| 1. |
- Gad, Helge, et al.
(författare)
-
MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
-
Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
-
Tidskriftsartikel (refereegranskat)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.
|
|
| 2. |
- Plaven-Sigray, Pontus, et al.
(författare)
-
Dopamine D1 receptor availability is related to social behavior : A positron emission tomography study
- 2014
-
Ingår i: NeuroImage. - : Elsevier BV. - 1053-8119 .- 1095-9572. ; 102, s. 590-595
-
Tidskriftsartikel (refereegranskat)abstract
- Dysfunctional interpersonal behavior is thought to underlie a wide spectrum of psychiatric disorders; however, the neurobiological underpinnings of these behavioral disturbances are poorly understood. Previous molecular imaging studies have shown associations between striatal dopamine (DA) D2-receptor binding and interpersonal traits, such as social conformity. The objective of this study was to explore, for the first time, the role of DA D1-receptors (D1-Rs) in human interpersonal behavior. Twenty-three healthy subjects were examined using positron emission tomography and the radioligand [C-11] SCH23390, yielding D1-R binding potential values. Striatal D1-R binding was related to personality scales selected to specifically assess one dimension of interpersonal behavior, namely a combination of affiliation and dominance (i.e., the Social Desirability, Verbal Trait Aggression and Physical Trait Aggression scales from Swedish Universities Scales of Personality). An exploratory analysis was also performed for extrastriatal brain regions. D1-R binding potential values in the limbic striatum(r= .52; p= .015), associative striatum(r= .55; p= .009), and sensorimotor striatum(r= .67; p= .001) were positively related to Social Desirability scores. D1-R binding potential in the limbic striatum (r= -.51; p = .019) was negatively associated with Physical Trait Aggression scores. For extrastriatal regions, Social Desirability scores showed positive correlations in the amygdala (r = .60; p = .006) and medial frontal cortex (r= .60; p = .004). This study provides further support for the role of DA function in the expression of disaffiliative and dominant traits. Specifically, D1-R availability may serve as a marker for interpersonal behavior in humans. Associations were demonstrated for the same dimension of interpersonal behavior as for D2-R, but in the opposite direction, suggesting that the two receptor subtypes are involved in the same behavioral processes, but with different functional roles.
|
|
| 3. |
- Andersson, J., et al.
(författare)
-
Worse survival for TP53 (p53)-mutated breast cancer patients receiving adjuvant CMF
- 2005
-
Ingår i: Ann Oncol. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 16:5, s. 743-8
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: TP53 has been described as a prognostic factor in many malignancies, including breast cancer. Whether it also might be a predictive factor with reference to chemo- and endocrine therapy is more controversial. PATIENTS AND METHODS: We investigated relapse-free (RFS), breast cancer-corrected (BCCS) and overall survival (OS) related to TP53 status in node-positive breast cancer patients that had received polychemotherapy [cyclophosphamide, methotrexate, 5-fluorouracil (CMF)] and/or endocrine therapy (tamoxifen). Sequence analyses of the whole TP53 coding region was performed in 376 patients operated on for primary breast cancer with axillary lymph node metastases between 1984 and 1989 (median follow-up time 84 months). RESULTS: TP53 mutations were found in 105 patients (28%). We found 90 (82%) of the 110 mutations in the more frequently analysed exons 5-8, while the other 20 (18%) were located in exons 3-4 and 9-10, respectively. Univariate analyses showed TP53 to be a significant prognostic factor with regard to RFS, BCCS and OS in patients who received adjuvant CMF. CONCLUSIONS: TP53 mutations might induce resistance to certain modalities of breast cancer therapy. Sequence-determined TP53 mutation was of negative prognostic value in the total patient population and in the CMF treated patients.
|
|
| 4. |
|
|
| 5. |
- Andreasson, Thomas, et al.
(författare)
-
Evaluation of anamnestic criteria for the identification of patients with acute community onset viral gastroenteritis in the emergency department-A prospective observational study.
