| 1. |
- Aits, Sonja, et al.
(författare)
-
HAMLET (human alpha-lactalbumin made lethal to tumor cells) triggers autophagic tumor cell death.
- 2009
-
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 124:5, s. 1008-1019
-
Tidskriftsartikel (refereegranskat)abstract
- HAMLET, a complex of partially unfolded alpha-lactalbumin and oleic acid, kills a wide range of tumor cells. Here we propose that HAMLET causes macroautophagy in tumor cells and that this contributes to their death. Cell death was accompanied by mitochondrial damage and a reduction in the level of active mTOR and HAMLET triggered extensive cytoplasmic vacuolization and the formation of double-membrane-enclosed vesicles typical of macroautophagy. In addition, HAMLET caused a change from uniform (LC3-I) to granular (LC3-II) staining in LC3-GFP-transfected cells reflecting LC3 translocation during macroautophagy, and this was blocked by the macroautophagy inhibitor 3-methyladenine. HAMLET also caused accumulation of LC3-II detected by Western blot when lysosomal degradation was inhibited suggesting that HAMLET caused an increase in autophagic flux. To determine if macroautophagy contributed to cell death, we used RNA interference against Beclin-1 and Atg5. Suppression of Beclin-1 and Atg5 improved the survival of HAMLET-treated tumor cells and inhibited the increase in granular LC3-GFP staining. The results show that HAMLET triggers macroautophagy in tumor cells and suggest that macroautophagy contributes to HAMLET-induced tumor cell death.
|
|
| 2. |
- Ahlquist, Mårten, et al.
(författare)
-
Rhodium(I) hydrogenation in water : Kinetic studies and the detection of an intermediate using C-13{H-1} PHIPNMR spectroscopy
- 2007
-
Ingår i: Inorganica Chimica Acta. - : Elsevier BV. - 0020-1693 .- 1873-3255. ; 360:5, s. 1621-1627
-
Tidskriftsartikel (refereegranskat)abstract
- The mechanism for hydrogenation of dimethylmaleate in water using cationic rhodium complexes with water-soluble bi-dentate phosphines has been investigated using kinetics and a novel method for the indirect detection of intermediates in catalytic hydrogenation reactions, whereby a late intermediate was detected. A mechanism is proposed involving fast, irreversible substrate binding followed by a rate-determining reaction with dihydrogen.
|
|
| 3. |
|
|
| 4. |
- Andersson, Niklas, et al.
(författare)
-
Steady-state cycles in digital oscillators
- 2014
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Digital recursive oscillators locked in steady-state can be used to generate sinusoids with high spectral purity. The locking occurs when the oscillator returns to a previously visited state and repeats its sequence. In this work we propose a new search algorithm and two new search strategies to find all steady-states for a given oscillator configuration. The improvement in spurious-free dynamic range is between 7 and 40 dB compared to previously reported results. The algorithm is also able to find oscillator sequences for more frequencies than previously reported work. A key part of the method is the reduction of the search space made possible by a proposed extension of existing theory on recursive oscillators. Specific properties of digital oscillators in a steady-state are also discussed. It is shown that the initial states can be used to individually control the phase, amplitude, spectral purity, and also cycle length of the oscillator output.
|
|
| 5. |
- Berglund, Sara, et al.
(författare)
-
Cardiorenal function and survival in in-hospital cardiac arrest : A nationwide study of 22,819 cases
- 2022
-
Ingår i: Resuscitation. - : Elsevier BV. - 0300-9572 .- 1873-1570. ; 172, s. 9-16
-
Tidskriftsartikel (refereegranskat)abstract
- Background: We studied the association between cardiorenal function and survival, neurological outcome and trends in survival after in-hospital Methods: We included cases aged 18 years in the Swedish Cardiopulmonary Resuscitation Registry during 2008 to 2020. The CKD-EPI equation was used to calculate estimated glomerular filtration rate (eGFR). A history of heart failure was defined according to contemporary guideline criteria. Logistic regression was used to study survival. Neurological outcome was assessed using cerebral performance category (CPC). Results: We studied 22,819 patients with IHCA. The 30-day survival was 19.3%, 16.6%, 22.5%, 28.8%, 39.3%, 44.8% and 38.4% in cases with eGFR < 15, 15-29, 30-44, 45-59, 60-89, 90-130 and 130-150 ml/min/1.73 m2, respectively. All eGFR levels below and above 90 ml/min/1.73 m2 were associated with increased mortality. Probability of survival at 30 days was 62% lower in cases with eGFR < 15 ml/min/1.73 m2, compared with normal kidney function. At every level of eGFR, presence of heart failure increased mortality markedly; patients without heart failure displayed higher mortality only at eGFR below 30 ml/min/1.73 m2. Among survivors with eGFR < 15 ml/min/1.73 m2, good neurological outcome was noted in 87.2%. Survival increased in most groups over time, but most for those with eGFR < 15 ml/min/1.73 m2, and least for those with normal eGFR. Conclusions: All eGFR levels below and above normal range are associated with increased mortality and this association is modified by the presence of heart failure. Neurological outcome is good in the majority of cases, across kidney function levels and survival is increasing.
