| 1. |
- Andréll, Paulin, 1978, et al.
(author)
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HEALTH-RELATED QUALITY OF LIFE IN FIBROMYALGIA AND REFRACTORY ANGINA PECTORIS: A COMPARISON BETWEEN TWO CHRONIC NON-MALIGNANT PAIN DISORDERS
- 2014
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In: Journal of Rehabilitation Medicine. - : Medical Journals Sweden AB. - 1650-1977 .- 1651-2081. ; 46:4, s. 341-347
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Journal article (peer-reviewed)abstract
- Objective: To compare health-related quality of life in 2 different populations with chronic pain: patients with fibromyalgia and patients with refractory angina pectoris. Previous separate studies have indicated that these patient groups report different impacts of pain on health-related quality of life. Methods: The Short-Form 36 was used to assess health-related quality of life. In order to adjust for age and gender differences between the groups, both patient groups were compared with age- and gender-matched normative controls. The difference in health-related quality of life between the 2 patient groups was assessed by transforming the Short-Form 36 subscale scores to a z-score. Results: The patients with fibromyalgia (n=203) reported poorer health-related quality of life in all the subscale scores of Short-Form 36 (p < 0.05-0.0001) than the patients with refractory angina (n = 146) when both groups were compared with their corresponding normal population (z-score). Conclusion: Patients with fibromyalgia experience greater impairment in health-related quality of life compared with the normal population than do patients with refractory angina pectoris, despite the fact that the latter have a potentially life-threatening disease. The great impairment in health-related quality of life in patients with fibromyalgia should be taken into consideration when planning rehabilitation.
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| 2. |
- Enell Smith, Karin, et al.
(author)
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ATOR-1017 (evunzekibart), an Fc-gamma receptor conditional 4-1BB agonist designed for optimal safety and efficacy, activates exhausted T cells in combination with anti-PD-1
- 2023
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In: Cancer Immunology, Immunotherapy. - 0340-7004. ; 72:12, s. 4145-4159
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Journal article (peer-reviewed)abstract
- Background: 4-1BB (CD137) is a co-stimulatory receptor highly expressed on tumor reactive effector T cells and NK cells, which upon stimulation prolongs persistence of tumor reactive effector T and NK cells within the tumor and induces long-lived memory T cells. 4-1BB agonistic antibodies have been shown to induce strong anti-tumor effects that synergize with immune checkpoint inhibitors. The first generation of 4-1BB agonists was, however, hampered by dose-limiting toxicities resulting in suboptimal dose levels or poor agonistic activity. Methods: ATOR-1017 (evunzekibart), a second-generation Fc-gamma receptor conditional 4-1BB agonist in IgG4 format, was designed to overcome the limitations of the first generation of 4-1BB agonists, providing strong agonistic effect while minimizing systemic immune activation and risk of hepatoxicity. The epitope of ATOR-1017 was determined by X-ray crystallography, and the functional activity was assessed in vitro and in vivo as monotherapy or in combination with anti-PD1. Results: ATOR-1017 binds to a unique epitope on 4-1BB enabling ATOR-1017 to activate T cells, including cells with an exhausted phenotype, and NK cells, in a cross-linking dependent, FcγR-conditional, manner. This translated into a tumor-directed and potent anti-tumor therapeutic effect in vivo, which was further enhanced with anti-PD-1 treatment. Conclusions: These preclinical data demonstrate a strong safety profile of ATOR-1017, together with its potent therapeutic effect as monotherapy and in combination with anti-PD1, supporting further clinical development of ATOR-1017.
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| 3. |
- Gad, Helge, et al.
(author)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Journal article (peer-reviewed)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 4. |
- Law, Lena L, et al.
(author)
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Moderate intensity physical activity associates with CSF biomarkers in a cohort at risk for Alzheimer's disease.
