| 1. |
- Ferner, Lars Larsson
(författare)
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Schēmatōn tōn en syntaxei trias, quam, ex permissu & adprobatione ampliss. colleg. philosoph. in incluta universitate Upsaliensi, publico philellēnōn examini qua decet modestia, sistunt, auctor s:æ r:æ m:tis alumnus, Laurentius Ferner, L. f. & respondens Canutus N. Lenæus, Uplandi. In auditorio Gustav. majori, ad d. XI. Decemb. a. p. n. C. MDCCIX. Horis ante meridiem solitis.
- 1709
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)
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| 2. |
- Aare, Sudhakar Reddy, 1978-
(författare)
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Intensive Care Unit Muscle Wasting : Skeletal Muscle Phenotype and Underlying Molecular Mechanisms
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Acute quadriplegic myopathy (AQM), or critical illness myopathy, is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients characterized by generalized muscle wasting and weakness of limb and trunk muscles. A preferential loss of the thick filament protein myosin is considered pathognomonic of this disorder, but the myosin loss is observed relatively late during the disease progression. In attempt to explore the potential role of factors considered triggering AQM in sedated mechanically ventilated (MV) ICU patients, we have studied the early effects, prior to the myosin loss, of neuromuscular blockade (NMB), corticosteroids (CS) and sepsis separate or in combination in a porcine experimental ICU model. Specific interest has been focused on skeletal muscle gene/protein expression and regulation of muscle contraction at the muscle fiber level. This project aims at improving our understanding of the molecular mechanisms underlying muscle specific differences in response to the ICU intervention and the role played by the different triggering factors.The sparing of masticatory muscle fiber function was coupled to an up-regulation of heat shock protein genes and down-regulation of myostatin are suggested to be key factors in the relative sparing of masticatory muscles. Up-regulation of chemokine activity genes and down-regulation of heat shock protein genes play a significant role in the limb muscle dysfunction associated with sepsis. The effects of corticosteroids in the development of limb muscle weakness reveals up-regulation of kinase activity and transcriptional regulation genes and the down-regulation of heat shock protein, sarcomeric, cytoskeletal and oxidative stress responsive genes. In contrast to limb and craniofacial muscles, the respiratory diaphragm muscle responded differently to the different triggering factors. MV itself appears to play a major role for the diaphragm muscle dysfunction. By targeting these genes, future experiments can give an insight into the development of innovative treatments expected at protecting muscle mass and function in critically ill ICU patients.
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| 3. |
- Aripaka, Karthik, 1986-
(författare)
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Studies on the biological functions of interaction between components in Wnt, TGF-β and HIF pathways for cancer progression
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer is a disease that involves aggressive changes in the genome and aberrant signals between the living cells. Signalling pathways such as TGF-β (Transforming growth factor-β), Wnt, EGF (epidermal growth factor) and HIF (Hypoxia-inducible factor) evolved to regulate growth and development in mammals. These factors are also implicated for tumorigenesis due to failure or aberrant expression of components in these pathways. Cancer progression is a multistep process, and these steps reflect genetic alterations driving the progressive transformation of healthy human cells into highly malignant derivatives. Many types of cancers are diagnosed in the human population, such as head & neck, cervical, brain, liver, colon, prostate, uterine, breast, and renal cell cancer.Prostate cancer is the second most common cancer and one of the foremost leading cancer-related deaths in men in the world. Aberrant Wnt3a signals promote cancer progression through the accumulation of β-Catenin. In the first paper, we have elucidated intriguing functions for Tumour necrosis factor receptor-associated factor 6 (TRAF6) as a coregulatory factor for the expression of Wnt-target genes which was