|
|
| 6. |
- Bost, Jeremy P., et al.
(författare)
-
Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides
- 2022
-
Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 5:1
-
Tidskriftsartikel (refereegranskat)abstract
- The therapeutic and research potentials of oligonucleotides (ONs) have been hampered in part by their inability to effectively escape endosomal compartments to reach their cytosolic and nuclear targets. Splice-switching ONs (SSOs) can be used with endosomolytic small molecule compounds to increase functional delivery. So far, development of these compounds has been hindered by a lack of high-resolution methods that can correlate SSO trafficking with SSO activity. Here we present in-depth characterization of two novel endosomolytic compounds by using a combination of microscopic and functional assays with high spatiotemporal resolution. This system allows the visualization of SSO trafficking, evaluation of endosomal membrane rupture, and quantitates SSO functional activity on a protein level in the presence of endosomolytic compounds. We confirm that the leakage of SSO into the cytosol occurs in parallel with the physical engorgement of LAMP1-positive late endosomes and lysosomes. We conclude that the new compounds interfere with SSO trafficking to the LAMP1-positive endosomal compartments while inducing endosomal membrane rupture and concurrent ON escape into the cytosol. The efficacy of these compounds advocates their use as novel, potent, and quick-acting transfection reagents for antisense ONs.
|
|
| 7. |
- Dejby, Ellen, et al.
(författare)
-
Left-sided valvular heart disease and survival in out-of-hospital cardiac arrest: a nationwide registry-based study.
- 2023
-
Ingår i: Scientific reports. - 2045-2322. ; 13:1
-
Tidskriftsartikel (refereegranskat)abstract
- Survival in left-sided valvular heart disease (VHD; aortic stenosis [AS], aortic regurgitation [AR], mitral stenosis [MS], mitral regurgitation [MR]) in out-of-hospital cardiac arrest (OHCA) is unknown. We studied all cases of OHCA in the Swedish Registry for Cardiopulmonary Resuscitation. All degrees of VHD, diagnosed prior to OHCA, were included. Association between VHD and survival was studied using logistic regression, gradient boosting and Cox regression. We studied time to cardiac arrest, comorbidities, survival, and cerebral performance category (CPC) score. We included 55,615 patients; 1948 with AS (3,5%), 384 AR (0,7%), 17 MS (0,03%), and 704 with MR (1,3%). Patients with MS were not described due to low case number. Time from VHD diagnosis to cardiac arrest was 3.7years in AS, 4.5years in AR and 4.1years in MR. ROSC occurred in 28% with AS, 33% with AR, 36% with MR and 35% without VHD. Survival at 30days was 5.2%, 10.4%, 9.2%, 11.4% in AS, AR, MR and without VHD, respectively. There were no survivors in people with AS presenting with asystole or PEA. CPC scores did not differ in those with VHD compared with no VHD. Odds ratio (OR) for MR and AR showed no difference in survival, while AS displayed OR 0.58 (95% CI 0.46-0.72), vs no VHD. AS is associated with halved survival in OHCA, while AR and MR do not affect survival. Survivors with AS have neurological outcomes comparable to patients without VHD.
|
|
| 8. |
- Düringer, Caroline, et al.
(författare)
-
HAMLET; a novel tool to identify apoptotic pathways in tumor cells.
