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- Thomas, HS, et al.
(author)
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- 2019
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swepub:Mat__t
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| 2. |
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| 3. |
- Figlioli, G, et al.
(author)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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In: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Journal article (peer-reviewed)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 4. |
- Vergallo, A., et al.
(author)
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Plasma amyloid beta 40/42 ratio predicts cerebral amyloidosis in cognitively normal individuals at risk for Alzheimer's disease
- 2019
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In: Alzheimers & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 15:6, s. 764-775
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Journal article (peer-reviewed)abstract
- Introduction: Blood-based biomarkers of pathophysiological brain amyloid beta (A beta) accumulation, particularly for preclinical target and large-scale interventions, are warranted to effectively enrich Alzheimer's disease clinical trials and management. Methods: We investigated whether plasma concentrations of the A beta(1-40)/A beta(1-42) ratio, assessed using the single-molecule array (Simoa) immunoassay, may predict brain A beta positron emission tomography status in a large-scale longitudinal monocentric cohort (N = 276) of older individuals with subjective memory complaints. We performed a hypothesis-driven investigation followed by a no-apriori hypothesis study using machine learning. Results: The receiver operating characteristic curve and machine learning showed a balanced accuracy of 76.5% and 81%, respectively, for the plasma A beta(1-40)/A beta(1-42) ratio. The accuracy is not affected by the apolipoprotein E (APOE) epsilon 4 allele, sex, or age. Discussion: Our results encourage an independent validation cohort study to confirm the indication that the plasma A beta(1-40)/A beta(1-42) ratio, assessed via Simoa, may improve future standard of care and clinical trial design. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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| 6. |
- Pesce, S., et al.
(author)
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Different Features of Tumor-Associated NK Cells in Patients With Low-Grade or High-Grade Peritoneal Carcinomatosis
- 2019
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In: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Journal article (peer-reviewed)abstract
- Peritoneal carcinomatosis (PC) is a rare disease defined as diffused implantation of neoplastic cells in the peritoneal cavity. This clinical picture occurs during the evolution of peritoneal tumors, and it is the main cause of morbidity and mortality of patients affected by these pathologies, though cytoreductive surgery with heated intra-peritoneal chemotherapy (CRS/HIPEC) is yielding promising results. In the present study, we evaluated whether the tumor microenvironment of low-grade and high-grade PC could affect the phenotypic and functional features and thus the anti-tumor potential of NK cells. We show that while in the peritoneal fluid (PF) of low-grade PC most CD56dim NK cells show a relatively immature phenotype (NKG2A+KIR-CD57-CD16dim), in the PF of high-grade PC NK cells are, in large majority, mature (CD56dimKIR+CD57+CD16bright). Furthermore, in low-grade PC, PF-NK cells are characterized by a sharp down-regulation of some activating receptors, primarily NKp30 and DNAM-1, while, in high-grade PC, PF-NK cells display a higher expression of the PD-1 inhibitory checkpoint. The compromised phenotype observed in low-grade PC patients corresponds to a functional impairment. On the other hand, in the high-grade PC patients PF-NK cells show much more important defects that only partially reflect the compromised phenotype detected. These data suggest that the PC microenvironment may contribute to tumor escape from immune surveillance by inducing different NK cell impaired features leading to altered anti-tumor activity. Notably, after CRS/HIPEC treatment, the altered NK cell phenotype of a patient with a low-grade disease and favorable prognosis was reverted to a normal one. Our present data offer a clue for the development of new immunotherapeutic strategies capable of restoring the NK-mediated anti-tumor responses in association with the CRS/HIPEC treatment to increase the effectiveness of the current therapy.
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| 9. |
- Montgomery, Scott, 1961-, et al.
