| 1. |
- Berkenstam, Anders, et al.
(författare)
-
The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans
- 2008
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 105:2, s. 663-667
-
Tidskriftsartikel (refereegranskat)abstract
- Atherosclerotic cardiovascular disease is a major problem despite the availability of drugs that influence major risk factors. New treatments are needed, and there is growing interest in therapies that may have multiple actions. Thyroid hormone modulates several cardiovascular risk factors and delays atherosclerosis progression in humans. However, use of thyroid hormone is limited by side effects, especially in the heart. To overcome this limitation, pharmacologically selective thyromimetics that mimic metabolic effects of thyroid hormone and bypass side effects are under development. In animal models, such thyromimetics have been shown to stimulate cholesterol elimination through LDL and HDL pathways and decrease body weight without eliciting side effects. We report here studies on a selective thyromimetic [KB2115, (3-[[3,5-dibromo-4- [4-hydroxy-3-(1-methylethyl)-phenoxy]-phenyl]-amino]-3-oxopropanoic acid)] in humans. In moderately overweight and hypercholesterolemic subjects KB2115 was found to be safe and well tolerated and elicited up to a 40% lowering of total and LDL cholesterol after 14 days of treatment. Bile acid synthesis was stimulated without evidence of increased cholesterol production, indicating that KB2115 induced net cholesterol excretion. KB2115 did not provoke detectable effects on the heart, suggesting that the pharmacological selectivity observed in animal models translates to humans. Thus, selective thyromimetics deserve further study as agents to treat dyslipidemia and other risk factors for atherosclerosis. © 2007 by The National Academy of Sciences of the USA.
|
|
| 2. |
- Welinder, Charlotte, et al.
(författare)
-
A protein deep sequencing evaluation of metastatic melanoma tissues.
- 2015
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
-
Tidskriftsartikel (refereegranskat)abstract
- Malignant melanoma has the highest increase of incidence of malignancies in the western world. In early stages, front line therapy is surgical excision of the primary tumor. Metastatic disease has very limited possibilities for cure. Recently, several protein kinase inhibitors and immune modifiers have shown promising clinical results but drug resistance in metastasized melanoma remains a major problem. The need for routine clinical biomarkers to follow disease progression and treatment efficacy is high. The aim of the present study was to build a protein sequence database in metastatic melanoma, searching for novel, relevant biomarkers. Ten lymph node metastases (South-Swedish Malignant Melanoma Biobank) were subjected to global protein expression analysis using two proteomics approaches (with/without orthogonal fractionation). Fractionation produced higher numbers of protein identifications (4284). Combining both methods, 5326 unique proteins were identified (2641 proteins overlapping). Deep mining proteomics may contribute to the discovery of novel biomarkers for metastatic melanoma, for example dividing the samples into two metastatic melanoma "genomic subtypes", ("pigmentation" and "high immune") revealed several proteins showing differential levels of expression. In conclusion, the present study provides an initial version of a metastatic melanoma protein sequence database producing a total of more than 5000 unique protein identifications. The raw data have been deposited to the ProteomeXchange with identifiers PXD001724 and PXD001725.
|
|
| 3. |
- Adman, Per, et al.
(författare)
-
171 forskare: ”Vi vuxna bör också klimatprotestera”
- 2019
-
Ingår i: Dagens nyheter (DN debatt). - Stockholm. - 1101-2447.
-
Tidskriftsartikel (populärvet., debatt m.m.)abstract
- DN DEBATT 26/9. Vuxna bör följa uppmaningen från ungdomarna i Fridays for future-rörelsen och protestera eftersom det politiska ledarskapet är otillräckligt. Omfattande och långvariga påtryckningar från hela samhället behövs för att få de politiskt ansvariga att utöva det ledarskap som klimatkrisen kräver, skriver 171 forskare i samhällsvetenskap och humaniora.
|
|
| 4. |
- Behrens, Anders, et al.