- 2005
-
Ingår i: Application of apoptosis to cancer treatment.. - Berlin/Heidelberg : Springer-Verlag. - 9781402033032 ; , s. 223-245
-
Bokkapitel (övrigt vetenskapligt/konstnärligt)abstract
- Tumor cells often carry mutations in genes that control cell survival, and become resistant to signals that trigger cell death. Yet, some cell death pathways remain intact in tumor cells. If identified, these pathways might be exploited to selectively remove tumor cells. HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex derived from human milk that activates cell death programs in tumor cells but not in healthy differentiated cells. We use HAMLET as a tool to identify apoptosis and apoptosis-like cell death mechanisms in tumor cells and to understand if these mechanisms differ between tumor and healthy cells. HAMLET interacts with the cell surface, translocates into the cytoplasm and accumulates in cell nuclei, where it disrupts the chromatin. Recent in vivo studies have shown that HAMLET maintains the tumoricidal activity in glioblastoma, papilloma and bladder cancer models, with no significant side effects. The results suggest that HAMLET should be explored as a new therapeutic agent with selectivity for the tumor and with little toxicity for adjacent healthy tissue. Such therapies are a much-needed complement to conventional treatments, to reduce the side effects and improve the selectivity.
|
|
| 9. |
- Ewerlöf, Sofia, et al.
(författare)
-
DN Debatt. ”Låt gräsklipparen stå – för naturens skull”
- 2023
-
Ingår i: Dagens nyheter (DN debatt). - 1101-2447.
-
Tidskriftsartikel (populärvet., debatt m.m.)abstract
- In an era of species extinction and climate change, we should abandon the well-trimmed lawn and let gardens grow wilder, writes Anna Persson and other researchers and landscape architects on DN Debatt.
|
|
| 10. |
- Gustafsson, Linnea, et al.
(författare)
-
Characteristics, survival and neurological outcome in out-of-hospital cardiac arrest in young adults in Sweden : A nationwide study.
- 2023
-
Ingår i: Resuscitation Plus. - 2666-5204. ; 16
-
Tidskriftsartikel (refereegranskat)abstract
- AIM: The aim of this study was to present a comprehensive overview of out-of-hospital cardiac arrests (OHCA) in young adults.METHODS: The data set analyzed included all cases of OHCA from 1990 to 2020 in the age-range 16-49 years in the Swedish Registry of Cardiopulmonary Resuscitation (SRCR). OHCA between 2010 and 2020 were analyzed in more detail. Clinical characteristics, survival, neurological outcomes, and long-time trends in survival were studied. Logistic regression was used to study 30-days survival, neurological outcomes and Utstein determinants of survival.RESULTS: Trends were assessed in 11,180 cases. The annual increase in 30-days survival during 1990-2020 was 5.9% with no decline in neurological function among survivors. Odds ratio (OR) for heart disease as the cause was 0.55 (95% CI 0.44 to 0.67) in 2017-2020 compared to 1990-1993. Corresponding ORs for overdoses and suicide attempts were 1.61 (95% CI 1.23-2.13) and 2.06 (95% CI 1.48-2.94), respectively. Exercise related OHCA was noted in roughly 5%. OR for bystander CPR in 2017-2020 vs 1990-1993 was 3.11 (95% CI 2.57 to 3.78); in 2020 88 % received bystander CPR. EMS response time increased from 6 to 10 minutes.CONCLUSION: Survival has increased 6% annually, resulting in a three-fold increase over 30 years, with stable neurological outcome. EMS response time increased with 66% but the majority now receive bystander CPR. Cardiac arrest due to overdoses and suicide attempts are increasing.
|
|
| 11. |
- Gustafsson, Lotta, et al.
(författare)
-
HAMLET kills tumor cells by apoptosis: Structure, cellular mechanisms, and therapy
- 2005
-
Ingår i: Journal of Nutrition. - 1541-6100. ; 135:5, s. 1299-1303
-
Tidskriftsartikel (refereegranskat)abstract
- New cancer treatments should aim to destroy tumor cells without disturbing normal tissue. HAMLET (human a-lactalbumin made lethal to tumor cells) offers a new molecular approach to solving this problem, because it induces apoptosis in tumor cells but leaves normal differentiated cells unaffected. After partial unfolding and binding to oleic acid, α-lactalbumin forms the HAMLET complex, which enters tumor cells and freezes their metabolic machinery. The cells proceed to fragment their DNA, and they disintegrate with apoptosis-like characteristics. HAMLET kills a wide range of malignant cells in vitro and maintains this activity in vivo in patients with skin papillomas. In addition, HAMLET has striking effects on human glioblastomas in a rat xenograft model. After convection-enhanced delivery, HAMLET diffuses throughout the brain, selectively killing tumor cells and controlling tumor progression without apparent tissue toxicity. HAMLET thus shows great promise as a new therapeutic with the advantage of selectivity for tumor cells and lack of toxicity.
|
|
| 12. |
|
|
| 13. |
- Gustafsson, Oskar, 1990-, et al.
