| 1. |
- Bazzurro, V., et al.
(författare)
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Involvement of GABA(A) receptors containing alpha(6) subtypes in antisecretory factor activity on rat cerebellar granule cells studied by two-photon uncaging
- 2022
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Ingår i: European Journal of Neuroscience. - : Wiley. - 0953-816X .- 1460-9568. ; 56:5, s. 4505-4513
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Tidskriftsartikel (refereegranskat)abstract
- The antisecretory factor (AF) is an endogenous protein that counteracts intestinal hypersecretion and various inflammation conditions in vivo. It has been detected in many mammalian tissues and plasma, but its mechanisms of action are largely unknown. To study the pharmacological action of the AF on different GABA(A) receptor populations in cerebellar granule cells, we took advantage of the two-photon uncaging method as this technique allows to stimulate the cell locally in well-identified plasma membrane parts. We compared the electrophysiological response evoked by releasing a caged GABA compound on the soma, the axon initial segment and neurites before and after administering AF-16, a 16 amino acids long peptide obtained from the amino-terminal end of the AF protein. After the treatment with AF-16, we observed peak current increases of varying magnitude depending on the neuronal region. Thus, studying the effects of furosemide and AF-16 on the electrophysiological behaviour of cerebellar granules, we suggest that GABA(A) receptors, containing the alpha(6) subunit, may be specifically involved in the increase of the peak current by AF, and different receptor subtype distribution may be responsible for differences in this increase on the cell.
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| 2. |
- Chen, Y, et al.
(författare)
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Increase in insulin-like growth factor I in hypertrophying smooth muscle
- 1994
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Ingår i: American Journal of Physiology - Endocrinology and Metabolism. - 1522-1555. ; 266:2 Pt 1, s. 224-229
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Tidskriftsartikel (refereegranskat)abstract
- The present study focuses on the role of the insulin-like growth factor (IGF) system in the development of smooth muscle hypertrophy. Hypertrophy was initiated by partial ligation of portal vein or urethra in female Sprague-Dawley rats weighing approximately 220 g. Levels of mRNA were analyzed by solution hybridization. Seven days after ligation, the wet weight of the portal vein was increased about threefold and the concentration of IGF-I mRNA was increased fourfold. The bladder wet weight was increased twofold 3 days after ligation and fourfold 10 days after ligation. IGF-I mRNA in the bladder was elevated 3-fold after 3 days and 2.5-fold after 10 days, whereas IGF binding protein 2 mRNA was increased approximately 2-fold after 3 days and 5-fold after 10 days. IGF-I receptor mRNA in the hypertrophying bladder remained unchanged. Increased levels of IGF-I were demonstrated with immunohistochemistry in both hypertrophying portal vein and urinary bladder. The results show a specific increase in IGF-I mRNA as well as an increased IGF-I immunoreactivity during hypertrophy of smooth muscle, which suggests that the local IGF-system may play a role in smooth muscle hypertrophy.
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| 3. |
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| 4. |
- Borenäs, Marcus, et al.
(författare)
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ALK signaling primes the DNA damage response sensitizing ALK-driven neuroblastoma to therapeutic ATR inhibition
- 2024
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - 1091-6490. ; 121:1
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Tidskriftsartikel (refereegranskat)abstract
- High-risk neuroblastoma (NB) is a significant clinical challenge. MYCN and Anaplastic Lymphoma Kinase (ALK), which are often involved in high-risk NB, lead to increased replication stress in cancer cells, suggesting therapeutic strategies. We previously identified an ATR (ataxia telangiectasia and Rad3-related)/ALK inhibitor (ATRi/ALKi) combination as such a strategy in two independent genetically modified mouse NB models. Here, we identify an underlying molecular mechanism, in which ALK signaling leads to phosphorylation of ATR and CHK1, supporting an effective DNA damage response. The importance of ALK inhibition is supported by mouse data, in which ATRi monotreatment resulted in a robust initial response, but subsequent relapse, in contrast to a 14-d ALKi/ATRi combination treatment that resulted in a robust and sustained response. Finally, we show that the remarkable response to the 14-d combined ATR/ALK inhibition protocol reflects a robust differentiation response, reprogramming tumor cells to a neuronal/Schwann cell lineage identity. Our results identify an ability of ATR inhibition to promote NB differentiation and underscore the importance of further exploring combined ALK/ATR inhibition in NB, particularly in high-risk patient groups with oncogene-induced replication stress.
