| 1. |
- Hollestelle, Antoinette, et al.
(författare)
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No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer
- 2016
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Ingår i: Gynecologic Oncology. - : Elsevier BV. - 0090-8258 .- 1095-6859. ; 141:2, s. 386-401
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Tidskriftsartikel (refereegranskat)abstract
- Objective Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3′ UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370. Methods Centralized genotyping and analysis were performed for 140,012 women enrolled in the Ovarian Cancer Association Consortium (15,357 ovarian cancer patients; 30,816 controls), the Breast Cancer Association Consortium (33,530 breast cancer patients; 37,640 controls), and the Consortium of Modifiers of BRCA1 and BRCA2 (14,765 BRCA1 and 7904 BRCA2 mutation carriers). Results We found no association with risk of ovarian cancer (OR = 0.99, 95% CI 0.94-1.04, p = 0.74) or breast cancer (OR = 0.98, 95% CI 0.94-1.01, p = 0.19) and results were consistent among mutation carriers (BRCA1, ovarian cancer HR = 1.09, 95% CI 0.97-1.23, p = 0.14, breast cancer HR = 1.04, 95% CI 0.97-1.12, p = 0.27; BRCA2, ovarian cancer HR = 0.89, 95% CI 0.71-1.13, p = 0.34, breast cancer HR = 1.06, 95% CI 0.94-1.19, p = 0.35). Null results were also obtained for associations with overall survival following ovarian cancer (HR = 0.94, 95% CI 0.83-1.07, p = 0.38), breast cancer (HR = 0.96, 95% CI 0.87-1.06, p = 0.38), and all other previously-reported associations. Conclusions rs61764370 is not associated with risk of ovarian or breast cancer nor with clinical outcome for patients with these cancers. Therefore, genotyping this variant has no clinical utility related to the prediction or management of these cancers.
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| 2. |
- Escala-Garcia, Maria, et al.
(författare)
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A network analysis to identify mediators of germline-driven differences in breast cancer prognosis
- 2020
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the underlying genetic drivers of the heritability of breast cancer prognosis remains elusive. We adapt a network-based approach to handle underpowered complex datasets to provide new insights into the potential function of germline variants in breast cancer prognosis. This network-based analysis studies similar to 7.3 million variants in 84,457 breast cancer patients in relation to breast cancer survival and confirms the results on 12,381 independent patients. Aggregating the prognostic effects of genetic variants across multiple genes, we identify four gene modules associated with survival in estrogen receptor (ER)-negative and one in ER-positive disease. The modules show biological enrichment for cancer-related processes such as G-alpha signaling, circadian clock, angiogenesis, and Rho-GTPases in apoptosis.
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| 3. |
- Grip, Jonathan
(författare)
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On bioenergetic failure in septic shock : lactate kinetics and mitochondrial respiration
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Septic shock, a dysregulated immune response to an infection, is a major cause of mortality and morbidity in patients treated in intensive care units (ICUs). The cause of the organ dysfunction seen in sepsis is still not fully elucidated, but a disrupted intracellular metabolism, a bioenergetics failure, has been suggested as a possible mechanism. In this thesis we investigate two aspects of these metabolic alterations – mitochondrial dysfunction and lactate metabolism. Compromised mitochondrial function and damaged mitochondria are described in septic ICU patients and various animal septic models. In our study we investigated if plasma from septic patients was able to alter the respiratory function of mitochondria of rat skeletal muscle. We examined this through incubation of isolated mitochondria as well as incubation of permeabilized muscle cells, but could not detect any difference in respiration compared to mitochondria incubated in control plasma. Elevated concentrations, and impaired clearance, of plasma lactate are known to correlate with increased mortality in patients with septic shock. We examined the development of plasma lactate in septic shock patients treated in our ICU to determine the optimal rate of hourly reduction to use for prognostication. All patients treated for septic shock with plasma lactate >2mmol/L and treatment with vasopressors during 2015 and 2016 (n= 104, mortality 34%) were included. Lactate values from all blood gas analyzes, until normalization (<1.5 mmol/L) or 24 hours, whichever came first, were included. Changes in lactate concentrations between each sampling point were used to determine the mean hourly lactate reduction in percent. Mean reduction <2.5%/h and admission lactate ≥4mmol/L provided the best cut-off values for prognostication of poor outcome. Of the 22 patients with admission lactate >4mmol/L