(författare)
-
Bayesian optimization of hyperparameters from noisy marginal likelihood estimates
- 2023
-
Ingår i: Journal of applied econometrics (Chichester, England). - : Wiley. - 0883-7252 .- 1099-1255. ; 38:4, s. 577-595
-
Tidskriftsartikel (refereegranskat)abstract
- Bayesian models often involve a small set of hyperparameters determined by maximizing the marginal likelihood. Bayesian optimization is an iterative method where a Gaussian process posterior of the underlying function is sequentially updated by new function evaluations. We propose a novel Bayesian optimization framework for situations where the user controls the computational effort and therefore the precision of the function evaluations. This is a common in econometrics where the marginal likelihood is often computed by Markov chain Monte Carlo or importance sampling methods. The new acquisition strategy gives the optimizer the option to explore the function with cheap noisy evaluations and therefore find the optimum faster. The method is applied to estimating the prior hyperparameters in two popular models on US macroeconomic time series data: the steady-state Bayesian vector autoregressive (BVAR) and the time-varying parameter BVAR with stochastic volatility.
|
|
| 14. |
|
|
| 15. |
- Gustafsson, Oskar, 1990-
(författare)
-
Some Contributions to Heteroscedastic Time Series Analysis and Computational Aspects of Bayesian VARs
- 2020
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Time-dependent volatility clustering (or heteroscedasticity) in macroeconomic and financial time series has been analyzed for more than half a century. The inefficiencies it causes in various inference procedures are well known and understood. Despite this, heteroscedasticity is surprisingly often neglected in practical work. The correct way is to model the variance jointly with the other properties of the time series by using some of the many methods available in the literature. In the first two papers of this thesis, we explore a third option, that is rarely used in the literature, in which we first remove the heteroscedasticity and only then fit a simpler model to the homogenized data.In the first paper, we introduce a filter that removes heteroscedasticity from simulated data without affecting other time series properties. We show that filtering the data leads to efficiency gains when estimating parameters in ARMA models, and in some cases to higher forecast precision for US GDP growth.The work of the first paper is extended to the case of multivariate time series in Paper II. In this paper, the stochastic volatility model is used for tracking the latent evolution of the time series variances. Also in this scenario variance stabilization offers efficiency gains when estimating model parameters.During the last decade, there has been an increasing interest in using large-scale VARs together with Bayesian shrinkage methods. The rich parameterization together with the need for simulations methods results in a computational bottleneck that either force concessions regarding the flexibility of the model or the size of the data set. In the last two papers, we address these issues with methods from the machine learning literature. In Paper III, we develop a new Bayesian optimization strategy for finding optimal hyperparameters for econometric models via maximization of the marginal likelihood. We illustrate that the algorithm finds optimal values fast compared to conventional methods. Finally, in Paper IV we present a fast variational inference (VI) algorithm for approximating the parameter posterior and predictive distribution of the steady-state BVAR. We show that VI produces results that are very close to those of the conventional Gibbs sampler but are obtained at a much lower computational cost. This is illustrated in both a simulation study and on US macroeconomic data.
|
|
| 16. |
|
|
| 17. |
- Gustafsson, Oskar, et al.
(författare)
-
Variance stabilizing filters
- 2019
-
Ingår i: Communications in Statistics - Theory and Methods. - : Informa UK Limited. - 0361-0926 .- 1532-415X. ; 48:24, s. 6155-6168
-
Tidskriftsartikel (refereegranskat)abstract
- In this paper new filters for removing unspecified form of heteroscedasticity are proposed. The filters build on the assumption that the variance of a pre-whitened time series can be viewed as a latent stochastic process by its own. This makes the filters flexible and useful in many situations. A simulation study shows that removing heteroscedasticity before fitting a model leads to efficiency gains and bias reductions when estimating the parameters of ARMA models. A real data study shows that pre-filtering can increase the forecasting precision of quarterly US GDP growth.
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
- Hallgren, Oskar, et al.
(författare)
-
Apoptosis and tumor cell death in response to HAMLET (human alpha-lactalbumin made lethal to tumor cells).