(författare)
-
The Computerized General Neuropsychological INPH Test (CoGNIT) revealed improvement in Idiopathic Normal Pressure Hydrocephalus (INPH) after shunt surgery
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundWe have developed the COmputerized General Neuropsychological INPH Test (CoGNIT) dedicated for patients with idiopathic normal pressure hydrocephalus (INPH). Previously, validity and reliability of included tests have been established. The aim was to evaluate the battery’s sensitivity to detect cognitive changes after shunt surgery in INPH patients.MethodsPreoperatively, thirty-one INPH patients were given CoGNIT, which includes tests assessing memory, executive functions, attention, manual dexterity and psychomotor speed. CoGNIT also includes the Geriatric Depression Scale (GDS). Re-examination was done four months after shunt surgery. Scores and test completion were examined and compared to healthy elderly (n=44).ResultsPreoperative INPH test results were significantly lower in all tests compared to healthy. Improvements after shunt surgery were seen in all cognitive domains: memory (Ten-word list test, p<0,01), executive functions (Stroop incongruent, (p<0.05), attention (Two choice reaction test, p<0.01), psychomotor speed (Stroop congruent, p<0.05) and manual dexterity (Four- finger tapping, p<0.01). No ceiling effects were observed. Depressive symptoms were more common in INPH versus healthy and did not change postoperatively. Preoperatively 81 % of INPH patients completed at least eight of the nine included test.ConclusionsCoGNIT is sensitive to cognitive impairment and to investigate changes after shunt surgery in INPH. Completion rates are good. CoGNIT has a potential to be useful in the cognitive assessment of INPH.
|
|
| 5. |
- Behrens, Anders, et al.
(författare)
-
The Computerized General Neuropsychological INPH Test revealed improvement in idiopathic normal pressure hydrocephalus after shunt surgery
- 2020
-
Ingår i: Journal of Neurosurgery. - : AMER ASSOC NEUROLOGICAL SURGEONS. - 0022-3085 .- 1933-0693. ; 132:3, s. 733-740
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE The Computerized General Neuropsychological INPH Test (CoGNIT) provides the clinician and the researcher with standardized and accessible cognitive assessments in patients with idiopathic normal pressure hydrocephalus (INPH). CoGNIT includes tests of memory, executive functions, attention, manual dexterity, and psychomotor speed. Investigations of the validity and reliability of CoGNIT have been published previously. The aim of this study was to evaluate CoGNIT's sensitivity to cognitive change after shunt surgery in patients with INPH.METHODS Forty-one patients with INPH (median Mini-Mental State Examination score 26) were given CoGNIT preoperatively and at a postoperative follow-up 4 months after shunt surgery. Scores were compared to those of 44 healthy elderly control volunteers. CoGNIT was administered by either a nurse or an occupational therapist.RESULTS Improvement after shunt surgery was seen in all cognitive domains: memory (10-word list test, p < 0.01); executive functions (Stroop incongruent color and word test, p < 0.01); attention (2-choice reaction test, p < 0.01); psychomotor speed (Stroop congruent color and word test, p < 0.01); and manual dexterity (4-finger tapping, p < 0.01). No improvement was seen in the Mini-Mental State Examination score. Preoperative INPH test scores were significantly impaired compared to healthy control subjects (p < 0.001 for all tests).CONCLUSIONS In this study the feasibility for CoGNIT to detect a preoperative impairment and postoperative improvement in INPH was demonstrated. CoGNIT has the potential to become a valuable tool in clinical and research work.
|
|
| 6. |
- Betancourt, Lazaro Hiram, et al.
(författare)
-
Improved survival prognostication of node-positive malignant melanoma patients utilizing shotgun proteomics guided by histopathological characterization and genomic data
- 2019
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Metastatic melanoma is one of the most common deadly cancers, and robust biomarkers are still needed, e.g. to predict survival and treatment efficiency. Here, protein expression analysis of one hundred eleven melanoma lymph node metastases using high resolution mass spectrometry is coupled with in-depth histopathology analysis, clinical data and genomics profiles. This broad view of protein expression allowed to identify novel candidate protein markers that improved prediction of survival in melanoma patients. Some of the prognostic proteins have not been reported in the context of melanoma before, and few of them exhibit unexpected relationship to survival, which likely reflects the limitations of current knowledge on melanoma and shows the potential of proteomics in clinical cancer research.
|
|
| 7. |
- Betancourt, Lazaro Hiram, et al.
(författare)
-
The hidden story of heterogeneous B-raf V600E mutation quantitative protein expression in metastatic melanoma—association with clinical outcome and tumor phenotypes
- 2019
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 11:12
-
Tidskriftsartikel (refereegranskat)abstract
- In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas clearly reveal the existence of inter-and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression in the mutated protein is associated with a more aggressive tumor progression. Our study design, comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis, may enable the eventual delineation of patient responders/non-responders and subsequent therapy for malignant melanoma.
|
|
| 8. |
|
|
| 9. |
- Betancourt, Lazaro Hiram, et al.
