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41.
  • Söderquist, Fanny (författare)
  • Melatonin in the gastrointestinal tract
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Melatonin is recognised as the pineal hormone regulating sleep and circadian rhythm. It has also been identified in peripheral tissues (mainly in animals) and thought to display a variety of actions, including anti-inflammatory properties, regulation of gastrointestinal (GI) functions, glucose homeostasis and beneficial effects in different tumour types. Patients with irritable bowel disorder commonly exhibit psychiatric co-morbidity and disturbances of the gut-brain axis have been proposed to play a role in these disorders. The focus of this thesis was to study melatonin and melatonin receptors in the normal human GI tract, the pancreas and small intestinal neuroendocrine tumours. The thesis also explores the complex relationship between GI symptoms and underlying psychiatric traits in the context of elevated levels of peripheral melatonin during waking hours.In paper I-II, tissue samples from the normal human GI tract and pancreas and tumour tissue from small intestinal neuroendocrine tumours were analysed for expression of melatonin and melatonin receptors using immunohistochemistry. For tumour patients, melatonin was also analysed in plasma and set in relation to symptoms and outcome. In paper III-IV, a cohort of young adults (18-25 years) seeking psychiatric care was examined for GI symptoms, melatonin levels in saliva, depressive symptoms and anxiety traits. Psychiatric assessments were performed using structured or semi structured interviews. Depressive symptoms were measured using the self-rating version of the Montgomery-Åsberg Depression Rating Scale; GI symptoms were measured using the Gastrointestinal Symptoms Rating Scale for Irritable Bowel Syndrome; and personality traits were evaluated using the Swedish Universities Scales of Personality.Melatonin and melatonin receptors were widely expressed in the normal human gut and pancreas (paper I) but even in small intestinal neuroendocrine tumours known to produce serotonin (paper II). The intensity of the melatonin immunoreactivity in tumour tissue was found to correlate with lower proliferation index. After treatment, plasma levels of melatonin were reduced in tumour patients. Young adult patients seeking psychiatric care reported more GI symptoms than healthy controls, regardless of the currently active psychotropic medication. The level of GI symptoms was associated with severity of depressive symptoms and trait anxiety (paper III). Higher postprandial levels of melatonin were associated with the GI symptoms of bloating and pain (paper IV).In summary, these findings demonstrate the widespread presence of melatonin in the human gut and confirm a link between melatonin, psychiatric health and GI symptoms.
42.
  • Toporski, Jacek, et al. (författare)
  • High-dose iodine-131-metaiodobenzylguanidine with haploidentical stem cell transplantation and posttransplant immunotherapy in children with relapsed/refractory neuroblastoma.
  • 2009
  • Ingår i: Biology of Blood and Marrow Transplantation. - Elsevier. - 1083-8791. ; 15:9, s. 1077-1085
  • Tidskriftsartikel (refereegranskat)abstract
    • We evaluated the feasibility and efficacy of using high-dose iodine-131-metaiodobenzylguanidine ((131)I-MIBG) followed by reduced-intensity conditioning (RIC) and transplantation of T cell-depleted haploidentical peripheral blood stem cells (designated haplo-SCT) to treat relapsing/refractory neuroblastoma (RRNB). Five RRNB patients were enrolled: 4 with relapse (3 after autologous SCT) and 1 with induction therapy failure. The preparative regimen included high-dose (131)I-MIBG on day -20, followed by fludarabine (Flu), thiotepa, and melphalan (Mel) from day -8 to -1. Granulocyte-colony stimulating factor (G-CSF)-mobilized, T cell-depleted haploidentical paternal stem cells were infused on day 0 together with cultured donor mesenchymal stem cells. A single dose of rituximab was given on day +1. After cessation of short immunosuppression (mycophenolate, OKT3), 4 children received donor lymphocyte infusion (DLI). (131)I-MIBG infusion and RIC were well tolerated. All patients engrafted. No primary acute graft-versus-host disease (aGVHD) was observed. Four children developed aGVHD after DLI and were successfully treated. Analysis of immunologic recovery showed fast reappearance of potentially immunocompetent natural killer (NK) and T cells, which might have acted as effector cells responsible for the graft-versus-tumor (GVT) effect. Two children are alive and well, with no evidence of disease 40 and 42 months after transplantation. One patient experienced late progression with new bone lesions (sternum) 38 months after haplo-SCT, and is being treated with local irradiation and reinstituted DLI. One patient rejected the graft, was rescued with autologous backup, and died of progressive disease 5 months after transplantation. Another child relapsed 7 months after transplantation and died 5 months later. High-dose (131)I-MIBG followed by RIC and haplo-SCT for RRNB is feasible and promising, because 2 of 5 children on that regimen achieved long-lasting remission. Further studies are needed to evaluate targeted therapy and immune-mediated tumor control in high-risk neuroblastoma.