- 2008
-
Ingår i: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. ; 606, s. 217-240
-
Forskningsöversikt (refereegranskat)abstract
- HAMLET (human alpha-lactalbumin made lethal to tumor cells) is a molecular complex derived from human milk that kills tumor cells by a process resembling programmed cell death. The complex consists of partially unfolded alpha-lactalbumin and oleic acid, and both the protein and the fatty acid are required for cell death. HAMLET has broad antitumor activity in vitro, and its therapeutic effect has been confirmed in vivo in a human glioblastoma rat xenograft model, in patients with skin papillomas and in patients with bladder cancer. The mechanisms of tumor cell death remain unclear, however. Immediately after the encounter with tumor cells, HAMLET invades the cells and causes mitochondrial membrane depolarization, cytochrome c release, phosphatidyl serine exposure, and a low caspase response. A fraction of the cells undergoes morphological changes characteristic of apoptosis, but caspase inhibition does not rescue the cells and Bcl-2 overexpression or altered p53 status does not influence the sensitivity of tumor cells to HAMLET. HAMLET also creates a state of unfolded protein overload and activates 20S proteasomes, which contributes to cell death. In parallel, HAMLET translocates to tumor cell nuclei, where high-affinity interactions with histones cause chromatin disruption, loss of transcription, and nuclear condensation. The dying cells also show morphological changes compatible with macroautophagy, and recent studies indicate that macroautophagy is involved in the cell death response to HAMLET. The results suggest that HAMLET, like a hydra with many heads, may interact with several crucial cellular organelles, thereby activating several forms of cell death, in parallel. This complexity might underlie the rapid death response of tumor cells and the broad antitumor activity of HAMLET.
|
|
| 21. |
|
|
| 22. |
- Hesser, Hugo, 1982-, et al.
(författare)
-
A Randomized Controlled Trial of Internet-Delivered Cognitive Behavior Therapy and Acceptance and Commitment Therapy in the Treatment of Tinnitus
- 2012
-
Ingår i: Journal of Consulting and Clinical Psychology. - Washington, DC, USA : American Psychological Association (APA). - 0022-006X .- 1939-2117. ; 80:4, s. 649-661
-
Tidskriftsartikel (refereegranskat)abstract
- Objective:Our aim in this randomized controlled trial was to investigate the effects on global tinnitus severity of 2 Internet-delivered psychological treatments, acceptance and commitment therapy (ACT) and cognitive behavior therapy (CBT), in guided self-help format.Method: Ninety-nine participants (mean age 48.5 years; 43% female) who were significantly distressed by tinnitus were recruited from the community. Participants were randomly assigned to CBT (n 32), ACT (n 35), or a control condition (monitored Internet discussion forum; n 32), and they were assessed with standardized self-report measures (Tinnitus Handicap Inventory; Hospital Anxiety and Depression Scale; Quality of Life Inventory; Perceived Stress Scale; Tinnitus Acceptance Questionnaire) at pre-, posttreatment (8 weeks), and 1-year follow-up.Results: Mixed-effects linear regression analysis of all randomized participants showed significant effects on the primary outcome (Tinnitus Handicap Inventory) for CBT and for ACT compared with control at posttreatment (95% CI [17.03, 2.94], d 0.70, and 95% CI [16.29, 2.53], d 0.68, respectively). Within-group effects were substantial from pretreatment through 1-year-follow-up for both treatments (95% CI [44.65, 20.45], d 1.34), with no significant difference between treatments (95% CI [14.87, 11.21], d 0.16).Conclusions: Acceptance-based procedures may be a viable alternative to traditional CBT techniques in the management of tinnitus. The Internet can improve access to psychological interventions for tinnitus.
|
|
| 23. |
- Hlynsson, Jón Ingi, et al.
(författare)
-
Uncertainty breeds anxiety and depression : The impact of the Russian invasion in Ukraine on a Swedish clinical population receiving internet-based psychotherapy
- 2024
-
Ingår i: Clinical Psychology in Europe. - 2625-3410. ; 6:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Recent global crises, such as the COVID-19 pandemic and the 2022 Russian invasion of Ukraine, have contributed to a rise in the global prevalence of anxiety and depressive disorders. This study examines the indirect impact of the Ukraine war on emotional disorders within a Swedish clinical population. Method: The sample comprised participants (n = 1,222) actively engaged in an internet-based psychotherapeutic intervention (cognitive-behavioral, psychodynamic, and waitlist) when the war broke out. The Patient Health Questionnaire-9 scale and the Generalized Anxiety Disorder-7 scale were used to measure depression and anxiety. Results: Anxiety and depressive symptom severity increased following the war's onset, with an average weekly increase of 0.77-points for anxiety (p = .001, Cohen's d = 0.08) and 0.09-points for depression (p = .70, Cohen's d = 0.01); however, the increase was negligible for depression. Furthermore, higher socioeconomic status (SES) predicted declines in depression and anxiety during the study period, with a 0.69-point average weekly decrease in anxiety (p < .001, Cohen's d = 0.32) and a 1.09-point decrease in depression (p < .001, Cohen's d = 0.48) per one unit increase in SES, suggesting that SES may serve as a protective factor that buffers against psychopathological development during crises. Conclusions: These findings have implications for mitigating the development of psychopathology during crises and interpreting treatment efficacy estimates during such events. Our findings also emphasize the potential of internet-based psychotherapy in addressing emotional disorders during crises. This study presents up-to-date information about the reaction of treatment-seeking individuals to abrupt uncertainty.
|
|
| 24. |
- Klaric, Lucija, et al.
