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| 13. |
- Janssen, Samuel, et al.
(författare)
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Pharmacokinetics, biodistribution, and antitumor efficacy of a human glandular kallikrein 2 (hK2)-activated thapsigargin prodrug
- 2006
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 66:4, s. 358-368
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Prostate cancer cells secrete unique proteases such as prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) that represent targets for the activation of prodrugs as systemic treatment of metastatic prostate cancer. Previously, a combinatorial peptide library was screened to identify a highly active peptide substrate for hK2. The peptide was coupled to an analog of the potent cytotoxin thapsigargin, L12ADT, to generate an hK2-activated prodrug that was efficiently hydrolyzed by purified hK2, stable to hydrolysis in human and mouse plasma in vitro and selectively toxic to hK2 producing prostate cancer cells in vitro. METHODS: In the current study, toxicology, pharmacokinetics, prodrug biodistribution, and antitumor efficacy studies were performed to evaluate the hK2-activated prodrug in vivo. RESULTS: The single intravenous maximally tolerated dose of prodrug was 6 mg/kg (i.e., 3.67 micromole/kg) which produced peak serum concentration of approximately 36 microM and had a half-life of approximately 40 min. In addition, over a 24 hr period <0.5% of free L12ADT analog was observed in plasma. The prodrug demonstrated significant antitumor effect in vivo while it was being administered, but prolonged intravenous administration was not possible due to local toxicity to tail veins. Subcutaneous administration of equimolar doses produced lower plasma AUC compared to intravenous dosing but equivalent intratumoral levels of prodrug following multiple doses. CONCLUSIONS: The hK2-activated prodrug was stable in vivo. The prodrug, however, was rapidly cleared and difficult to administer over prolonged dosing interval. Additional studies are underway to assess antitumor efficacy with prolonged administration of higher subcutaneous doses of prodrug. Second-generation hK2-activated thapsigargin prodrugs with increased half-lives and improved formulations are also under development.
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- Karlsson, Martin, et al.
(författare)
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Measurement of the differential cross section for the two-body photodisintegration of He-3 at theta(LAB)=90 degrees using tagged photons in the energy range 14-31 MeV
- 2009
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Ingår i: Physical Review C (Nuclear Physics). - 0556-2813. ; 80:4
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Tidskriftsartikel (refereegranskat)abstract
- The two-body photodisintegration of He-3 has been investigated using tagged photons with energies from 14-31 MeV at MAX-lab in Lund, Sweden. The two-body breakup channel was unambiguously identified by the (nonsimultaneous) detection of both protons and deuterons. This approach was made feasible by the overdetermined kinematic situation afforded by the tagged-photon technique. Proton-and deuteron-energy spectra were measured using four silicon surface-barrier detector telescopes located at a laboratory angle of 90 degrees with respect to the incident photon-beam direction. Average statistical and systematic uncertainties of 5.7% and 6.6% in the differential cross section were obtained for 11 photon-energy bins with an average width of 1.2 MeV. The results are compared to previous experimental data measured at comparable photon energies as well as to the results of two recent Faddeev calculations which employ realistic potential models and take into account three-nucleon forces and final-state interactions. Both the accuracy and precision of the present data are improved over those obtained in the previous measurements. The data are in good agreement with most of the previous results, and favor the inclusion of three-nucleon forces in the calculations.
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| 21. |
- Klintberg, B, et al.
(författare)
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Fewer allergic respiratory disorders among farmers' children in a closed birth cohort from Sweden
- 2001
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 17:6, s. 1151-1157
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to investigate the prevalence of respiratory allergy, eczema and atopic sensitization in a closed birth cohort of Swedish schoolchildren, 7–8 yrs of age (n=707), of farmers and nonfarmers on the island of Gotland, in the Baltic Sea. All children were born and raised on the island.The survey comprised a questionnaire on atopic diseases and lifestyle factors. Atopic sensitization was assessed by the skin-prick test (SPT) with 15 standardized allergens.The risk ratio (RR) for ever having asthma and/or allergic rhinoconjunctivitis was significantly lower among children of farmers compared to children of nonfarmers (RR=0.38, confidence interval (CI) 95% 0.19–0.77). SPTs (test rate 92%) showed that 32% of the children had at least one positive test. Although the number of positive SPTs did not differ between the groups, there was a reduced risk among children of farmers for having both respiratory symptoms and sensitization to any International Study on Asthma and Allergy in Childhood allergen (RR=0.28, CI 95% 0.09–0.88).The present indicate that living in a farming population seems to protect against development of respiratory allergic disorders but not against allergic sensitization.