confirmed in vivo by using CRISPR/Cas9 genomic editing, in zebrafish. Our data suggest that Wnt3a promotes TRAF6 interaction with Wnt components, and TRAF6 is required for gene expression of β-Catenin as well as for the Wnt-ligand co-receptor LRP5. From the in vivo studies, we elucidated positive regulation of TRAF6, which is crucial for survival and development of zebrafish. This study identifies TRAF6 as an evolutionary conserved co-regulatory protein in the Wnt pathway that also promotes the progression of prostate and colorectal cancer due to its positive effects on Wnt3a signalling.Hypoxia is a condition due to O2 deprivation, and Hypoxia-inducible factors (HIF) transcription factors are responsible for the maintenance of oxygen homeostasis in living cells. Irregularities in these HIF transcription factors trigger pathological cellular responses for initiation and progression of malignant cancers. Renal cell carcinoma, malignant cancer arising in renal parenchyma and renal pelvis and, hypoxia plays a vital role in its progression. In the second paper, we have investigated the clinicopathological relevance of several hypoxic and TGF-β component proteins such as HIF-1α/2α/3α, TGF-β type 1 receptor (ALK5-FL) and the intracellular domain of ALK5 (ALK5-ICD), SNAI1 and PAI-1 with patient survival in clear cell renal cell carcinoma (ccRCC). We showed that HIF-2α associated with low cancer-specific survival. HIF-2α and SNAI1 positively correlated with ALK5-ICD, pSMAD2/3, PAI-1 and SNAI1 with HIF-2α; HIF-1α positively correlated with pSMAD2/3. Further, under normoxic conditions, our data suggest that ALK5 interacts with HIF-1α and HIF-2α, and promotes their expression and target genes such as GLUT1 and CA9, in a VHL dependent manner through its kinase activity. These findings shed light on the critical aspect of cross-talk between TGF-β signalling and hypoxia pathway, and also the novel finding of an interaction between ALK5 and HIF-α might provide a more in-depth understanding of mechanisms behind tumour progressionIn the third paper, an ongoing study, we investigated the role of HIF-3α in the progression of Renal cell carcinoma and its association with the components of TGF-β and HIF pathways. We have observed increased levels of HIF-3α in ccRCC and pRCC (papillary renal cell carcinoma) which are associated with advanced tumour stage, metastasis and larger tumours. Also, we found HIF-3α show a significant positive association with pro-invasive gene SNAI1, which is a crucial regulator of epithelial to mesenchymal transition. TRAF6 an E3 ligase known to be a prognostic marker in RCC and we observed HIF-3α associates with TRAF6.
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| 4. |
- Banduseela, Varuna Chaminda, 1972-
(författare)
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Molecular And Cellular Networks in Critical Illness Associated Muscle Weakness : Skeletal Muscle Proteostasis in the Intensive Care Unit
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Critical illness associated muscle weakness and muscle dysfunction in intensive care unit (ICU) patients lead to severe morbidity and mortality as well as significant adverse effect on quality of life. Immobilization, mechanical ventilation, neuromuscular blocking agents, corticosteroids, and sepsis have been implicated as important risk factors, but the underlying molecular and cellular mechanisms remain unclear. A unique porcine ICU model was employed to investigate the effect of these risk factors on the expression profiles, gene expression and contractile properties of limb and diaphragm muscle, in the early phase of ICU stay. This project has focused on unraveling the underlying molecular and cellular pathways or networks in response to ICU and critical illness interventions.Upregulation of heat shock proteins indicated to play a protective role despite number of differentially transcribed gene groups that would otherwise have a negative effect on muscle fiber structure and function in response to immobilization and mechanical ventilation. Mechanical ventilation appears to play a critical role in development of diaphragmatic dysfunction. Impaired autophagy, chaperone expression and protein synthesis are indicated to play a pivotal role in exacerbating muscle weakness in response to the combined effect of risk factors in ICU. These results may be of therapeutic importance in alleviating critical illness associated muscle weakness.