(författare)
-
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
- 2021
-
Ingår i: medRxiv : the preprint server for health sciences. - : Cold Spring Harbor Laboratory. ; , s. 1-28
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
|
|
| 25. |
- Labori, Knut Jørgen, et al.
(författare)
-
Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial
- 2024
-
Ingår i: The Lancet Gastroenterology & Hepatology. - : The Lancet Group. - 2468-1253. ; 9:3, s. 205-217
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.MethodsNORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.FindingsBetween Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.InterpretationThis phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
|
|
| 26. |
- Labori, Knut Jørgen, et al.
(författare)
-
Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial
- 2024
-
Ingår i: The Lancet Gastroenterology & Hepatology. - : Elsevier. - 2468-1253. ; 9:3, s. 205-217
-
Tidskriftsartikel (refereegranskat)abstract
- Background: In patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.Methods: NORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.Findings: Between Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.Interpretation: This phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
|
|
| 27. |
|
|
| 28. |
- Leijon, Mats, et al.
(författare)
-
Wave Energy from the North Sea : Experiences from the Lysekil Research Site
- 2008
-
Ingår i: Surveys in geophysics. - : Springer Science and Business Media LLC. - 0169-3298 .- 1573-0956. ; 29:3, s. 221-240
-
Forskningsöversikt (refereegranskat)abstract
- This paper provides a status update on the development of the Swedish wave energy research area located close to Lysekil on the Swedish West coast. The Lysekil project is run by the Centre for Renewable Electric Energy Conversion at Uppsala University. The project was started in 2004 and currently has permission to run until the end of 2013. During this time period 10 grid-connected wave energy converters, 30 buoys for studies on environmental impact, and a surveillance tower for monitoring the interaction between waves and converters will be installed and studied. To date the research area holds one complete wave energy converter connected to a measuring station on shore via a sea cable, a Wave Rider™ buoy for wave measurements, 25 buoys for studies on environmental impact, and a surveillance tower. The wave energy converter is based on a linear synchronous generator which is placed on the sea bed and driven by a heaving point absorber at the ocean surface. The converter is directly driven, i.e. it has no gearbox or other mechanical or hydraulic conversion system. This results in a simple and robust mechanical system, but also in a somewhat more complicated electrical system.
|
|
| 29. |
- Lindahl, Markus, et al.
(författare)
-
Possibilities and constraints of grid flexible control of todays and tomorrows heat pumps
- 2020
-
Ingår i: 13th IEA Heat Pump Conference..
-
Konferensbidrag (refereegranskat)abstract
- In this article possibilities and constraints of grid flexible control of heat pumps for domestic heating are investigated. By creating dynamic coalitions of heat pumps and control their power consumption, demand response can be offered to the power grid. For a functional power grid, the heat pumps electrical power consumption needs to follow the electrical grids needs accurately. Possibilities to externally control the power consumption of a ground source heat pump has been investigated. Both direct control, where the compressor speed is set directly, and indirect control, achieved with outdoor temperature sensor override, has been evaluated. For the evaluation a test cycle for laboratory testing of a heat pumps grid flexibility has been developed. Based on the test cycle, the heat pumps possibilities to follow the load profile using both direct and indirect control was tested in laboratory. Both control methods were possible to use, with the direct control being significantly more accurate. Using direct control, the power consumption of the compressor managed to be within ±10% of the stated power consumption for 97% of the time.
|
|
| 30. |
- Macdonald-Dunlop, Erin, et al.