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- Lilja, I, et al.
(författare)
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Presence of group IIa secretory phospholipase A(2) in mast cells and macrophages in normal human ileal submucosa and in Crohn's disease
- 2000
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Ingår i: Clinical Chemistry and Laboratory Medicine. - 1434-6621 .- 1437-4331. ; 38:12, s. 1231-1236
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Tidskriftsartikel (refereegranskat)abstract
- Secretory group IIa phospholipase A(2) (PLA(2)-II) is an important regulator of proinflammatory lipid mediator production and may play a role in ileal inflammation in Crohn's disease. The enzyme has previously only been detected in epithelial Paneth cells. However, one characteristic feature of Crohn's disease is the transmural inflammation. Full thickness ileal sections from nine patients with Crohn's disease, and histologically normal sections from patients with colonic cancer (n=7) and chronic severe constipation (n=1) as controls, were used in this study. PLA(2)-II-positive cells were detected by immunofluorescence and in situ hybridization. Metachromatic staining and esterase staining were used to identify mast cells and macrophages, respectively. It was shown that mast cells and macrophages in the ileal submucosa in both patients and controls showed positive PLA(2)-II staining. The number of PLA(2)-II-labeled cells that did not react with metachromasia, e.g. macrophages, was significantly greater in inflamed Crohn's disease compared to controls. This is, to our knowledge, the first study that has described the presence in healthy, while presence and upregulation of PLA(2)-II-positive cells in inflamed human ileal submucosa. Our findings suggest a proinflammatory potential for secretory PLA(2)-II in submucosa, while proinflammatory stimulation of mast cells and macrophages in vitro has shown that the enzyme is responsible for delayed prostaglandin formation.
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- Lonn, Stefan, et al.
(författare)
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Long-term mobile phone use and brain tumor risk
- 2005
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Ingår i: American Journal of Epidemiology. - : Oxford University Press (OUP). - 0002-9262 .- 1476-6256. ; 161:6, s. 526-535
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Tidskriftsartikel (refereegranskat)abstract
- Handheld mobile phones were introduced in Sweden during the late 1980s. The purpose of this population-based, case-control study was to test the hypothesis that long-term mobile phone use increases the risk of brain tumors. The authors identified all cases aged 20-69 years who were diagnosed with glioma or meningioma during 2000-2002 in certain parts of Sweden. Randomly selected controls were stratified on age, gender, and residential area. Detailed information about mobile phone use was collected from 371 (74%) glioma and 273 (85%) meningioma cases and 674 (71%) controls. For regular mobile phone use, the odds ratio was 0.8 (95% confidence interval: 0.6, 1.0) for glioma and 0.7 (95% confidence interval: 0.5, 0.9) for meningioma. Similar results were found for more than 10 years' duration of mobile phone use. No risk increase was found for ipsilateral phone use for tumors located in the temporal and parietal lobes. Furthermore, the odds ratio did not increase, regardless of tumor histology, type of phone, and amount of use. This study includes a large number of long-term mobile phone users, and the authors conclude that the data do not support the hypothesis that mobile phone use is related to an increased risk of glioma or meningioma.
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| 29. |
- Lundin, Magnus, et al.
(författare)
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Compton scattering from the deuteron and extracted neutron polarizabilities
- 2003
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Ingår i: Physical Review Letters. - 1079-7114. ; 90:19
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Tidskriftsartikel (refereegranskat)abstract
- Differential cross sections for Compton scattering from the deuteron were measured at MAX-Lab for incident photon energies of 55 and 66 MeV at nominal laboratory angles of 45degrees, 125degrees, and 135degrees. Tagged photons were scattered from liquid deuterium and detected in three NaI spectrometers. By comparing the data with theoretical calculations in the framework of a one-boson-exchange potential model, the sum and the difference of the isospin-averaged nucleon polarizabilities, alpha(N) + beta(N) = 17.4 +/- 3.7 and alpha(N) - beta(N) = 6.4 +/- 2.4 (in units of 10(-4) fm(3)), have been determined. By combining the latter with the global-averaged value for alpha(p) - beta(p) and using the predictions of the Baldin sum rule for the sum of the nucleon polarizabilities, we have obtained values for the neutron electric and magnetic polarizabilities of alpha(n) = 8.8 +/- 2.4(total) +/- 3.0(model) and beta(n) = 6.5 -/+ 2.4(total) -/+ 3.0(model), respectively.