- 2014
-
Ingår i: Scandinavian journal of infectious diseases. - : Informa UK Limited. - 1651-1980 .- 0036-5548. ; 46:8, s. 561-565
-
Tidskriftsartikel (refereegranskat)abstract
- Background: To our knowledge no clinical criteria for the identification of community onset viral gastroenteritis in individual patients have been evaluated systematically with modern PCR-based diagnostic assays as gold standard. Objective: The aim of this study was to identify factors independently associated with the detection of virus by PCR in rectal swab samples from patients with acute community onset gastroenteritis. Methods: A prospective observational study was conducted from December 2010 through March 2011 at the emergency department (ED) of a large teaching hospital. All patients who reported vomiting and/or diarrhoea up to 48 h prior to their visit to the ED were asked to participate. A rectal swab sample was obtained from each patient. Symptoms, date of onset, and epidemiological data were recorded. Samples were analysed with a multiple real-time PCR targeting 6 viral agents (astrovirus, adenovirus, rotavirus, sapovirus, and norovirus GI and GII). Results: Two hundred and five patients fulfilled the inclusion criteria, of whom 66 agreed to participate; their median (IQR) age was 65 (38-84) y and 43 (65%) were females. Thirty-one (47%) were positive by PCR for at least 1 of the agents examined (26 norovirus, 2 sapovirus, 2 rotavirus, and 1 adenovirus). Diarrhoea and a short duration of symptoms (≤ 2 days) were independently associated with a positive rectal swab sample, with odds ratios of 7.5 (95% confidence interval (CI) 2.0-28) and 10.4 (95% CI 1.9-56), respectively (p < 0.01 for both). A multivariate model including these 2 variables had a sensitivity of 81% (25/31) and a specificity of 69% (24/35). Conclusions: Diarrhoea and a short duration of symptoms were the only anamnestic criteria independently associated with acute community onset viral gastroenteritis confirmed by PCR.
|
|
| 6. |
- Andreen, Niklas, et al.
(författare)
-
Mortality of COVID-19 is associated with comorbidity in patients with chronic obstructive pulmonary disease
- 2022
-
Ingår i: Infectious Diseases. - : Informa UK Limited. - 2374-4235 .- 2374-4243. ; 54:7, s. 508-513
-
Tidskriftsartikel (refereegranskat)abstract
- Background The aim of this study was to compare the outcome of coronavirus disease 2019 (COVID-19) in hospitalised patients with chronic obstructive pulmonary disease (COPD) with the outcome in matched COVID-19 patients without COPD. Methods Sixty-three COPD patients hospitalised for acute COVID-19 from March through August 2020 were retrospectively identified and 63 hospitalised COVID-19 patients without COPD were selected and matched for age, gender and month of hospital admission. Results COPD patients had a higher rate of comorbidities, especially cardiovascular disease, and a trend towards a higher 30-day mortality than control patients (35% vs. 22%). In the COPD group, high Charlson comorbidity index (p = 0.03) and previous cerebrovascular disease (p = 0.04) were associated with 30-day mortality in univariate analysis. Inhaled corticosteroids maintenance therapy was not associated with lower mortality. Conclusion COPD patients hospitalised for acute COVID-19 disease had significantly more comorbidities and a high risk of severe outcome and death within 30 days. Comorbidity, especially cardiovascular diseases, was associated with mortality among COPD patients.
|
|
| 7. |
- Andrén, Niclas, et al.
(författare)
-
Euron och konkurrens mellan EU-länder
- 2002
-
Ingår i: Europaperspektiv 2002. Årsbok för Europaforskning. - 9189449274 ; , s. 73-104
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)
|
|
| 8. |
- Arvidsson, Eva, 1959-, et al.
(författare)
-
Vägen framåt
- 2013
-
Ingår i: Att välja rättvist. - Lund : Studentlitteratur AB. ; , s. 207-214
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Som vi visat har utvecklingen av metoder och strukturer för öppna prioriteringar i Sverige kommit långt. Många frågor återstår likväl. Under vårt arbete med denna bok har vi identifierat ett antal förbättringsområden och utmaningar som vi avslutningsvis vill lyfta fram. Det rör sig om vilka som ska delta i prioriteringarna, tydliggörande av värdegrunden, behov av bättre kunskap, baserad på både vetenskaplig metod och erfarenhet, och fortsatt utveckling av prioriteringsprocesser på olika nivåer och i olika sammanhang. Även om vi i Sverige skulle nå en god enighet kring principer och kriterier för prioriteringar så kommer vi alltid finna många olika sätt att praktiskt lösa specifika prioriteringsproblem.
|
|
| 9. |
- Beck-Friis, Thomas, et al.