(author)
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Infections in patients with multiple sclerosis : a nationwide cohort study in Sweden
- 2019
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 25:Suppl. 2, s. 388-388
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Journal article (other academic/artistic)abstract
- Introduction: Previous studies suggest that susceptibility to infections is not raised among multiple sclerosis (MS) patients in general, but certain specific infections, such as those of the urinary or respiratory tract, are more common in patients with higher disability. However, contemporary MS cohorts to a higher degree are treated with newer disease-modifying treatments (DMTs) that exert stronger effects on the immune defence. Here we investigated the rate of infections in patients before and after MS diagnosis as compared with a matched MS-free population.Methods: Incident MS patients diagnosed in 2008-2016 were identified in the Swedish National Patient Register. MS patients were matched to 10 MS-free individuals by age, sex, and region of residence. Incidence rates per 10,000 person-years and incidence rate ratios (IRRs) of first infection by site and type were calculated after the MS diagnosis date.Results: In total, 6,602 MS patients were identified and compared with 61,828 without MS (female, 69%; median age, 40 years). During the year before MS diagnosis, MS patients showed higher proportions of urinary and kidney infections, meningitis and encephalitis, and bacterial infections compared with the MS-free cohort.After MS diagnosis, an increased risk of non-serious (IRR 1.65; 95% CI 1.56-1.75) and serious (admitted to hospital) infections (IRR 2.59; 95% CI 2.33-2.89) was detected among MS patients relative to the MS-free cohort. The risk of some bacterial (IRR 2.23; 95% CI 1.98-2.52) and some viral infections (IRR 1.70; 95% CI 1.48-1.96) was higher in MS patients of both sexes while only males showed an increased risk of fungal infections (IRR 1.91; 95% CI 1.26-2.89). Relative to the MS-free cohort, MS patients had an increased risk of all infection types, such as meningitis and encephalitis (IRR 6.16; 95% CI 4.47-8.48), other opportunistic infections (IRR 2.72; 95% CI 2.08-3.55), urinary and kidney infections (IRR 2.44; 95% CI 2.24-2.66), herpes virus (IRR 2.32; 95% CI 1.77-3.05), pneumonia and influenza (IRR 1.92; 95% CI 1.66-2.23), and skin infections (IRR 1.89; 95% CI 1.65-2.16).Conclusions: After MS diagnosis, patients had higher incidences of non-serious and serious infections compared with a cohort without MS. MS patients had an increased risk of being diagnosed during follow-up with most infection types compared with controls. This risk was particularly high for meningitis and encephalitis.
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| 10. |
- Montgomery, Scott, 1961-, et al.
(author)
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Risk of osteoporosis and fractures in patients with multiple sclerosis : a nationwide cohort study in Sweden
- 2019
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In: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 25:Suppl. 2, s. 387-388
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Journal article (other academic/artistic)abstract
- Introduction: While multiple sclerosis (MS) is usually diagnosed in young adults, many individuals living with the diagnosis are above age 40 years. Osteoporosis and fractures, which are morbidities generally associated with ageing but also physical inactivity, were determined in patients before and after MS diagnosis and compared with a matched MS-free population.Methods: Incident MS patients diagnosed in 2008-2016 were identified in the Swedish National Patient Register and matched with 10 MS-free individuals by age, sex, and region of residence. Incidence rates (IR) per 10,000 person-years and incidence rate ratios (IRRs; vs the MS-free cohort) of osteoporosis and fractures by sex and age at event were calculated after MS diagnosis based on ICD-10 codes from inpatient and outpatient specialist care.Results: In total, 6,602 MS patients were identified and compared with 61,828 without MS (female, 69%; median age, 40 years). Before MS diagnosis, MS patients showed significantly increased proportions of osteoporosis (0.5% vs 0.3%) and fractures (12.6% vs 11.4%) compared with the MS-free cohort.After diagnosis, MS patients had an increased risk of osteoporosis (IRR 1.69; 95% confidence interval [CI] 1.22-2.35). The increased risk of osteoporosis among MS patients was observed for both sexes (females, IRR 1.60; 95% CI 1.13-2.28 and males, IRR 2.56; 95% CI 1.04-6.31), as well as in the older age strata 40-59 years (IRR 2.39; 95% CI 1.47-3.89) and ⩾60 years (IRR 1.69; 95% CI 1.06-2.70), but not among those aged < 40 years. Similarly, an increased risk of fractures among MS patients (IRR 1.37; 95% CI 1.24-1.51) was shown for both females (IRR 1.40; 95% CI 1.25-1.58) and males (IRR 1.29; 95% CI 1.07-1.55), as well as the age strata 40-59 years (IRR 1.52; 95% CI 1.31-1.76) and ⩾60 years (IRR 1.92; 95% CI 1.58-2.33), but not those aged < 40 years.Conclusions: The risk of osteoporosis and fractures was moderately increased in MS patients of both sexes and in the older age groups, which may relate to physical inactivity and an increased risk of falls.
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