(författare)
-
The human melanoma proteome atlas-Defining the molecular pathology
- 2021
-
Ingår i: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 11:7, s. 1-20
-
Tidskriftsartikel (refereegranskat)abstract
- The MM500 study is an initiative to map the protein levels in malignant melanoma tumor samples, focused on in-depth histopathology coupled to proteome characterization. The protein levels and localization were determined for a broad spectrum of diverse, surgically isolated melanoma tumors originating from multiple body locations. More than 15,500 proteoforms were identified by mass spectrometry, from which chromosomal and subcellular localization was annotated within both primary and metastatic melanoma. The data generated by global proteomic experiments covered 72% of the proteins identified in the recently reported high stringency blueprint of the human proteome. This study contributes to the NIH Cancer Moonshot initiative combining detailed histopathological presentation with the molecular characterization for 505 melanoma tumor samples, localized in 26 organs from 232 patients.
|
|
| 10. |
- Birnefeld, Johan, 1989-
(författare)
-
Cerebral hemodynamics in stroke, cerebral small vessel disease and pharmacological interventions : a 4D flow MRI study
- 2024
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background and aim: Current cerebrovascular imaging techniques provide important information on arterial anatomy and structural pathologies, such as stenoses and occlusions, but physicians are left to infer how the blood flow is affected. In addition, the relationship between blood pressure and cerebral blood flow is complex and poorly understood. Increased transmission of cardiac pulsatility to the cerebral microvasculature has been suggested as a causative factor of cerebral small vessel disease (CSVD) but previous research have yielded conflicting results regarding this relationship. 4D flow magnetic resonance imaging (MRI) is a novel and promising technique enabling time-resolved blood flow quantification with whole-brain coverage and relatively short scan times. However, despite its obvious potential, there is not yet an evidence-based application for the use of 4D flow MRI within stroke or CSVD. This dissertation aimed to apply 4D flow MRI to describe blood flow patterns in posterior circulation stroke and cerebral blood flow responses to common pharmacological agents used to alter arterial blood pressure as well as to examine the relationship between cerebral arterial pulsatility and CSVD.Methods and Results: This doctoral dissertation consisted of four papers, referred to by roman numerals. 4D flow MRI and computed tomography angiography (CTA) were applied in 25 patients with acute ischemic stroke in the posterior circulation and a reference population of 15 healthy elderly (paper I). Individual flow profiles were created for each stroke patient and hemodynamic disturbances as well as collateral compensation were described. We show that hemodynamic findings were related to structural findings from CTA.The cross-sectional relationship between cerebral arterial pulsatility (quantified using 4D flow MRI as pulsatility index [PI] and flow volume pulsatility [FVP]) and features of CSVD were examined using regression analysis in 89 patients with acute ischemic stroke (paper II) and a population-based sample of 862 elderly (paper III). Internal carotid artery FVP was associated with increasing white matter hyperintensity (WMH) volume in patients with stroke and TIA (paper II). In addition, increasing middle cerebral artery FVP and PI were associated with worse cognitive function. In the population sample, high FVP and PI were associated with increasing WMH volume, lower brain volume and the presence of lacunes, but not the composite MRI-CSVD (paper III). Among subjects with MRI-CSVD, displaying symptoms consistent with cerebral small vessel disease was associated with higher WMH volume, lower brain volume and active smoking, but not any measure of pulsatility.Eighteen healthy volunteers were administered noradrenaline to increase mean arterial pressure by 20% above baseline, and labetalol to decrease mean arterial pressure to 15% below baseline (paper IV). Cerebral blood flow was measured using phase-contrast MRI at each blood pressure level and compared to baseline. Despite a marked increase in blood pressure, noradrenaline administration caused a reduction in cerebral blood flow and cardiac output. Meanwhile, labetalol administration caused no change in cerebral blood flow but an increased cardiac output.Conclusions: 4D flow MRI can detect hemodynamic disturbances and discriminate between hemodynamic disturbances and normal flow in patients with structural vascular pathologies. This additional information compared to structural imaging alone could potentially be used for prognosis and selection for procedures in clinical care. Cerebral arterial pulsatility is modestly associated with several MRI and clinical features of CSVD but not all. Cerebral arterial pulsatility as the main risk factor of CSVD seems unlikely but its involvement in the pathophysiology cannot be ruled out. Raising the blood pressure with noradrenaline decreases cerebral blood flow and cardiac output without any redistribution from peripheral to cerebral flow. This highlights the pitfalls of using blood pressure as a surrogate for cerebral blood flow and questions the validity of our understanding of cerebral autoregulation. Lowering the blood pressure with labetalol does not affect cerebral blood flow, reassuring its use in clinical routine. 4D flow MRI can be integrated into an in-patient work-up in selected cases of acute ischemic stroke and into the workflow of large epidemiological studies.
|
|
| 11. |
- Eklund, Sanna A., et al.