and decrease <2.5%/h, 14 died within 60 hours of ICU admission. To study lactate metabolism, production as well as consumption, we examined two different approaches using intravenous administration of 13C-labeled lactate, which can be distinguished from endogenous lactate through laboratory analysis. First we examined a continuous infusion of 13C- lactate in healthy subjects. Samples were drawn from arterial and femoral venous lines and a skeletal muscle biopsy was taken at tracer steady state. An infusion of adrenaline was used to increase plasma lactate (from 1 to 4 mmol/L) and sampling was repeated after three hours. Skeletal muscle was a net contributor of lactate and adrenaline increased maximal mitochondrial respiration by 30%. The muscle biopsies showed a large variability and will not be used in clinical studies on septic patients. We then investigated a less invasive protocol for studying whole body lactate metabolism. First healthy volunteers were administered a bolus dose of 13C-lactate and a total of 43 blood samples were drawn during 2 hours. 10 ICU patients were then investigated using the same protocol. This protocol rendered similar values for lactate rate of appearance as other methods in healthy volunteers. ICU patients with normal lactate concentrations showed similar lactate metabolism as healthy volunteers. Simulations showed that blood samples can be decreased from 43 to 14 with the same accuracy. We conclude that the protocol using infusion and arterio-venous sampling yield more information, but is more invasive and may be suitable for smaller physiological studies while the bolus approach is simpler and may be useful in larger cohorts. We plan on using these approaches to examine lactate kinetics in patients with septic shock. Other patient groups that may be interesting to study in the future includes post cardiac arrest, traumatic brain injury or postoperatively to major surgery.
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| 4. |
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| 5. |
- Jonmarker, Sandra, et al.
(författare)
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A retrospective multicenter cohort study of the association between anti-Factor Xa values and death, thromboembolism, and bleeding in patients with critical COVID-19
- 2023
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Ingår i: Thrombosis Journal. - 1477-9560. ; 21, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with critical COVID-19 have a high risk of thromboembolism, but intensified thromboprophylaxis has not been proven beneficial. The activity of low-molecular-weight heparins can be monitored by measuring anti-Factor Xa. We aimed to study the association between anti-Factor Xa values and death, thromboembolism, and bleeding in patients with critical COVID-19.METHOD: This retrospective cohort study included adult patients with critical COVID-19 admitted to an intensive care unit at three Swedish hospitals between March 2020 and May 2021 with at least one valid peak and/or trough anti-Factor Xa value. Within the peak and trough categories, patients' minimum, median, and maximum values were determined. Logistic regressions with splines were used to assess associations.RESULTS: In total, 408 patients had at least one valid peak and/or trough anti-Factor Xa measurement, resulting in 153 patients with peak values and 300 patients with trough values. Lower peak values were associated with thromboembolism for patients' minimum (p = 0.01), median (p = 0.005) and maximum (p = 0.001) values. No association was seen between peak values and death or bleeding. Higher trough values were associated with death for median (p = 0.03) and maximum (p = 0.002) values and with both bleeding (p = 0.01) and major bleeding (p = 0.02) for maximum values, but there were no associations with thromboembolism.CONCLUSIONS: Measuring anti-Factor Xa activity may be relevant for administrating low-molecular-weight heparin to patients with critical COVID-19. Lower peak values were associated with an increased risk of thromboembolism, and higher trough values were associated with an increased risk of death and bleeding. Prospective studies are needed to confirm the results.TRIAL REGISTRATION: The study was retrospectively registered at Clinicaltrials.gov, NCT05256524, February 24, 2022.
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| 6. |
- Mavaddat, Nasim, et al.
(författare)
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Prediction of Breast Cancer Risk Based on Profiling With Common Genetic Variants
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 1460-2105 .- 0027-8874. ; 107:5, s. 036-036
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Tidskriftsartikel (refereegranskat)abstract
- Background: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking. Methods: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates. Results: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer. Conclusions: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
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| 7. |
- Meth, Elisa M. S., et al.
