| 1. |
- Hilbert, Kevin, et al.
(författare)
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Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group.
- 2024
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Ingår i: The American Journal of Psychiatry. - 1535-7228. ; 181:8, s. 728-740
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Tidskriftsartikel (refereegranskat)abstract
- Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults).Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis.Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents.Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.
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| 2. |
- Hollander, Peter
(författare)
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Epidemiology and prognosis in classical Hodgkin lymphoma
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Classical Hodgkin lymphoma (HL) is a B cell derived neoplasm with an overall good prognosis. Its etiology and pathogenesis are largely unknown. The tumor microenvironment consists of sparse malignant cells and abundant leukocytes. In paper I we found that patients with rheumatoid arthritis (RA) had an increased risk of developing HL, especially patients with proxies of more severe RA. In addition, patients with RA had an especially increased risk of developing Epstein-Barr virus positive HL. These findings indicate that patients exposed to chronic inflammation have an increased risk of developing HL. We further studied the inflammatory milieu in the microenvironment of HL in paper II by investigating different leukocytes with immunohistochemical markers on diagnostic HL biopsies. We demonstrated that an anergic immune signature with a high amount of immune suppressive regulatory T lymphocytes was associated with inferior time to progression in an age-adjusted analysis. Another mechanism utilized by malignant cells and leukocytes to induce a suppressed antitumor immune response is to upregulate expression of programmed death ligands 1 and 2 (PD-L1 and PD-L2), that induces apoptosis in tumor killing leukocytes by binding to programmed death receptor 1 (PD-1). In paper III, we investigated the prognostic impact of PD-1, PD-L1 and PD-L2 in the tumor microenvironment of diagnostic HL biopsies with immunohistochemistry. We found that high proportions of PD-1+ and PD-L1+ leukocytes were associated with worse outcome in fully adjusted multivariate analyses. However, both PD-1 and PD-L1 are expressed to variable degrees in malignancies. Therefore, in paper IV we wanted to determine how expression of PD-1 and PD-L1 changes in repeated biopsies from both untreated and treated patients with relapsed HL. There were increased proportions of PD-1+ and PD-L1+ leukocytes, and PD-L1+ tumor cells in the relapse biopsies compared to the primary biopsies. These findings indicate that the PD-1 pathway is upregulated due to primary treatment, longer disease duration or altered conditions in the microenvironment at relapse.
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| 3. |
- Urayama, Kevin Y., et al.
(författare)
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Genome-Wide Association Study of Classical Hodgkin Lymphoma and Epstein-Barr Virus Status-Defined Subgroups
- 2012
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Ingår i: Journal of the National Cancer Institute. - Oxford : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 104:3, s. 240-253
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Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification. We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided. Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 x 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 x 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 x 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 x 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 x 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 x 10(-4)) and replication series (P = .03). Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.
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