(författare)
-
Vascular risk profiles for predicting outcome and long-term mortality in patients with idiopathic normal pressure hydrocephalus : comparison of clinical decision support tools
- 2023
-
Ingår i: Journal of Neurosurgery. - : Journal of Neurosurgery Publishing Group (JNSPG). - 0022-3085 .- 1933-0693. ; 138:2, s. 476-482
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Vascular risk factors (VRFs) may act synergistically, and clinical decision support tools (CDSTs) have been developed that present vascular risk as a summarized score. Because VRFs are a major issue in patients with idiopathic normal pressure hydrocephalus (INPH), a CDST may be useful in the diagnostic workup. The objective was to compare 4 CDSTs to determine which one most accurately predicts short-term outcome and 10-year mortality after CSF shunt surgery in INPH patients.METHODS: One-hundred forty INPH patients who underwent CSF shunt surgery were included. For each patient, 4 CDST scores (Systematic Coronary Risk Evaluation–Older Persons [SCORE-OP], Framingham Risk Score [FRS], Revised Framingham Stroke Risk Profile, and Kiefer’s Comorbidity Index [KCI]) were estimated. Short-term outcome (3 months after CSF shunt surgery) was defined on the basis of improvements in gait, Mini-Mental State Examination score, and modified Rankin Scale score. The 10-year mortality rate after surgery was noted. The CDSTs were compared by using Cox regression analysis, receiver operating characteristic curve analysis, and the chi-square test.RESULTS: For 3 CDSTs, increased score was associated with increased risk of 10-year mortality. A 1-point increase in the FRS indicated a 2% higher risk of death within 10 years (HR 1.02, 95% CI 1.003–1.035, p = 0.021); SCORE-OP, 5% (HR 1.05, 95% CI 1.019–1.087, p = 0.002); and KCI, 12% (HR 1.12, 95% CI 1.03–1.219, p = 0.008). FRS predicted short-term outcome of surgery (p = 0.024). When the cutoff value was set to 32.5%, the positive predictive value was 80% and the negative predictive value was 48% (p = 0.012).CONCLUSIONS: The authors recommend using FRS to predict short-term outcome and 10-year risk of mortality in INPH patients. The study indicated that extensive treatment of the risk factors of INPH may decrease risk of mortality.
|
|
| 12. |
- Eklund, Sanna A., et al.
(författare)
-
Vascular risk profiles for predicting outcome and long-term mortality in patients with idiopathic normal pressure hydrocephalus: comparison of clinical decision support tools
- 2023
-
Ingår i: Journal of Neurosurgery. - : AMER ASSOC NEUROLOGICAL SURGEONS. - 0022-3085 .- 1933-0693. ; 138:2, s. 476-482
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Vascular risk factors (VRFs) may act synergistically, and clinical decision support tools (CDSTs) have been developed that present vascular risk as a summarized score. Because VRFs are a major issue in patients with idiopathic normal pressure hydrocephalus (INPH), a CDST may be useful in the diagnostic workup. The objective was to compare 4 CDSTs to determine which one most accurately predicts short-term outcome and 10-year mortality after CSF shunt surgery in INPH patients. METHODS One-hundred forty INPH patients who underwent CSF shunt surgery were included. For each patient, 4 CDST scores (Systematic Coronary Risk Evaluation-Older Persons [SCORE-OP], Framingham Risk Score [FRS], Revised Framingham Stroke Risk Profile, and Kiefers Comorbidity Index [KCI]) were estimated. Short-term outcome (3 months after CSF shunt surgery) was defined on the basis of improvements in gait, Mini-Mental State Examination score, and modified Rankin Scale score. The 10-year mortality rate after surgery was noted. The CDSTs were compared by using Cox regression analysis, receiver operating characteristic curve analysis, and the chi-square test. RESULTS For 3 CDSTs, increased score was associated with increased risk of 10-year mortality. A 1-point increase in the FRS indicated a 2% higher risk of death within 10 years (HR 1.02, 95% CI 1.003-1.035, p = 0.021); SCORE-OP, 5% (HR 1.05, 95% CI 1.019-1.087, p = 0.002); and KCI, 12% (HR 1.12, 95% CI 1.03-1.219, p = 0.008). FRS predicted short-term outcome of surgery (p = 0.024). When the cutoff value was set to 32.5%, the positive predictive value was 80% and the negative predictive value was 48% (p = 0.012). CONCLUSIONS The authors recommend using FRS to predict short-term outcome and 10-year risk of mortality in INPH patients. The study indicated that extensive treatment of the risk factors of INPH may decrease risk of mortality. Clinical trial registration no.: NCT01850914 (ClinicalTrials.gov)
|
|
| 13. |
- Eriksson, Jonatan, et al.