43.
  • Wängberg, Bo, 1953-, et al. (författare)
  • Intraoperative detection of somatostatin-receptor-positive neuroendocrine tumours using indium-111-labelled DTPA-D-Phe1-octreotide.
  • 1996
  • Ingår i: British journal of cancer. - 0007-0920. ; 73:6, s. 770-5
  • Tidskriftsartikel (refereegranskat)abstract
    • After injection of 111In-labelled DTPA-D-Phe1-octreotide, intraoperative tumour localisation was performed using a scintillation detector in 23 patients with neuroendocrine tumours. Count rates from suspect tumour lesions and adjacent normal tissue were expressed as a ratio before (Rin situ) and after (Rex vivo) excision. 111In activity concentration ratios of tumour tissue to blood (T/B) were determined in a gamma counter. In patients with midgut carcinoids, (all scintigraphy positive), false Rin situ recordings were found in 4/29 macroscopically identified tumours. T/B ratios were all high (27-650). In patients with medullary thyroid carcinomas (eight out of ten scintigraphy positive), misleading Rin situ results were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in midgut carcinoids. Two out of four patients with endocrine pancreatic tumours had positive scintigraphy, reliable intraoperative measurements and very high T/B ratios (910-1500). One patient with a gastric carcinoid had correct measurements in situ and ex vivo with high T/B ratios (71-210). In situ measurements added little information to preoperative scintigraphy and surgical findings using the present detection system. Rex vivo measurements were more reliable. The very high T/B ratios seen in midgut carcinoids and some endocrine pancreatic tumours would be favourable for future radiation therapy via somatostatin receptors.
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44.
  • Carlzon, Daniel, et al. (författare)
  • Insulin-like growth factor I and risk of incident cancer in elderly men - results from MrOS (Osteoporotic Fractures in Men) in Sweden.
  • 2016
  • Ingår i: Clinical endocrinology. - 1365-2265. ; 84:5
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectiveStudies of the association between circulating IGF-I and cancer risk have shown conflicting results. We have previously observed a U-shaped association between IGF-I and cancer mortality. This study test the hypotheses of a U-shaped association between IGF-I and incident cancer. DesignElderly men (2368), randomly recruited from the general community. MethodsIGF-I was measured in a cohort of elderly men. Complete data for incident cancer were obtained from the Swedish Cancer Registry. Statistical analyses included Cox proportional hazards regressions with or without a spline approach. ResultsThree hundred and sixty-nine participants had incident cancer after baseline. Prostate cancer was most frequent (n = 140). There was no association between serum IGF-I and all cancer or prostate cancer incidence. However, there was a nonlinear association between IGF-I and nonprostate cancer incidence (P = <005). Exploratory analyses were performed for low and high serum IGF-I (quintiles 1 and 5) vs intermediate (quintiles 2-4, referent). There was a tendency of increased nonprostate cancer risk in men with high IGF-I (HR = 126, 95% confidence interval (CI): 092-171, P = 015). After excluding participants with follow-up of less than 26 years (half median follow-up time), to control for potential diagnostic delay, the association was statistically significant (HR = 155, CI: 103-235). ConclusionThere was a significant nonlinear association between IGF-I and nonprostate cancer. No association between IGF-I and prostate cancer was observed. Future studies are warranted to further investigate this nonlinear association, including whether IGF-I concentration is a reproducible, and useful, risk marker of nonprostate cancer.