(författare)
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A weighted blanket increases pre-sleep salivary concentrations of melatonin in young, healthy adults
- 2023
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Ingår i: Journal of Sleep Research. - : John Wiley & Sons. - 0962-1105 .- 1365-2869. ; 32:2
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Tidskriftsartikel (refereegranskat)abstract
- Weighted blankets have emerged as a potential non-pharmacological intervention to ease conditions such as insomnia and anxiety. Despite a lack of experimental evidence, these alleged effects are frequently attributed to a reduced activity of the endogenous stress systems and an increased release of hormones such as oxytocin and melatonin. Thus, the aim of the present in-laboratory crossover study (26 young and healthy participants, including 15 men and 11 women) was to investigate if using a weighted blanket (~12% of body weight) at bedtime resulted in higher salivary concentrations of melatonin and oxytocin compared with a light blanket (~2.4% of body weight). We also examined possible differences in salivary concentrations of the stress hormone cortisol, salivary alpha-amylase activity (as an indicative metric of sympathetic nervous system activity), subjective sleepiness, and sleep duration. When using a weighted blanket, the 1 hour increase of salivary melatonin from baseline (i.e., 22:00) to lights off (i.e., 23:00) was about 32% higher (p = 0.011). No other significant differences were found between the blanket conditions, including subjective sleepiness and total sleep duration. Our study is the first to suggest that using a weighted blanket may result in a more significant release of melatonin at bedtime. Future studies should investigate whether the stimulatory effect on melatonin secretion is observed on a nightly basis when frequently using a weighted blanket over weeks to months. It remains to be determined whether the observed increase in melatonin may be therapeutically relevant for the previously described effects of the weighted blanket on insomnia and anxiety.
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| 8. |
- Mårtensson, Johan, et al.
(författare)
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COVID-19 critical illness in Sweden : characteristics and outcomes at a national population level
- 2020
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Ingår i: Critical Care and Resuscitation. - Strawberry Hills, NSW, Australia : AUSTRALASIAN MED PUBL CO LTD. - 1441-2772. ; 22:4, s. 312-320
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Tidskriftsartikel (refereegranskat)abstract
- Objective: During the coronavirus disease 2019 (COVID-19) pandemic, baseline demographics and comorbidities of patients with COVID-19 have been presented, but there are limited data on outcomes of severely ill patients. We aimed to examine the association between patient characteristics and 30-day mortality among patients with COVID-19 treated in the intensive care unit (ICU).Design: Population-based cohort study.Setting: ICUs in Sweden.Participants: All consecutive patients with COVID-19 admitted to Swedish ICUs from 6 March to 5 April 2020.Main outcome measures: The primary outcome was 30-day mortality after ICU admission. Patient demographics, comorbidities and clinical characteristics were also retrieved.Results: A total of 604 patients were included. The median age was 61 years (interquartile range [IQR], 52-70 years) and 458 patients (76%) were males. The most common comorbidities were hypertension (35.9%) and diabetes (25.7%), whereas 36.4% of patients had no comorbidities. Median Simplified Acute Physiology Score (SAPS) 3 was 53 (IQR, 46-60). Of 573 patients with available respiratory support data, 487 (85.0%) received invasive mechanical ventilation. Among 518 patients with available data, 117 (22.6%) received renal replacement therapy. Median length of stay was 13 days (IQR, 6-20 days). Mortality at 30 days was 32.6%. In the multivariable Cox regression model, age (hazard ratio [HR] 1.06; 95% CI, 1.04-1.07 per year), the presence of one or more comorbidities (HR, 1.80; 95% CI, 1.20-2.68), chronic obstructive pulmonary disease or asthma (HR, 1.68; 95% CI, 1.12-2.50), hypertension (HR, 1.41; 95% CI, 1.01-1.99), and acute illness severity (SAPS 3 excluding age and comorbidity) (HR, 1.06; 95% CI, 1.04-1.09) were associated with 30-day mortality.Conclusions: This population-based cohort study presents 30-day mortality of 604 ICU patients with COVID-19. The higher mortality was explained by older age, the presence chronic illness, and acute illness severity.
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| 9. |
- Stevens, Kristen N, et al.
(författare)
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19p13.1 is a triple negative-specific breast cancer susceptibility locus
- 2012
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 72, s. 1795-
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Tidskriftsartikel (refereegranskat)abstract
- The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 - 1.15, p=3.49 x 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 - 1.31, p=2.22 x 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 - 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 - 1.33, p=3.31 x 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
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