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| 5. |
- Borgenvik, Anna, 1987-
(författare)
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MYC-driven Medulloblastoma : New Targeted Therapies and Mechanisms of Recurrence
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Medulloblastoma is the most common malignant brain tumor of childhood. It arises in the posterior fossa but presents with distinct histological and molecular features. Hence, medulloblastoma is divided into four molecular subgroups, WNT, SHH, Group 3, and Group 4. The overall 5-year survival is ~70% across subgroups but varies with high- and low-risk disease. Standard treatment of medulloblastoma consists of maximal safe tumor resection, radiotherapy, and adjuvant chemotherapy. Despite the rather high success rate of treatment for many patients it also comes with severe long-term debilitating side effects. MYC proteins are master regulators of gene expression often deregulated in cancer. MYC family members MYC and MYCN share similar roles and are found overexpressed or amplified in most medulloblastoma subgroups and correlate with a poor prognosis. Medulloblastoma dissemination and recurrence patterns differ between subgroups but are always associated with a poor prognosis. Recurrent medulloblastoma is not yet curable and will lead to death. In this thesis, we present the first transgenic mouse model of medulloblastoma recurrence and highlight the role of the transcription factor SOX9 in MYC-driven relapse mechanisms. By studying this recurrence model and matched primary-recurrent patient samples we propose a mechanism in which treatment-refractory and quiescent SOX9-positive cells in Group 3 medulloblastoma are necessary for tumor relapse, and how the recurrent tumors can be specifically treated with MGMT inhibitors and doxorubicin.In addition, we address efficient treatment options of primary MYC-driven medulloblastoma where BET bromodomain inhibition (JQ1) in combination with CDK2 inhibition (milciclib) of human Group 3 medulloblastoma will lead to apoptosis and prolonged survival of xenografted mice. This is explained by a dual hit on MYC transcriptional output and MYC protein stability exerted by JQ1 and milciclib respectively. Finally, in a different novel transgenic model of MYC-driven medulloblastoma, we show how temporal Cdk2 knock-out has no effect on MYC protein stability but slows down proliferation and prolongs survival of allografted mice. The need for better treatments and increased understanding of recurrent medulloblastoma is huge. To that end, this thesis focuses on and addresses novel treatments, the role of the cell cycle protein CDK2 as well as relapse mechanisms depending on dormant SOX9-positive cells in highly aggressive MYC-driven medulloblastoma.
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| 7. |
- Cristea, Alexander, 1966-
(författare)
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Effects of Ageing and Physical Activity on Regulation of Muscle Contraction
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this study were to investigate the mechanisms underlying (1) the ageing-related motor handicap at the whole muscle, cellular, contractile protein and myonuclear levels; and (2) ageing-related differences in muscle adaptability.In vivo muscles function was studied in the knee extensors. Decreases were observed in isokinetic and isometric torque outputs in old age in the sedentary men and women and elite master sprinters. A 20-week long specific sprint and resistance training successfully improved the maximal isometric force and rate of force development in a subgroup of master sprinters.In vitro measurements were performed in muscle biopsies from the vastus lateralis muscle. Immunocytochemical and contractile measurements in single membrane permeabilized muscle fibres demonstrated ageing- and gender-related changes at the myofibrillar level. In sedentary subjects, data showed a preferential decrease in the size of muscle fibres expressing type IIa MyHC in men, lower force generating capacity in muscle fibres expressing the type I MyHC isoform in both men and women and lower maximum velocity of unloaded shortening (V0) in fibres expressing types I and IIa MyHC isoforms in both men and women. The master sprinters also experienced the typical ageing-related reduction in the size of fast-twitch fibres, a shift toward a slower MyHC isoform profile and a lower V0 of type I MyHC fibres, which played a role in the decline in explosive force production capacity. The fast-twitch fibre area increased after the resistance training period. A model combining single muscle fibre confocal microscopy with a novel algorithm for 3D imaging of myonuclei in single muscle fibre segments was introduced to study the spatial organisation of myonuclei and the size of individual myonuclear domains (MNDs). Significant changes in the MND size variability and myonuclear organization were observed in old age, irrespective gender and fibre type. Those changes may influence the local quantity of specific proteins per muscle fibre volume by decreased and/or local cooperativity of myonuclei in a gender and muscle fibre specific manner.In conclusion, the ageing-related impairments in in vivo muscle function were related to significant changes in morphology, contractile protein expression and regulation at the muscle fibre level. It is suggested that the altered myonuclear organisation observed in old age impacts on muscle fibre protein synthesis and degradation with consequences for the ageing-related changes in skeletal muscle structure and function. However, the improved muscle function in response to a 20-week intense physical training regime in highly motivated physically active old subjects demonstrates that all ageing-related in muscle function are not immutable.
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