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2.
Mol Psychiatry ; 26(12): 7610-7620, 2021 12.
Article in English | MEDLINE | ID: mdl-34381171

ABSTRACT

Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.


Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Animals , Autism Spectrum Disorder/diagnostic imaging , Autism Spectrum Disorder/genetics , Autistic Disorder/diagnostic imaging , Autistic Disorder/genetics , Brain , Brain Mapping , Magnetic Resonance Imaging , Mice , Neural Pathways
3.
Support Care Cancer ; 27(7): 2617-2623, 2019 Jul.
Article in English | MEDLINE | ID: mdl-30467793

ABSTRACT

PURPOSE: Cancer-related fatigue (CRF) biology remains poorly understood. Responsible mechanisms may be central or peripheral and originate anywhere from the brain to muscle fiber. Objective measurement is complex and previously limited to specialized laboratories. Portable electroencephalography (EEG) and electromyography (EMG) may enhance objective measurement. This study evaluated the feasibility and acceptability of portable EMG-EEG in CRF assessment. METHODS: A prospective observational feasibility study compared ten outpatients with inoperable, treatment-naïve non-small cell lung cancer and CRF to ten healthy volunteers. All completed a sustained isometric hand-grip contraction at 30% maximal level until self-perceived exhaustion. 128-channel EEG and 2-channel EMG signals of forearm muscles were recorded. Device acceptability was evaluated by questionnaire. RESULTS: The task was evaluated in two stages; first and last 20 s. CRF cohort perceived exhaustion earlier than volunteers (mean 137 ± 76 s vs 208 ± 51 s). As fatigue progressed, EMG amplitude increased significantly (CRF p = 0.02; volunteers: p = 0.04) in both groups as did EMG beta band power (CRF p = 0.008; volunteers: p = 0.006). The increase was significantly less in CRF (amplitude p = 0.032; beta power: p = 0.014). EEG beta band power in the contralateral motor cortex increased significantly (CRF p = 0.03; volunteers: p = 0.019) in both cohorts but to greater extent (p = 0.024) in CRF. One hundred percent device acceptability was reported. CONCLUSIONS: A laboratory-based evaluation was successfully adapted to the outpatient setting during routine visits. High acceptability supports clinical utility. In CRF, a higher degree of cortical activation was required to drive a much lower level of muscle performance. This suggests impairment of both central and peripheral mechanisms in CRF.


Subject(s)
Carcinoma, Non-Small-Cell Lung/physiopathology , Electroencephalography/instrumentation , Electromyography/instrumentation , Fatigue/diagnosis , Lung Neoplasms/physiopathology , Adult , Carcinoma, Non-Small-Cell Lung/diagnosis , Electroencephalography/methods , Electromyography/methods , Fatigue/physiopathology , Feasibility Studies , Female , Humans , Isometric Contraction , Lung Neoplasms/diagnosis , Male , Muscle Fatigue/physiology , Muscle, Skeletal/physiology , Patient Acceptance of Health Care , Prospective Studies
4.
J BUON ; 18(2): 321-7, 2013.
Article in English | MEDLINE | ID: mdl-23818341

ABSTRACT

PURPOSE: To evaluate the influence of molecular biomarkers (estrogen receptor - ER, progesterone receptor - PR, and human epidermal growth factor receptor2 - HER2) and pathological parameters on metastasis free interval (MFI) in adjuvantly tamoxifen-treated breast cancer patients, during different follow up periods (0-2.5 years, 2.5-5 years and 5-12 years). METHODS: The study included 113 postmenopausal breast cancer patients with known pathological parameters. Steroid receptors were determined by ligand-binding assay and HER2 amplification status by chromogenic in situ hybridization (CISH). RESULTS: During the first 2.5 years of therapy patients with ER <5 fmol/mg, PR <5 fmol/mg or pT2 (≥2cm) tumors had higher probability of distant metastasis. For the period between 2.5-5 years, analysis of MFI according to pathological parameters and molecular biomarkers, separately, did not show any statistically significant difference. Patients with pT≥2 cm and HER2 amplification had much greater chance of developing distant metastasis when compared to other phenotypes (HER2-negative/pT1, HER2-negative/pT2 and HER2-positive/pT1). Patiens with ER ≥160 fmol/mg and PR ≥45 fmol/mg had good prognosis after 5 years of tamoxifen therapy. CONCLUSION: Our study indicates that there is a change of influence of the analyzed pathological parameters on MFI, depending on different follow up periods. Steroid receptor status, tumor size and HER2 status (alone or in combination) are significant parameters for the course of disease of postmenopausal ER-positive breast cancer patients, but during different periods of follow up.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Biomarkers, Tumor/analysis , Breast Neoplasms/chemistry , Breast Neoplasms/drug therapy , Neoplasms, Hormone-Dependent/chemistry , Neoplasms, Hormone-Dependent/drug therapy , Tamoxifen/therapeutic use , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Neoplasms, Hormone-Dependent/pathology , Postmenopause , Receptor, ErbB-2/genetics , Receptors, Estrogen/analysis , Receptors, Progesterone/analysis , Risk Factors , Time Factors , Treatment Outcome , Tumor Burden
5.
Clin Exp Metastasis ; 22(4): 363-8, 2005.
Article in English | MEDLINE | ID: mdl-16170672