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45.
  • Eriksson, Erik M, et al. (författare)
  • Participation in a Swedish cervical cancer screening program among women with psychiatric diagnoses: a population-based cohort study.
  • 2019
  • Ingår i: BMC public health. - 1471-2458. ; 19:1
  • Tidskriftsartikel (refereegranskat)abstract
    • In Sweden, organized screening programs have significantly reduced the incidence of cervical cancer. For cancers overall, however, women with psychiatric diagnoses have lower survival rates than other women. This study explores whether women with psychiatric diagnoses participate in cervical cancer screening programs to a lesser extent than women on average, and whether there are disparities between psychiatric diagnostic groups based on grades of severity.
46.
  • Borné, Yan, et al. (författare)
  • Cadmium exposure and incidence of diabetes mellitus - results from the malmö diet and cancer study.
  • 2014
  • Ingår i: PLoS ONE. - Public Library of Science. - 1932-6203. ; 9:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Cadmium is a pollutant with multiple adverse health effects: renal dysfunction, osteoporosis and fractures, cancer, and probably cardiovascular disease. Some studies have reported associations between cadmium and impaired fasting glucose and diabetes. However, this relationship is controversial and there is a lack of longitudinal studies.
47.
  • Elfving, Maria, et al. (författare)
  • Ectopic recurrence of a craniopharyngioma in a 15-year-old girl 9 years after surgery and conventional radiotherapy: case report.
  • 2011
  • Ingår i: Child's Nervous System. - Springer. - 1433-0350. ; 27, s. 845-851
  • Tidskriftsartikel (refereegranskat)abstract
    • This 15-year-old girl was operated due to an ectopic recurrence of a craniopharyngioma along the previous surgical route. She presented with a sellar craniopharyngioma at the age of 4 years and underwent a right subfrontal craniotomy. Two and a half years later she had a local recurrence in the sella that was resected along the same surgical route. Postoperative cranial radiotherapy was administered with 50 Gy divided into 28 fractions. Nine years later, magnetic resonance imaging (MRI) revealed a local recurrence within the sella together with a supraorbital cystic mass. Both tumors were surgically removed. Microscopic examination revealed recurrence of an adamantinous craniopharyngioma at both localisations. Histopathological preparations showed a higher MIB-1 index at the simultaneous recurrences in the sella and in the frontal lobe and also an elevated focal p53 expression, compared to previous operations, suggesting a transformation to a more aggressive tumor. This is the first case report of ectopic recurrence in a child that had received conventional radiotherapy of 50 Gy to the sella. Careful intra-operative procedure is probably crucial for preventing ectopic recurrences. The future will reveal if the transsphenoidal surgical route will put an end to ectopic tumor recurrence in patients with a craniopharyngioma.
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48.
  • Hofving, Tobias, 1989-, et al. (författare)
  • 177Lu-octreotate therapy for neuroendocrine tumours is enhanced by Hsp90 inhibition
  • 2019
  • Ingår i: Endocrine-Related Cancer. - 1351-0088 .- 1479-6821. ; 26:4, s. 437-449
  • Tidskriftsartikel (refereegranskat)abstract
    • Lu-177-octreotate is an FDA-approved radionuclide therapy for patients with gastroenteropancreatic neuroendocrine tumours (NETs) expressing somatostatin receptors. The Lu-177-octreotate therapy has shown promising results in clinical trials by prolonging progression-free survival, but complete responses are still uncommon. The aim of this study was to improve the Lu-177-octreotate therapy by means of combination therapy. To identify radiosensitising inhibitors, two cell lines, GOT1 and P-STS, derived from small intestinal neuroendocrine tumours (SINETs), were screened with 1224 inhibitors alone or in combination with external radiation. The screening revealed that inhibitors of Hsp90 can potentiate the tumour cell-killing effect of radiation in a synergistic fashion (GOT1; false discovery rate < 3.2 x 10(-11)). The potential for Hsp90 inhibitor ganetespib to enhance the anti-tumour effect of Lu-177-octreotate in an in vivo setting was studied in the somatostatin receptor-expressing GOT1 xenograft model. The combination led to a larger decrease in tumour volume relative to monotherapies and the tumour-reducing effect was shown to be synergistic. Using patient-derived tumour cells from eight metastatic SINETs, we could show that ganetespib enhanced the effect of Lu-177-octreotate therapy for all investigated patient tumours. Levels of Hsp90 protein expression were evaluated in 767 SINETs from 379 patients. We found that Hsp90 expression was upregulated in tumour cells relative to tumour stroma in the vast majority of SINETs. We conclude that Hsp90 inhibitors enhance the tumour-killing effect of Lu-177-octreotate therapy synergistically in SINET tumour models and suggest that this potentially promising combination should be further evaluated.