(författare)
-
Mapping genetic determinants of 184 circulating proteins in 26,494 individuals to connect proteins and diseases
- 2021
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We performed the largest genome-wide meta-analysis (GWAMA) (Max N=26,494) of the levels of 184 cardiovascular-related plasma protein levels to date and reported 592 independent loci (pQTL) associated with the level of at least one protein (1308 significant associations, median 6 per protein). We estimated that only between 8-37% of testable pQTL overlap with established expression quantitative trait loci (eQTL) using multiple methods, while 132 out of 1064 lead variants show evidence for transcription factor binding, and found that 75% of our pQTL are known DNA methylation QTL. We highlight the variation in genetic architecture between proteins and that proteins share genetic architecture with cardiometabolic complex traits. Using cis-instrument Mendelian randomisation (MR), we infer causal relationships for 11 proteins, recapitulating the previously reported relationship between PCSK9 and LDL cholesterol, replicating previous pQTL MR findings and discovering 16 causal relationships between protein levels and disease. Our MR results highlight IL2-RA as a candidate for drug repurposing for Crohn’s Disease as well as 2 novel therapeutic targets: IL-27 (Crohn’s disease) and TNFRSF14 (Inflammatory bowel disease, Multiple sclerosis and Ulcerative colitis). We have demonstrated the discoveries possible using our pQTL and highlight the potential of this work as a resource for genetic epidemiology.
|
|
| 31. |
- Olsson, Oskar, et al.
(författare)
-
Simulation of distribution system for low temperature district heating in future urban areas – Case study of a planned city district in Gävle
- 2023
-
Ingår i: Proceedings of the 64th International Conference of Scandinavian Simulation Society, SIMS 2023. - : Scandinavian Simulation Society. - 9789180753487
-
Konferensbidrag (refereegranskat)abstract
- In Europe, the prices of natural gas and electricity reached an all-time high in 2022. A way to mitigate high electricity costs is to expand district heating systems in urban areas, this will reduce electric load as well as increase the power generation possibilities in combined heat and power plants. District heating has been the dominant heat supply technology in urban areas in Sweden since the 1980s. However, as the energy efficiency in buildings increase, district heating distribution losses must be reduced to ensure a cost-efficient heat supply. This has led to the idea of the 4th generation district heating which is characterized by low distribution temperatures. In this study, low-temperature district heating distribution in a planned future city district is simulated using a Python-based tool. Two different low-temperature distribution systems are investigated: 1) 2-pipe low-temperature system, and 2) a cascading 3-pipe low-temperature system. The focus is on simulating the distribution losses, temperature drop, and mass flow in the pipe network. The scope of the analysis also includes an investigation of the effect of lower return temperatures on the central district heating network. The results indicate that the low-temperature distribution system with the 2-pipe system performs better than the cascading system when considering distribution losses and temperature drop. The mass flow depends on the temperature demand in the heating systems in the buildings and is considerably high for both low-temperature distribution systems investigated.
|
|
| 32. |
- Ossipov, Dmitri A., et al.
(författare)
-
Combination of Coordination and Releasable Covalent Binding for the Delivery of Antisense Therapeutics by BisphosphonateHyaluronan-Oligonucleotide Conjugates
- 2021
-
Ingår i: ACS APPLIED POLYMER MATERIALS. - : American Chemical Society (ACS). - 2637-6105. ; 3:4, s. 2197-2210
-
Tidskriftsartikel (refereegranskat)abstract
- To address the current problems of delivery of antisense oligonucleotide (ON) therapeutics, a macromolecular platform was proposed based on the combination of metal-ion coordination and releasable covalent conjugation. Two kinds of therapeutic molecules, bisphosphonate (BP) and antisense ON, were conjugated to a natural polysaccharide hyaluronic acid (HA). The use of two linkers with a set of terminal chemoselective groups including Nhydroxysuccinimide carbonate, 2-dithiopyridyl, and aromatic aldehyde allowed orthogonal conjugation of the two therapeutics with subsequent detachment under potentially different conditions. In this work, disulfide linkages of varied steric accessibility were utilized in the linkers allowing the release of the linked therapeutics with different kinetics upon incubation in a reducing buffer. The therapeutics were conjugated to HA via their amino groups, and the self-immolative feature of the linkers permitted traceless release of both drugs as free amines. The obtained dual macromolecular prodrug was converted into either nanogels or macroscopic hydrogels upon coordination with calcium ions via Ca2+-mediated bridging of BP groups. Macroscopic hydrogels demonstrated self-healing properties which are useful for the noninvasive administration of ONs as biodegradable implants. Moreover, transformation of the macromolecular prodrug into a nanogel under dilute conditions is a useful property to prolong the circulation of the prodrug and protect antisense ON therapeutics against degradation in vivo.
|
|
| 33. |
- Räftegård, Oskar, et al.