- 2018
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In: Alzheimer's & dementia (Amsterdam, Netherlands). - : Wiley. - 2352-8729. ; 10, s. 188-195
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Journal article (peer-reviewed)abstract
- Alzheimer's disease (AD) is characterized by the presence of amyloid β (Aβ) plaques, neurofibrillary tangles, and neurodegeneration, evidence of which may be detected invivo via cerebrospinal fluid (CSF) sampling. Physical activity (PA) has emerged as a possible modifier of these AD-related pathological changes. Consequently, the aim of this study was to cross-sectionally examine the relationship between objectively measured PA and CSF levels of Aβ42 and tau in asymptomatic late-middle-aged adults at risk for AD.Eighty-five cognitively healthy late-middle-aged adults (age=64.31years, 61.2% female) from the Wisconsin Registry for Alzheimer's Prevention participated in this study. They wore an accelerometer (ActiGraph GT3X+) for one week to record free-living PA, yielding measures of sedentariness and various intensities of PA (i.e., light, moderate, and vigorous). They also underwent lumbar puncture to collect CSF, from which Aβ42, total tau, and phosphorylated tau were immunoassayed. Regression analyses were used to examine the association between accelerometer measures and CSF biomarkers, adjusting for age, sex, and other relevant covariates.Engagement in moderate PA was associated with higher Aβ42 (P=.008), lower total tau/Aβ42 (P=.006), and lower phosphorylated tau/Aβ42 (P=.030). In contrast, neither light nor vigorous PA was associated with any of the biomarkers. Increased sedentariness was associated with reduced Aβ42 (P=.014).In this cohort, moderate PA, but not light or vigorous, was associated with a favorable AD biomarker profile, while sedentariness was associated with greater Aβ burden. These findings suggest that a physically active lifestyle may play a protective role against the development of AD.
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| 5. |
- Nelson, Michelle H., et al.
(author)
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The Bispecific Tumor Antigen-Conditional 4-1BB x 5T4 Agonist, ALG.APV-527, Mediates Strong T-Cell Activation and Potent Antitumor Activity in Preclinical Studies
- 2023
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In: Molecular Cancer Therapeutics. - 1538-8514. ; 22:1, s. 89-101
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Journal article (peer-reviewed)abstract
- 4-1BB (CD137) is an activation-induced costimulatory receptor that regulates immune responses of activated CD8 T and natural killer cells, by enhancing proliferation, survival, cytolytic activity, and IFNγ production. The ability to induce potent antitumor activity by stimulating 4-1BB on tumor-specific cytotoxic T cells makes 4-1BB an attractive target for designing novel immuno-oncology therapeutics. To minimize systemic immune toxicities and enhance activity at the tumor site, we have developed a novel bispecific antibody that stimulates 4-1BB function when co-engaged with the tumor-associated antigen 5T4. ALG.APV-527 was built on the basis of the ADAPTIR bispecific platform with optimized binding domains to 4-1BB and 5T4 originating from the ALLIGATOR-GOLD human single-chain variable fragment library. The epitope of ALG.APV-527 was determined to be located at domain 1 and 2 on 4-1BB using X-ray crystallography. As shown in reporter and primary cell assays in vitro, ALG.APV-527 triggers dose-dependent 4-1BB activity mediated only by 5T4 crosslinking. In vivo, ALG.APV-527 demonstrates robust antitumor responses, by inhibiting growth of established tumors expressing human 5T4 followed by a long-lasting memory immune response. ALG.APV-527 has an antibody-like half-life in cynomolgus macaques and was well tolerated at 50.5 mg/kg. ALG.APV-527 is uniquely designed for 5T4-conditional 4-1BB-mediated antitumor activity with potential to minimize systemic immune activation and hepatotoxicity while providing efficacious tumor-specific responses in a range of 5T4-expressing tumor indications as shown by robust activity in preclinical in vitro and in vivo models. On the basis of the combined preclinical dataset, ALG.APV-527 has potential as a promising anticancer therapeutic for the treatment of 5T4-expressing tumors.
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| 6. |
- Rosendahl-Santillo, A., et al.
(author)
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DBT-skills system for cognitively challenged individuals with self-harm: a Swedish pilot study
- 2021
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In: International Journal of Developmental Disabilities. - : Informa UK Limited. - 2047-3869 .- 2047-3877. ; 69:4, s. 533-545
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Journal article (peer-reviewed)abstract
- Background: Dialectical behavior therapy (DBT) is an evidence-based treatment for self-harm and emotion regulation difficulties. A modified version, DBT-Skills System (DBT-SS), has been developed in the USA for individuals with cognitive difficulties. The present study is a pilot study, testing the DBT-SS in a Swedish context. Methods: Six participants were treated with individual therapy and group skills training for 48 sessions each. A case series design was used to follow individual development over time. The primary outcome measure was reduction in challenging behaviors. Secondary outcomes were level of functioning in daily life, hospital admissions, and resilience and vulnerabilities in different risk domains. Data was analyzed using time-series diagrams. Effect sizes of changes were calculated using Cohen's d. Results: Challenging behaviors decreased over time and participants' global level of functioning increased. There was a reduction in number of hospital admissions over time. As for resilience and vulnerabilities, participants' overall level of risk in various areas remained unchanged or decreased after treatment. Conclusions: The results indicate that DBT-SS might be a promising treatment for cognitively challenged individuals with emotion regulation difficulties and challenging behaviors in a Swedish context. The study provides suggestions for a future randomized controlled trial. Supplemental data for this article is available online at here.