49.
  • Kjölhede, P., et al. (författare)
  • Individualized treatment for ovarian cancer may become possible
  • 2015
  • Ingår i: Läkartidningen. - 0023-7205. ; 112
  • Tidskriftsartikel (refereegranskat)abstract
    • Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy in developed countries. Several promising steps toward individualized therapy have been taken recently due to increased knowledge of molecular biology. Multidisciplinary conferences for treatment planning and the centralization to tertiary surgical centers improve quality of surgery and survival. The primary treatment of EOC is radical surgery followed by adjuvant chemotherapy with carboplatin and paclitaxel. Bevacizumab added to the chemotherapy and used as maintenance treatment is standard in the primary treatment of patients with residual tumor or inoperable patients. The PARP inhibitor olaparib is recommended as maintenance treatment of women with platinum sensitive relapsed BRCA mutated high-grade serous EOC who have responded to platinum-based chemotherapy. BRCA testing should be offered to women with EOC. In platinum-resistant recurrence addition of bevacizumab to chemotherapy should be considered.
  •  
50.
  • Linge, Helena, et al. (författare)
  • The Antibacterial Chemokine MIG/CXCL9 Is Constitutively Expressed in Epithelial Cells of the Male Urogenital Tract and Is Present in Seminal Plasma.
  • 2008
  • Ingår i: Journal of Interferon and Cytokine Research. - Mary Ann Liebert, Inc.. - 1079-9907. ; 28:3, s. 190-196
  • Tidskriftsartikel (refereegranskat)abstract
    • ABSTRACT The integrity of the urogenital tract against potentially invasive pathogens is important for the health of the individual, fertilization, and continuance of species. Antibiotic peptides with broad antimicrobial activity, among them chemokines, are part of the innate immune system. We investigated the presence of the antibacterial interferon (IFN)-dependent CXC chemokines, MIG/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11, in the human male reproductive system. MIG/CXCL9 was detected at 25.0 nM (range 8.1-40.6 nM; n = 14), whereas IP-10/CXCL10 and I-TAC/CXCL11 were detected at lower levels (mean 1.8 nM, range 0.3-5.8 nM and mean 0.6, 0.2-1.6 nM, respectively) in seminal plasma of fertile donors. The levels of MIG/CXCL9 are more than 300-fold higher than those previously reported in blood plasma. In vasectomized donors, significantly lower levels of MIG/CXCL9 (mean 14.7 nM, range 6.6-21.8) were found, suggesting that the testis and epididymis, in addition to the prostate, significantly contribute to the MIG/CXCL9 content of seminal plasma. Strong expression of MIG/CXCL9 was found in the epithelium of testis, epididymis, and prostate, as detected by immunohistochemistry. MIG/CXCL9 at concentrations in the order of those found in seminal plasma possessed antibacterial activity against the urogenital pathogen Neisseria gonorrhoeae. The relatively high levels of MIG/CXCL9 in seminal plasma point to roles for this chemokine in both host defense of the male urogenital tract and during fertilization.
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