| 1. |
- Dimopoulos, Meletios A., et al.
(författare)
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Safety and efficacy of pomalidomide plus low-dose dexamethasone in STRATUS (MM-010) : A phase 3b study in refractory multiple myeloma
- 2016
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 128:4, s. 497-503
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Tidskriftsartikel (refereegranskat)abstract
- Patients with relapsed and/or refractory multiple myeloma (RRMM) have poor prognosis. The STRATUS study assessed safety and efficacy of pomalidomide plus low-dose dexamethasone in the largest cohort to date of patients with RRMM. Patients who failed treatment with bortezomib and lenalidomide and had adequate prior alkylator therapy were eligible. Pomalidomide 4 mg was given on days 1-21 of 28-day cycles with low-dose dexamethasone 40 mg (20 mg for patients aged >75 years) on days 1, 8, 15, and 22 until progressive disease or unacceptable toxicity. Safety was the primary end point; secondary end points included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Among 682 patients enrolled, median age was 66 years, and median time since diagnosis was 5.3 years. Median number of prior regimens was 5. Most patients were refractory to both lenalidomide and bortezomib (80.2%). Median follow-up was 16.8 months; median duration of treatment was 4.9 months. Most frequent grade 3/4 treatment-emergent adverse events were hematologic (neutropenia [49.7%], anemia [33.0%], and thrombocytopenia [24.1%]). Most common grade 3/4 nonhematologic toxicities were pneumonia (10.9%) and fatigue (5.9%). Grade 3/4 venous thromboembolism and peripheral neuropathy were rare (1.6% each). The ORR was 32.6%, and the median DOR was 7.4 months. Median PFS and OS were 4.6 months and 11.9 months, respectively. We present the largest trial to date evaluating pomalidomide plus low-dose dexamethasone in patients with RRMM, further confirming that this regimen offers clinically meaningful benefit and is generally well tolerated. www.Clinicaltrials.gov identifier NCT01712789.
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| 2. |
- Heinonen, Ilkka, 1982-, et al.
(författare)
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Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement
- 2020
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Ingår i: Scientific Reports. - London : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Göttingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitrosoredox balance, increased superoxide production—principally due to endothelial nitric oxide synthase (eNOS) uncoupling—reduced nitric oxide (NO) production, alterations in myocardial gene-expression— particularly genes related to glucose and fatty acid metabolism—and mitochondrial dysfunction. These abnormalities were accompanied by increased passive force of isolated cardiomyocytes, and impaired LV diastolic function, evidenced by reduced LV peak untwist velocity and increased E/e′. However, LV weight, volume, collagen content, and cardiomyocyte cross-sectional area were unchanged at this stage of DMetD. In conclusion, DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profle and mitochondrial dysfunction. These molecular alterations are associated with stifening of the cardiomyocytes and early diastolic dysfunction before any structural cardiac remodeling occurs. Therapies should be directed to ameliorate these early DMetDinduced myocardial changes to prevent the development of overt cardiac failure. © 2020, The Author(s).
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| 3. |
- Moreau, Philippe, et al.
(författare)
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Adverse event management in patients with relapsed and refractory multiple myeloma taking pomalidomide plus low-dose dexamethasone : A pooled analysis
- 2017
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441. ; 99:3, s. 199-206
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Heavily pretreated patients with relapsed and refractory multiple myeloma are susceptible to treatment-related adverse events (AEs). Managing AEs are important to ensure patients continue therapy long enough to receive the best clinical benefit. Data from the MM-002, MM-003, and MM-010 trials were pooled to further characterize the safety profile of pomalidomide plus low-dose dexamethasone and AE management. Methods: This analysis included 1088 patients who received ≥ 2 prior therapies, including lenalidomide and bortezomib, and progressed ≤ 60 days of last therapy. Patients received 28-day cycles of pomalidomide 4 mg/day on days 1-21 and low-dose dexamethasone 40 mg (20 mg if aged > 75 years) weekly until disease progression or unacceptable toxicity. Thromboprophylaxis was required. Results: The most common grade 3/4 AEs were neutropenia (56.2%), anemia (32.3%), and thrombocytopenia (25.8%), which occurred within the first few cycles of treatment. Grade 3/4 infections occurred in 33.7% patients, of whom 13.9% had pneumonia, and 40.3% had neutropenia. Pomalidomide dose reductions or interruptions were reported in 24.2% and 66.0% of patients, respectively. AEs were managed by dose modifications and/or supportive care. Conclusions: Pomalidomide plus low-dose dexamethasone showed an acceptable safety profile, and AEs were well managed according to study protocols and established guidelines.