(författare)
-
Energin under mark ska upp till ytan : Strategisk innovationsagenda för geoenergi
- 2016
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The Swedish Strategic Innovation Agenda for Geoenergy develops a strategy for highlighting the need for geoenergy research, development and innovation in relation to the business community and authorities. Sweden has a strong global position in the field. Geothermal energy is the thirdlargest renewable energy source in Sweden, along with wind power. Currently, approximately 18 TWh of renewable heat per year is supplied to household, industrial and commercial buildings. In addition, there is 12 TWh of cooling. There is a great need for a longterm strategy and financial plan for geoenergy research and innovation in Sweden, in order to maintain and further develop research groups and the country's leading position in the field. Today, Swedish research in this field comprises about 14 fulltime positions at universities, institutes and companies. This is little compared to the existing use of geothermal energy, about 19 TWh, which is worth about 15 billion SEK in consumer sales. It is also little in relation to possible future contributions to sustainable development in Sweden and abroad. The agenda is divided into short independent chapters that are tailored to different target groups/ applications. Each chapter consists of an introduction to the current situation, how geoenergy can strategically contribute to a sustainable society, and what actions/needs are a priority.
|
|
| 34. |
|
|
| 35. |
- Svanborg, Catharina, et al.
(författare)
-
HAMLET kills tumor cells by an apoptosis-like mechanism--cellular, molecular, and therapeutic aspects.
- 2003
-
Ingår i: Advances in Cancer Research. - 0065-230X. ; 88, s. 1-29
-
Forskningsöversikt (refereegranskat)abstract
- HAMLET (human α-lactalbumin made lethal to tumor cells) is a protein-lipid complex that induces apoptosis-like death in tumor cells, but leaves fully differentiated cells unaffected. This review summarizes the information on the in vivo effects of HAMLET in patients and tumor models, on the tumor cell biology, and on the molecular characteristics of the complex. HAMLET limits the progression of human glioblastomas in a xenograft model and removes skin papillomas in patients. This broad anti-tumor activity includes >40 different lymphomas and carcinomas and apoptosis is independent of p53 or bcl-2. In tumor cells, HAMLET enters the cytoplasm, translocates to the perinuclear area, and enters the nuclei, where it accumulates. HAMLET binds strongly to histones and disrupts the chromatin organization. In the cytoplasm, HAMLET targets ribosomes and activates caspases. The formation of HAMLET relies on the propensity of α-lactalbumin to alter its conformation when the strongly bound Ca2+ ion is released and the protein adopts the apo-conformation that exposes a new fatty acid binding site. Oleic acid (C18:1,9 cis) fits this site with high specificity, and stabilizes the altered protein conformation. The results illustrate how protein folding variants may be beneficial, and how their formation in peripheral tissues may depend on the folding change and the availability of the lipid cofactor. One example is the acid pH in the stomach of the breast-fed child that promotes the formation of HAMLET This mechanism may contribute to the protective effect of breastfeeding against childhood tumors. We propose that HAMLET should be explored as a novel approach to tumor therapy.
|
|
| 36. |
- Svensson, Malin, et al.
(författare)
-
alpha-Lactalbumin unfolding is not sufficient to cause apoptosis, but is required for the conversion to HAMLET (human alpha-lactalbumin made lethal to tumor cells).
- 2003
-
Ingår i: Protein Science. - : Wiley. - 1469-896X .- 0961-8368. ; 12:12, s. 2794-2804
-
Tidskriftsartikel (refereegranskat)abstract
- HAMLET (human -lactalbumin made lethal to tumor cells) is a complex of human -lactalbumin and oleic acid (C18:1:9 cis) that kills tumor cells by an apoptosis-like mechanism. Previous studies have shown that a conformational change is required to form HAMLET from -lactalbumin, and that a partially unfolded conformation is maintained in the HAMLET complex. This study examined if unfolding of -lactalbumin is sufficient to induce cell death. We used the bovine -lactalbumin Ca2+ site mutant D87A, which is unable to bind Ca2+, and thus remains partially unfolded regardless of solvent conditions. The D87A mutant protein was found to be inactive in the apoptosis assay, but could readily be converted to a HAMLET-like complex in the presence of oleic acid. BAMLET (bovine -lactalbumin made lethal to tumor cells) and D87A-BAMLET complexes were both able to kill tumor cells. This activity was independent of the Ca2+site, as HAMLET maintained a high affinity for Ca2+ but D87A-BAMLET was active with no Ca2+ bound. We conclude that partial unfolding of -lactalbumin is necessary but not sufficient to trigger cell death, and that the activity of HAMLET is defined both by the protein and the lipid cofactor. Furthermore, a functional Ca2+-binding site is not required for conversion of -lactalbumin to the active complex or to cause cell death. This suggests that the lipid cofactor stabilizes the altered fold without interfering with the Ca2+site.
|
|
| 37. |
|
|
| 38. |
|
|