ABSTRACT

In order to address the heterogeneity of the pT1 breast cancer stages, we have been examining the natural and the clinical course of disease in relation to cathepsin D expression, as a molecular marker for the tumor progression that leads to metastasis. The original aim of our pilot study was to determine whether it was possible to distinguish high-risk from low-risk patients, on the basis of nonestrogen- vs. estrogen-regulated cathepsin D expression. Our results showed that estrogen-regulated cathepsin D expression could be useful as surrogate marker of node-positive status. Further, during the natural course of disease, none of 7 pT1N0 patients with tumors bearing nonestrogen-regulated cathepsin D expression developed metastasis. During the clinical course of disease, nonestrogen-regulated cathepsin D expression defined low-risk while estrogen-regulated cathepsin D expression defined high-risk pT1N+ subgroup of patients. Although there is no consensus with respect to metastasis-related prognostic value of cathepsin D expression, our pilot study implies its prognostic value in pT1 breast cancer patients and supports the hypothesis that cathepsin D may promote metastasis in this early stage of disease.


Subject(s)
Biomarkers, Tumor/analysis , Breast Neoplasms/diagnosis , Carcinoma/diagnosis , Cathepsin D/analysis , Biomarkers, Tumor/metabolism , Breast Neoplasms/pathology , Carcinoma/secondary , Cathepsin D/metabolism , Disease-Free Survival , Female , Humans , Neoplasm Staging , Pilot Projects , Prognosis , Risk Factors
6.
Clin Exp Metastasis ; 21(7): 581-5, 2004.
Article in English | MEDLINE | ID: mdl-15787095

ABSTRACT

A pilot study was conducted to assess whether plasma levels of transforming growth factor-beta1 (TGF-beta1) might facilitate biological subgrouping of postmenopausal metastatic breast cancer patients, and, accordingly, its applicability in clinical oncology. This study included 29 postmenopausal metastatic breast cancer patients. Plasma TGF-beta1 levels were detected by enzyme-linked immunosorbent assay (ELISA). Estrogen and progesterone receptors were assayed by radioligand binding, in accordance with the recommendation of the EORTC. Concentrations of 17-beta estradiol were determined by using ELISA-microwell method (DIALAB). Overall survival was followed for 24 months for each individual patient. Stratification of the patients by ER/PR status showed that 14 patients with estrogen receptor-negative, progesterone receptor-negative carcinomas displayed a statistically significant increase in plasma TGF-beta1 levels when compared to plasma TGF-beta1 levels of 6 patients with ER-positive, PR-positive carcinomas (P=0.04). In this study, 7 out of 14 patients with negative receptors' status had no plasma TGF-beta1 values overlapping with patients having positive receptors' status. The TGF-beta1 cut-off value was defined as the highest plasma TGF-beta1 level of ER-positive, PR-positive patients: 3.28 ng/ml. This plasma TGF-beta1 cut-off value defined low-risk subgroup of 19 patients (< or = 3.28 ng/ml) and high-risk subgroup of 10 patients (> 3.28 ng/ml) (P=0.047). Plasma TGF-beta1-related survival was independent of the classical prognostic factors of metastatic breast cancer. Accordingly, a clinical significance of elevated plasma TGF-beta1 levels may be suggested.


Subject(s)
Breast Neoplasms/physiopathology , Postmenopause , Survival Analysis , Transforming Growth Factor beta/blood , Breast Neoplasms/blood , Breast Neoplasms/pathology , Enzyme-Linked Immunosorbent Assay , Estradiol/blood , Female , Humans , Neoplasm Metastasis , Radioligand Assay , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Transforming Growth Factor beta1
7.
J Exp Clin Cancer Res ; 22(4): 543-9, 2003 Dec.
Article in English | MEDLINE | ID: mdl-15053295

ABSTRACT

This study attempted to evaluate the first-generation prognostic factors in terms of relapse-free interval in 297 node-negative breast cancer patients treated with locoregional therapy alone. Predictors of outcome were, in order of strength: tumor size (RR 2.09), tumor grade (RR 2.03) and age (RR 0.97). Age was a single independent prognostic parameter in premenopausal patients younger than 45 (RR 0.82). Tumor size was also a single independent prognostic parameter in middle-aged patients (RR 2.05). In older patients, aged 60 and over, tumor grade (RR 11.6) and type (RR 0,52) in addition to tumor size (RR 7.00) were independent prognostic parameters. Our study of disease-free survival identified high risk-related subgroups: patients younger than 35, middle-aged post-menopausal patients bearing pT2 carcinoma with steroid receptor content lower than 5 fmol/mg, and patients older than 59 bearing pT2 carcinoma with grade 11 and unfavorable types-ductal, lobular.


Subject(s)
Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Adult , Age Factors , Breast Neoplasms/classification , Breast Neoplasms/physiopathology , Disease-Free Survival , Female , Humans , Lymphatic Metastasis/pathology , Menopause/physiology , Middle Aged , Multivariate Analysis , Prognosis , Receptors, Cytoplasmic and Nuclear/metabolism , Risk Factors , Steroids/metabolism , Survival Rate
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