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| 4. |
- Uurasmaa, Tytti-Maria, et al.
(författare)
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Melanoma Impairs Mouse Heart Function Which Short-Term Exercise Cannot Restore
- 2022
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Ingår i: The FASEB Journal. - Hoboken, NJ : John Wiley & Sons. - 0892-6638 .- 1530-6860. ; 36:S1
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate whether melanoma impairs intrinsic heart function in mice and whether short-term voluntary running wheel exercise could reduce the possible negative effects. Additionally, we investigated whether changes in cell size, capillary density, calcium channel levels, metabolic enzyme activities or oxidative stress could explain the possible changes in heart function. Advanced melanoma has been shown to cause cardiac muscle wasting and influence heart function in vivo, we hypothesized that melanoma would also impair intrinsic heart function, which has not been investigated previously. We also hypothesized that voluntary short-term exercise could reduce the effects of melanoma on cardiac function since exercise training is known to improve cardiovascular function and reduce the negative effects of some cancers. Male mice were divided into untrained tumor-free group (control) and untrained melanoma group and trained melanoma group. The mice did voluntary running-wheel exercise until predetermined tumor size after which their hearts were isolated. The cardiac function was measured in retrograde perfusion at a constant pressure in multiple oxygen levels using Langendorff apparatus. The molecular and tissue level markers were measured afterwards. The melanoma animals were not cachectic as indicated lack of body weight loss. The rate of pressure production, pressure amplitude and rate of pressure decline were all significantly lower in the isolated hearts of the melanoma animals as compared to tumor-free animals. However, the heart function did not differ between the untrained and trained melanoma groups. Furthermore, there were no differences between the groups in the calcium channel levels, reactive oxygen species, catalase activity, lipid peroxidation or citrate synthase and lactate dehydrogenase activity. However, mice from both melanoma groups had significantly lower superoxide dismutase activity as compared to tumor-free animals, which might reduce the heart's ability to respond to possible changes in oxidative stress. Exercise trained animals had higher capillary density, but their cell size and heart weights did not significantly differ from the untrained groups. Running wheel exercise did not affect the final tumor growth either even though there was tendency at the beginning of the experiment that running wheel exercise could slow down the tumor growth. One reason for this could be that when melanoma proceeded, the mouse running activity reduced significantly. In conclusion, melanoma is an aggressive cancer that impairs intrinsic heart function even when no cachexia is present. The aggressiveness of melanoma also prevented the short-term voluntary exercise from alleviating the changes caused by melanoma. Future studies should combine the training to medical cancer treatment in order to estimate whether exercise training could be beneficial as adjunct therapy in melanoma treatment. © FASEB.
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| 5. |
- Uurasmaa, Tytti-Maria, et al.
