triggered a review of the DP trends to determine the threshold-crossing fraction Fx when the violations occurred. The prediction model accuracy was determined as the difference between calculated and predicted DP values with 95% confidence intervals (CI95).ResultsRTapp was able to address the needs of treatment adaptation. Specifically, we identified 18/27 studies (67%) for violating PTV coverage or parotid Dmean at EOT. Twelve PTVs had V95&lt;95% (mean coverage decrease of −6.8 ± 2.9%) including six flagged for adaptation at median Fx= 6 (range, 1–16). Seventeen parotids were flagged for exceeding Dmean dose constraints with a median increase of +2.60 Gy (range, 0.99–6.31 Gy) at EOT, including nine with DP&gt;DE10. The differences between predicted and calculated PTV V95 and parotid Dmean was up to 7.6% (mean ± CI95, −2.7 ± 4.1%) and 5 Gy (mean ± CI95, 0.3 ± 1.6 Gy), respectively. The most accurate predictions were obtained closest to the threshold-crossing fraction. For parotids, the results showed that Fx ranged between fractions 1 and 23, with a lack of specific trend demonstrating that the need for treatment adaptation may be verified for every fraction.ConclusionIntegrated in an ART clinical workflow, RTapp aids in predicting whether specific treatment would require adaptation up to four fractions ahead of time.
Differentiation of Thyroid Nodules (C-TIRADS 4) by Combining Contrast-Enhanced Ultrasound Diagnosis Model With Chinese Thyroid Imaging Reporting and Data System
Authors: Zhu Tiantong , Chen Jiahui , Zhou Zimo , Ma Xiaofen , Huang Ying 
Published: June 2022

ObjectivesTo establish a contrast-enhanced ultrasound (CEUS) diagnostic schedule by CEUS analysis of thyroid nodules of C-TIRADS 4. To establish a CEUS-TIRADS diagnostic model to differentiate thyroid nodules (C-TIRADS 4) by combining CEUS with Chinese thyroid imaging reporting and data system (C-TIRADS).MethodsA total of 228 thyroid nodules (C-TIRADS 4) were estimated by CEUS. The arrival time, enhancement degree, enhancement homogeneity, enhancement pattern, enhancement ring, and wash-out time were analyzed in CEUS for all of the nodules. Multivariate factors logistic analysis was performed and a CEUS diagnostic schedule was established. If the nodule had a regular hyper-enhancement ring or got a score of less than 2 in CEUS analysis, CEUS-TIRADS subtracted 1 category. If the nodule got a score of 2 in the CEUS schedule, the CEUS-TIRADS category remained the same as before. If the nodule got a score of more than 2 in the CEUS schedule, CEUS-TIRADS added 1 category. When it reflected an absent enhancement in CEUS, the nodule was judged as CEUS-TIRADS 3. All of the C-TIRADS 4 nodules were re-graded by CEUS-TIRADS. We then compare the diagnosis performance of C-TIRADS, CEUS, and CEUS-TIRADS by sensitivity, specificity, and accuracy.ResultsAmong the 228 C-TIRADS 4 nodules, 69 were determined as C-TIRADS 4a, 114 were C-TIRADS 4b, and 45 were C-TIRADS 4c. The sensitivity, specificity, and accuracy of C-TIRADS were 93.1%, 55.3%, and 74.6% respectively. The area under the curve was 0.753. Later arrival time, hypo-enhancement, heterogeneous enhancement, centripetal enhancement, and rapid washout were risk factors of malignancy in multivariate analysis. The sensitivity, specificity, and accuracy of CEUS were 78.7%, 87.5%, and 83.3% respectively. The area under the curve was 0.803. By CEUS-TIRADS diagnostic model combining CEUS with C-TIRADS, a total of 127 cases were determined as malignancy (111 were malignant and 16 were benign) and 101 were diagnosed as benign ones (5 were malignant and 96 were benign). The sensitivity, specificity, and accuracy of CEUS-TIRADS were 95.7%, 85.7%, and 92.1% respectively. The area under the curve was 0.916. The diagnostic performance of CEUS-TIRADS was significantly better than CEUS and C-TIRADS. The difference was statistically significant (P&lt;0.05).ConclusionsThe diagnostic schedule of CEUS could get better diagnostic performance than US in the differentiation of thyroid nodules. The CEUS-TIRADS combining CEUS analysis with C-TIRADS could make up for the deficient sensibility of C-TIRADS, showing a better diagnostic performance than US and CEUS.
Prognostic Significance of FDG PET/CT in Esophageal Squamous Cell Carcinoma in the Era of the 8th AJCC/UICC Staging System
Authors: Lee Hyunjong , Lee Kyung Soo , Min Yang Won , Kim Hong Kwan , Zo Jae Ill , Shim Young Mog , Choi Joon Young 
Published: June 2022