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| 7. |
- Schultz, Kristofer, et al.
(author)
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Reduced CSF CART in dementia with Lewy bodies.
- 2009
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In: Neuroscience letters. - : Elsevier BV. - 0304-3940. ; 453:2, s. 104-6
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Journal article (peer-reviewed)abstract
- Dementia with Lewy bodies (DLB) is the second most common form of neurodegenerative dementia after Alzheimer's disease (AD). The underlying neurobiological mechanism of DLB is not fully understood and no generally accepted biomarkers are yet available for the diagnosis of DLB. In a recent MRI study, DLB patients displayed hypothalamic atrophy whereas this region was not affected in AD patients. Cocaine and amphetamine regulated transcript (CART) is a neuropeptide expressed selectively in neurons in the hypothalamus. Here, we found that CSF CART levels were significantly reduced by 30% in DLB patients (n = 12) compared to controls (n = 12) as well as to AD patients (n = 14) using radioimmunoassay. Our preliminary results suggest that reduced CSF CART is a sign of hypothalamic dysfunction in DLB and that it may serve as a biomarker for this patient group.
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| 8. |
- Stenseke, Marie, et al.
(author)
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Kris i naturen – vår existens har blivit sårbar
- 2019
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In: Svenska Dagbladet, Stockholm. - 1101-2412.
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Journal article (pop. science, debate, etc.)abstract
- Fler arter än någonsin i mänsklighetens historia hotas av utrotning och den biologiska mångfalden lokalt har förändrats kraftigt i en stor del av världens ekosystem. Grundläggande förändringar behövs både i samhället och för individer, för att bromsa den negativa trenden, skriver en rad debattörer.
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| 9. |
- Treccani, Giulia, et al.
(author)
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Hippocampal NG2+ pericytes in chronically stressed rats and depressed patients : a quantitative study
- 2021
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In: Stress. - : Informa UK Limited. - 1025-3890 .- 1607-8888. ; 24:3, s. 353-358
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Journal article (peer-reviewed)abstract
- Objective: The suggested link between major depression disorder (MDD) and blood–brain barrier (BBB) alterations supports an impact on the neurovascular unit in this disease condition. Here we investigate how pericytes, a major component in the neurovascular unit, respond to stress, stress hormones, proinflammatory cytokine and depression. Method: Hippocampal sections of chronic unpredictable stressed (CMS) rats, MDD patients and respective controls were immuno-stained against NG2, where the number of NG2+ pericytes in the molecular layer was counted. Proliferation of cultured pericytes after treatment with cortisol and IL-1β was analyzed using radioactive-labeled thymidine. Findings: The number of NG2+ pericytes was significantly higher in CMS animals than controls. Higher number of NG2+ pericytes was also detected in MDD patients, but the increase did not reach significance. IL-1β, but not cortisol, induced a significant increase in proliferation of cultured pericytes. Conclusion: Our results indicate that exposure to stressful conditions affects the hippocampal pericyte population. These findings add to our knowledge about the impact of stress on the neurovascular unit, which might be relevant for understanding the alterations in BBB found in MDD patients.
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| 10. |
- Vesperman, Clayton J., et al.
(author)
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Cardiorespiratory fitness and cognition in persons at risk for Alzheimer's disease
- 2022
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In: Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring. - : Alzheimer's Association. - 2352-8729. ; 14:1
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Journal article (peer-reviewed)abstract
- Introduction: This study examined the relationship between cardiorespiratory fitness (CRF) and longitudinal cognitive functioning in a cohort enriched with risk factors for Alzheimer's disease (AD).Methods: A total of 155 enrollees in the Wisconsin Registry for Alzheimer's Prevention completed repeat comprehensive neuropsychological evaluations that assessed six cognitive domains. Peak oxygen consumption (VO2peak) was the primary measure of CRF. Random effects regression was used to investigate the effect of CRF on cognitive trajectories.Results: Higher CRF was associated with slower decline in the cognitive domains of verbal learning and memory (P < .01) and visual learning and memory (P < .042). Secondary analyses indicated that these effects were stronger among men than women, and for noncarriers of the apolipoprotein E ε4 allele.Discussion: Higher CRF was associated with a slower rate of the decline in episodic memory that occurs as a natural consequence of aging in a cohort enriched with risk factors for AD.
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