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| 33. |
- Tomlins, Scott A., et al.
(författare)
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The role of SPINK1 in ETS rearrangement-negative prostate cancers
- 2008
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Ingår i: Cancer Cell. - Amsterdam : Elsevier. - 1535-6108 .- 1878-3686. ; 13:6, s. 519-28
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Tidskriftsartikel (refereegranskat)abstract
- ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.
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| 34. |
- Villanueva, Josep, et al.
(författare)
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Differential exoprotease activities confer tumor-specific serum peptidome patterns
- 2006
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Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 116:1, s. 271-284
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies have established distinctive serum polypeptide patterns through mass spectrometry (MS) that reportedly correlate with clinically relevant outcomes. Wider acceptance of these signatures as valid biomarkers for disease may follow sequence characterization of the components and elucidation of the mechanisms by which they are generated. Using a highly optimized peptide extraction and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) MS-based approach, we now show that a limited subset of serum peptides (a signature) provides accurate class discrimination between patients with 3 types of solid tumors and controls without cancer. Targeted sequence identification of 61 signature peptides revealed that they fall into several tight clusters and that most are generated by exopeptidase activities that confer cancer type-specific differences superimposed on the proteolytic events of the ex vivo coagulation and complement degradation pathways. This small but robust set of marker peptides then enabled highly accurate class prediction for an external validation set of prostate cancer samples. In sum, this study provides a direct link between peptide marker profiles of disease and differential protease activity, and the patterns we describe may have clinical utility as surrogate markers for detection and classification of cancer. Our findings also have important implications for future peptide biomarker discovery efforts.
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| 35. |
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| 36. |
- Wiklund, Fredrik, et al.
(författare)
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Association of Reported Prostate Cancer Risk Alleles With PSA Levels Among Men Without a Diagnosis of Prostate Cancer
- 2009
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Ingår i: The Prostate. - : Wiley. - 0270-4137 .- 1097-0045. ; 69:4, s. 419-427
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Prostate specific antigen (PSA) is widely used for prostate cancer screening but its levels are influenced by many non cancer-related factors. The goal of the study is to estimate the effect of genetic variants on PSA levels. METHODS. We evaluated the association of SNPs that were reported to be associated with prostate cancer risk in recent genome-wide association studies with plasma PSA levels in a Swedish study population, including 1,722 control subjects without a diagnosis of prostate cancer. RESULTS. Of the 16 SNPs analyzed in control subjects, significant associations with PSA levels (P <= 0.05) were found for six SNPs. These six SNP's had a cumulative effect on PSA levels; the mean PSA levels in men were almost twofold increased across increasing quintile of number of PSA associated alleles, P-trend = 3.4 x 10(-14). In this Swedish study population risk allele frequencies were similar among T1c case patients (cancer detected by elevated PSA levels alone) as compared to T2 and above prostate cancer case patients. CONCLUSIONS. Results from this study may have two important clinical implications. The cumulative effect of six SNPs on PSA levels suggests genetic-specific PSA cutoff values may be used to improve the discriminatory performance of this test for prostate cancer; and the dual associations of these SNPs with PSA levels and prostate cancer risk raise a concern that some of reported prostate cancer risk-associated SNPs may be confounded by the prevalent use of PSA screening. Prostate 69: 419-427, 2009. (C) 2008 Wiley-Liss, Inc.
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| 37. |
- Zackrisson, B, et al.