IntroductionRecently, the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system was updated for its 8th edition. F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a useful imaging tool to diagnose and predict prognoses for esophageal cancer. However, there was no previous study to explore the role of FDG PET/CT in the staging system based on the 8th edition. The prognostic value of FDG PET/CT was investigated in patients with esophageal squamous cell carcinoma (SqCC) considering the new 8th AJCC/UICC staging system.MethodsSubjects were 721 patients with esophageal SqCC undergoing pretherapeutic FDG PET/CT. Clinico-pathological variables and the maximum standardized uptake value (SUVmax) of the primary tumor were included in survival analysis. Subgroup analysis was performed to compare hazard ratios according to pathological stage and SUVmax. A new staging classification including FDG uptake was proposed.ResultsIn multivariate survival analysis, pathological stage and SUVmax of the primary tumor were selected as independent prognostic factors for overall survival in both the 7th and 8th editions. The proposed new staging system showed better discrimination for overall survival between stage I and II than did the conventional staging system (hazard ratios: 2.250 vs. 1.341).ConclusionsThe FDG uptake of the primary tumor was found to be an independent prognostic factor along with pathological stage based on both 7th and 8th AJCC/UICC staging systems in patients with esophageal SqCC. The suggested new staging system including SUVmax was better for predicting prognoses than the conventional staging system.
Integrative Proteo-Genomic Analysis for Recurrent Survival Prognosis in Colon Adenocarcinoma
Authors: Ai FeiYan , Wang Wenhao , Liu Shaojun , Zhang Decai , Yang Zhenyu , Liu Fen 
Published: June 2022

BackgroundThe survival prognosis is the hallmark of cancer progression. Here, we aimed to develop a recurrence-related gene signature to predict the prognosis of colon adenocarcinoma (COAD).MethodsThe proteomic data from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and genomic data from the cancer genomic maps [The Cancer Genome Atlas (TCGA)] dataset were analyzed to identify co-differentially expressed genes (cDEGs) between recurrence samples and non-recurrence samples in COAD using limma package. Functional enrichment analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway was conducted. Univariate and multivariate Cox regressions were applied to identify the independent prognostic feature cDEGs and establish the signature whose performance was evaluated by Kaplan–Meier curve, receiver operating characteristic (ROC), Harrell’s concordance index (C-index), and calibration curve. The area under the receiver operating characteristic (ROC) curve (AUROC) and a nomogram were calculated to assess the predictive accuracy. GSE17538 and GSE39582 were used for external validation. Quantitative real-time PCR and Western blot analysis were carried out to validate our findings.ResultsWe identified 86 cDEGs in recurrence samples compared with non-recurrence samples. These genes were primarily enriched in the regulation of carbon metabolic process, fructose and mannose metabolism, and extracellular exosome. Then, an eight-gene-based signature (CA12, HBB, NCF1, KBTBD11, MMAA, DMBT1, AHNAK2, and FBLN2) was developed to separate patients into high- and low-risk groups. Patients in the low-risk group had significantly better prognosis than those in the high-risk group. Four prognostic clinical features, including pathological M, N, T, and RS model status, were screened for building the nomogram survival model. The PCR and Western blot analysis results suggested that CA12 and AHNAK2 were significantly upregulated, while MMAA and DMBT1 were downregulated in the tumor sample compared with adjacent tissues, and in non-recurrent samples compared with non-recurrent samples in COAD.ConclusionThese identified recurrence-related gene signatures might provide an effective prognostic predictor and promising therapeutic targets for COAD patients.
Low-Grade Uterine Endometrial Stromal Sarcoma: Prognostic Analysis of Clinico-Pathological Characteristics, Surgical Management, and Adjuvant Treatments. Experience From Two Referral Centers
Authors: Borella Fulvio , Bertero Luca , Cassoni Paola , Piovano Elisa , Gallio Niccolò , Preti Mario , Cosma Stefano , Ferraioli Domenico , Pace Luca , Mariani Luca , Biglia Nicoletta , Benedetto Chiara 
Published: June 2022

ObjectiveLow-grade uterine endometrial stromal sarcoma (LG-ESS) is a rare tumor characterized by an overall good survival but showing a indolent behavior and a variable risk of recurrence. There is no clear consensus on the optimal management of these tumors and no prognostic or predictive factors have been established. With this study, we evaluated the prognostic relevance of several clinical, surgical, and pathological features in patients affected by LG-ESS to identify risk factors associated with recurrence.MethodsWe retrospectively analyzed 52 LG-ESS cases, treated from January 1st, 1994, to May 31st, 2020, in two referral centers. The relationship between recurrence and clinicopathological characteristics as well as surgical treatment was investigated. Risk of recurrence and disease-free survival (DFS) were estimated by Cox regression and the Kaplan-Meier analysis, respectively.ResultsOf 52 patients with LG-ESS, 8 experienced recurrence (15%). The median follow-up was 100 months (SD ± 96, range: 15–336). By univariate analysis, fragmentation/morcellation, tumor size, FIGO stage, higher mitotic count, presence of necrosis, and lymphovascular space invasion (LSVI) resulted associated with a poorer outcome. Conversely, the surgical modality (laparotomic vs laparoscopic and hysterectomy with bilateral salpingo-oophorectomy vs local excision) and pelvic lymphadenectomy were not. Even the different modalities of adjuvant therapy (hormonal therapy, radiotherapy, and chemotherapy) showed no prognostic significance. Tumor fragmentation/morcellation and higher mitotic count resulted independent prognostic variables at multivariate analysis.ConclusionsThis data supports the avoidance of any type of morcellation if LG-ESS is suspected preoperatively. Higher mitotic count and, possibly, tumor size, advanced FIGO stage, necrosis, and LVSI could be exploited to tailor the adjuvant therapy, but these results need to be confirmed in larger prospective studies.