(författare)
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Short-term exercise affects cardiac function ex vivo partially via changes in calcium channel levels, without influencing hypoxia sensitivity
- 2021
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Ingår i: Journal of physiology and biochemistry. - Dordrecht : Springer Netherlands. - 1138-7548 .- 1877-8755. ; 77:4, s. 639-651
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Tidskriftsartikel (refereegranskat)abstract
- Exercise is known to improve cardiac recovery following coronary occlusion. However, whether short-term exercise can improve cardiac function and hypoxia tolerance ex vivo independent of reperfusion injury and the possible role of calcium channels in improved hypoxia tolerance remains unknown. Therefore, in the current study, heart function was measured ex vivo using the Langendorff method at different oxygen levels after a 4-week voluntary wheel-running regimen in trained and untrained male mice (C57Bl/6NCrl). The levels of cardiac Ca2+-channels: L-type Ca2+-channel (CACNA1C), ryanodine receptor (RyR-2), sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2), and sodium-calcium exchanger were measured using western blot. Trained mice displayed lower cardiac afterload pressure generation capacity (rate and amplitude), but unaltered hypoxia tolerance when compared to untrained mice with similar heart rates. The level of CACNA1C positively correlated with the pressure generation rate and amplitude. Furthermore, the CACNA1C-RYR-2 ratio also positively correlated with the pressure generation rate. While the 4-week training period was not enough to alter the intrinsic cardiac hypoxia tolerance, interestingly it decreased pressure generation capacity and slowed pressure decreasing capacity in the mouse hearts ex vivo. This reduction in pressure generation rate could be linked to the level of channel proteins in sarcolemmal Ca2+-cycling in trained mice. However, the Ca2+-channel levels did not differ significantly between the groups, and thus, the level of calcium channels cannot fully explain all the functional alterations, despite the detected correlations. Therefore, additional studies are warranted to reveal further mechanisms that contribute to the reduced intrinsic capacity for pressure production in trained mouse hearts. © 2021, The Author(s).
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| 6. |
- Uurasmaa, Tytti Maria, et al.
(författare)
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Subcutaneous B16 melanoma impairs intrinsic pressure generation and relaxation of the heart, which are not restored by short-term voluntary exercise in mice
- 2022
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Ingår i: American Journal of Physiology. Heart and Circulatory Physiology. - Rockville : American Physiological Society. - 0363-6135 .- 1522-1539. ; 322:6, s. H1044-H1056
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate whether subcutaneous melanoma impairs intrinsic cardiac function and hypoxia tolerance in mice. In addition, it was investigated whether these changes could be prevented by voluntary wheel-running exercise. The roles of different molecular pathways were also analyzed. Male mice (C57Bl/6NCrl) were divided into unexercised tumor-free group, unexercised melanoma group, and exercised melanoma group. The experiment lasted 2.7 ± 0.1 wk (determined by the tumor size) after which the heart function was measured in different oxygen levels ex vivo using Langendorff method. All the melanoma mice had lower pressure amplitude (50.3%), rate of pressure production (54.1%), and decline (52.5%) in hearts ex vivo when compared with tumor-free group. There were no functional differences between the two melanoma groups. All the groups had similar weight changes, heart weights, cardiomyocyte sizes, levels of Ca2+ channels, energy metabolism enzyme activities, lipid peroxidation, and reactive oxygen species in their cardiac tissue homogenates. However, all the melanoma mice had 7.4% lower superoxidase dismutase activity compared with the control animals, which might reduce the ability of the heart to react to changes in oxidative stress. The exercising melanoma group had a 28.6% higher average heart capillary density compared with the unexercised melanoma group. Short-term wheel running did not affect the tumor growth. In conclusion, subcutaneous melanoma seems to impair intrinsic heart function even before cachexia, and these functional alterations were not caused by any of the measured molecular markers. Short-term voluntary wheel-running exercise was insufficient to alleviate the intrinsic cardiac impairments caused by melanoma.NEW & NOTEWORTHY Melanoma has been shown to induce cardiac atrophy and impair cardiac function in vivo, however, it has not been investigated how melanoma affects the intrinsic heart function. Here, we showed that subcutaneous melanoma can impair intrinsic heart function in noncachectic mice, decreasing the heart's pressure production and relaxation. In addition, we investigated whether short-term voluntary wheel-running exercise could attenuate the impairment of intrinsic cardiac function. However, our results do not seem to support this hypothesis. © 2022 the American Physiological Society.
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