(författare)
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Follow-up of men with elevated prostate-specific antigen and one set of benign biopsies at prostate cancer screening
- 2003
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Ingår i: European Urology. - 1873-7560. ; 43:4, s. 327-332
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To study the follow-up of men with elevated prostate-specific antigen (PSA) (>3 ng/ml) after one benign set of sextant biopsies. From the Goteborg branch of the European Randomised Study of Screening for Prostate Cancer (ERSPC). Method: 456 men with one set of benign sextant biopsies were followed every second year for 4 years with PSA determinations. In cases of elevated PSA, transrectal ultrasound (TRUS) guided sextant biopsies were suggested. Digital rectal examination (DRE), prostate volume, PSA, PSA density (PSAD) and the ratio between free and total PSA (PSA F/T) were recorded. Results: Complete data were available for 322 men. 3 groups were identified. In 84/322 (26%) men cancer was found ("cancer" group). 182/322 (56%) had benign biopsies ("benign" group) and 56/322 (17%) had normalised PSA ("normalised PSA" group). Median prostate volumes were 36, 46, and 33 cc respectively in the three groups. DRE and/or TRUS were abnormal in only 30% of the men in all groups. Cancer was not found in any prostate >70 cc volume. In prostates of <20 cc either cancer was found or PSA was normalised. The "normalised PSA" group had initial PSA, PSAD and PSA F/T similar to cancer, normalising during follow-up. Conclusions: Patients with one negative sextant biopsy still have a high likelihood of cancer, especially men with persistently elevated PSA and small prostates (<20 cc) while the majority of men with large prostates (>70 cc) have PSA elevation due to benign prostate hyperplasia (BPH) and not to cancer. (C) 2003 Elsevier Science B.V. All rights reserved.
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| 38. |
- Zackrisson, B, et al.
(författare)
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The risk of finding focal cancer (less than 3 mm) remains high on re-biopsy of patients with persistently increased prostate specific antigen but the clinical significance is questionable
- 2004
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 171:4, s. 1500-1503
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: We evaluated the significance of focal prostate cancer found in sextant biopsies in men participating in a biennial prostate specific antigen (PSA) based screening program. Materials and Methods: In 1995, 10,000 men 50 to 65 years old were randomized to biennial screening with PSA testing. Sextant biopsies were recommended when total PSA was 3 ng/ml or greater at screening rounds 1 and 2, and 2.54 ng/ml or greater at subsequent screening rounds. Focal cancer was defined as total a core cancer length of less than 3 mm in the biopsy specimen. Low volume cancer was defined as a total tumor volume of less than 0.5 cm(3) in the radical retropubic prostatectomy specimen. Results: The number of men who underwent biopsy and the number of cancers detected in the 5 possible sets of biopsies were 1,725 and 402, 706 and 124, 307 and 36, 103 and 9, and 13 and 0, respectively. The risk of detecting focal cancer was 7.9%, 10.2%, 7.5%, 5.8% and 0%, respectively, but the relative ratio (focal-to-all cancers) increased 34%, 58%, 64%, 67% and, not applicable, respectively. In men with a total core cancer length of less than 10 mm there was no correlation between core cancer length and total tumor volume, as measured in the prostatectomy specimen. Two-thirds of men with a total core cancer length of less than 3 mm had a tumor volume of greater than 0.5 cm, while the risk of low volume cancer was less than 5% only in men with a total core cancer length of greater than 10 mm. Conclusions: In a repeat PSA based screening program sextant biopsies are of little or no value for predicting tumor volume.
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| 41. |
- Zhang, W, et al.
(författare)
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Tomosyn is expressed in beta-cells and negatively regulates insulin exocytosis
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:3, s. 574-581
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Tidskriftsartikel (refereegranskat)abstract
- Tomosyn, a syntaxin-binding protein, is capable of dissociating mammalian homolog of the Caenorhabditis elegans unc-18 gene from syntaxin and is involved in the regulation of exocytosis. We have investigated the expression, cellular localization, and functional role of tomosyn in pancreatic β-cells. Western blotting revealed a 130-kDa protein corresponding to tomosyn in insulin-secreting β-cell lines. RT-PCR amplification showed that b-, m-, and s-tomosyn isoform mRNAs are expressed in β-cell lines and rat pancreatic islets. Immunohistochemistry revealed punctate tomosyn immunoreactivity in the cytoplasm of insulin-, glucagon-, pancreatic polypeptide–, and somatostatin-containing islet cells. Syntaxin 1 coimmunoprecipitated with tomosyn in extracts of insulin-secreting cells. Overexpression of m-tomosyn in mouse β-cells significantly decreased exocytosis, whereas inhibition of tomosyn expression by small interfering RNA increased exocytosis. Hence, in the pancreatic β-cell, tomosyn negatively regulates insulin exocytosis.
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