(författare)
-
Burden of rotavirus infection in hospitalized elderly individuals prior to the introduction of rotavirus vaccination in Sweden
- 2019
-
Ingår i: Journal of Clinical Virology. - : Elsevier BV. - 1386-6532. ; 119, s. 1-5
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Rotavirus gastroenteritis (GE) in the elderly has been much less studied than in children. Objectives: The aim of this study was to determine the morbidity and mortality for elderly hospitalized patients with rotavirus GE prior to the introduction of rotavirus vaccination in Sweden, and to investigate the epidemiology of rotavirus genotypes in these patients. Study design: All patients 60 years or older who were hospitalized at Sahlgrenska University Hospital, Gothenburg, Sweden, and were rotavirus positive in a clinical diagnostic test from 2009 to 2016, were included. Medical records were reviewed and rotavirus genotyping real-time PCR was performed. Results: One hundred and fifty-nine patients were included, corresponding to an annual incidence of hospitalization due to rotavirus GE of 16/100 000 inhabitants aged 60 years or older. G2P[4] was the most common genotype, followed by G1P[8] and G4P[8]. The majority of patients had community-onset of symptoms and no or few pre-existing health disorders. Four patients (2.5%) died within 30 days of sampling. Patients with hospital-onset rotavirus GE had a longer median length of stay following diagnosis compared with patients with community-onset of symptoms (19 vs. 5 days, p = 0.001) and higher 30-day mortality (8.6% (3/35) vs. < 1% (1/124), p = 0.03). Conclusions: Hospitalization due to rotavirus GE among the elderly seems to mainly affect otherwise healthy individuals and is associated with low 30-day mortality.
|
|
| 10. |
- Beck-Friis, Thomas, et al.
(författare)
-
Outdoor Absolute Humidity Predicts the Start of Norovirus GII Epidemics
- 2023
-
Ingår i: Microbiology Spectrum. - : American Society for Microbiology. - 2165-0497. ; 11:2
-
Tidskriftsartikel (refereegranskat)abstract
- Seasonal variation of viral gastroenteritis is related to weather conditions, but the relationship with the incidence of viral gastroenteritis (GE) is not fully understood. This study examined the impact of outdoor climate factors on seasonal variation in detection rates of gastroenteritis viruses, with emphasis on norovirus. Weekly detection rates of norovirus genogroup I (GI) and II (GII), rotavirus, adenovirus, astrovirus, and sapovirus were analyzed in relation to average weekly means of meteorological parameters. Associations between rates of PCR detection of the viral GE pathogens and climate factors were investigated with generalized linear models. Low absolute humidity was correlated with increased detection of adenovirus (P = 0.007), astrovirus (P = 0.005), rotavirus (P = 0.004), norovirus GI (P = 0.001), and sapovirus (P = 0.002). In each investigated season, a drop in absolute humidity preceded the increase in norovirus GII detections. We found a correlation between declining absolute humidity and increasing norovirus GII detection rate. Absolute humidity was a better predictor of gastrointestinal virus seasonality compared to relative humidity.IMPORTANCE Viral gastroenteritis causes considerable morbidity, especially in vulnerable groups such as the elderly and chronically ill. Predicting the beginning of seasonal epidemics is important for the health care system to withstand increasing demands. In this paper we studied the association of outdoor climate factors on the detection rates of gastrointestinal viruses and the association between these factors and the onset of annual norovirus epidemics. Declining absolute humidity preceded the increase in diagnosed norovirus GII cases by approximately 1 week. These findings contribute to the understanding of norovirus epidemiology and allow health care services to install timely preventive measures and can help the public avoid transmission. Viral gastroenteritis causes considerable morbidity, especially in vulnerable groups such as the elderly and chronically ill. Predicting the beginning of seasonal epidemics is important for the health care system to withstand increasing demands.
|
|