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| 5. |
- Hultborn, Ragnar, 1946, et al.
(författare)
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Ex Vivo Vascular Imaging and Perfusion Studies of Normal Kidney and Tumor Vasculature
- 2024
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Ingår i: CANCERS. - 2072-6694. ; 16:10
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Tidskriftsartikel (refereegranskat)abstract
- Simple Summary Organs as well as cancer require a supply of nutrients and oxygen and removal of waste products. These tasks are carried out by the vascular system. Knowledge of the vascular properties in organs and tumors is key for understanding normal and abnormal function. For cancer, vascular function is also highly relevant to understand response to treatment, metastasis, and tumor progression. In this study, we use various techniques to characterize the vascular tree and flow in kidneys with kidney cancer. We connected kidneys to a perfusion system and used barium sulphate contrast to visualize the vascular architecture contact microangiography. Immunohistochemistry was used to visualize the vessels in relation to perfusion. The vascular resistance was measured using the radioactive microspheres and in cases that were feasible, we used micro-CT to characterize the vascular tree. This work aims to suggest the use of these techniques for any organ or tumor available for ex vivo perfusion.Abstract This work describes a comprehensive study of the vascular tree and perfusion characteristics of normal kidney and renal cell carcinoma. Methods: Nephrectomy specimens were perfused ex-vivo, and the regional blood flow was determined by infusion of radioactive microspheres. The vascular architecture was characterized by micronized barium sulphate infusion. Kidneys were subsequently sagitally sectioned, and autoradiograms were obtained to show the perfusate flow in relation to adjacent contact X-ray angiograms. Vascular resistance in defined tissue compartments was quantified, and finally, the tumor vasculature was 3D reconstructed via the micro-CT technique. Results show that the vascular tree of the kidney could be distinctly defined, and autoradiograms disclosed a high cortical flow. The peripheral resistance unit of the whole perfused specimen was 0.78 +/- 0.40 (n = 26), while that of the renal cortex was 0.17 +/- 0.07 (n = 15 with 114 samples). Micro-CT images from both cortex and medulla defined the vascular architecture. Angiograms from the renal tumors demonstrated a significant vascular heterogeneity within and between different tumors. A dense and irregular capillary network characterized peripheral tumor areas, whereas central parts of the tumors were less vascularized. Despite the dense capillarity, low perfusion through vessels with a diameter below 15 mu m was seen on the autoradiograms. We conclude that micronized barium sulphate infusion may be used to demonstrate the vascular architecture in a complex organ. The vascular resistance was low, with little variation in the cortex of the normal kidney. Tumor tissue showed a considerable vascular structural heterogeneity with low perfusion through the peripheral nutritive capillaries and very poor perfusion of the central tumor, indicating intratumoral pressure exceeding the perfusion pressure. The merits and shortcomings of the various techniques used are discussed.
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| 7. |
- Pagoldh, Maria, et al.
(författare)
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Faecal analysis and plasma complement factor 3c levels at admission for an acute attack of ulcerative colitis are predictive of the need for colectomy
- 2014
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Ingår i: European Journal of Gastroenterology and Hepathology. - : Ovid Technologies (Wolters Kluwer Health). - 0954-691X .- 1473-5687. ; 26:3, s. 295-300
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundUlcerative colitis is a chronic inflammation limited to the large bowel. Early identification of reliable predictive markers addressing the risk of need for colectomy in a severe attack of ulcerative colitis is of crucial importance.ObjectiveTo evaluate faecal characteristics and peripheral blood tests as predictive markers for subsequent risk of colectomy in a severe attack of ulcerative colitis.MethodsThis was an observational study. Samples were collected in a cohort of 18 patients with a severe attack of ulcerative colitis. A panel of selected variables was evaluated (faecal characteristics, peripheral blood samples including complement factor 3c, circulating cytokines and antisecretory factor) for ability to predict colectomy. The patients were observed for up to 58 months (median 37.5, range 0.5-58 months) and allocated to one of two groups depending on the clinical outcome on the basis of the need for colectomy.ResultsSeven patients underwent colectomy. The present study showed a positive correlation between increased bowel movements (P=0.01), faecal weight/bowel movement (P=0.03) and complement factor 3c levels (P=0.01) and a need for later colectomy. None of the other laboratory markers investigated were shown to be predictive of risk for later colectomy.ConclusionEarly faecal analysis and measurement of complement factor 3c may be useful as predictive markers of the need for colectomy related to a severe attack of ulcerative colitis.
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