(författare)
-
Merging clinical chemistry biomarker data with a COPD database - building a clinical infrastructure for proteomic studies
- 2017
-
Ingår i: Proteome Science. - : Springer Science and Business Media LLC. - 1477-5956. ; 15:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Data from biological samples and medical evaluations plays an essential part in clinical decision making. This data is equally important in clinical studies and it is critical to have an infrastructure that ensures that its quality is preserved throughout its entire lifetime. We are running a 5-year longitudinal clinical study, KOL-Örestad, with the objective to identify new COPD (Chronic Obstructive Pulmonary Disease) biomarkers in blood. In the study, clinical data and blood samples are collected from both private and public health-care institutions and stored at our research center in databases and biobanks, respectively. The blood is analyzed by Mass Spectrometry and the results from this analysis then linked to the clinical data. Method: We built an infrastructure that allows us to efficiently collect and analyze the data. We chose to use REDCap as the EDC (Electronic Data Capture) tool for the study due to its short setup-time, ease of use, and flexibility. REDCap allows users to easily design data collection modules based on existing templates. In addition, it provides two functions that allow users to import batches of data; through a web API (Application Programming Interface) as well as by uploading CSV-files (Comma Separated Values). Results: We created a software, DART (Data Rapid Translation), that translates our biomarker data into a format that fits REDCap's CSV-templates. In addition, DART is configurable to work with many other data formats as well. We use DART to import our clinical chemistry data to the REDCap database. Conclusion: We have shown that a powerful and internationally adopted EDC tool such as REDCap can be extended so that it can be used efficiently in proteomic studies. In our study, we accomplish this by using DART to translate our clinical chemistry data to a format that fits the templates of REDCap.
|
|
| 14. |
- Friberg, Andrew S, et al.
(författare)
-
Transplantable functional islet mass – predictive biomarkers of graft function in islet after kidney transplanted patients
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal. Analysis of donor, islet isolation, quality control and recipient variables was undertaken in 110 islet after kidney (IAK) transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio (ΔCP/GCr). Using backward multiple regression the variables positively associated to ΔCP/GCr were islet volume transplanted (p<0.001) and glucose stimulated insulin secretion (SI) (p=0.009). Factors negatively associated to ΔCP/GCr were cold ischemia time (CIT) (p=0.002) and total tissue volume (p=0.009). Donor age, donor body mass index, number of retrieved organs from the donor, preservation solution, islet insulin content, body weight of the recipient of the islets had no influence on transplant function. The transplantable functional islet mass (TFIM), accounting for islet volume transplanted, SI, CIT, and total tissue volume explained 39% of the variance of the clinical outcome in the IAK data set. Therefore, the TFIM provides a straightforward and potent tool to guide the decision to utilize a specific islet preparation for clinical transplantation.
|
|
| 15. |
- Friberg, Andrew S., et al.
(författare)
-
Transplanted functional islet mass : donor islet preparation, and recipitent factors influence early graft function in islet-after-kidney patients
- 2012
-
Ingår i: Transplantation. - 0041-1337 .- 1534-6080. ; 93:6, s. 632-638
-
Tidskriftsartikel (refereegranskat)abstract
- Background.The ability to predict clinical function of a specific islet batch released for clinical transplantation using standardized variables remains an elusive goal.Methods. Analysis of 10 donor, 7 islet isolation, 3 quality control, and 6 recipient variables was undertaken in 110 islet-after-kidney transplants and correlated to the pre- to 28-day posttransplant change in C-peptide to glucose and creatinine ratio ([DELTA]CP/GCr).Results.Univariate analysis yielded islet volume transplanted (Spearman r=0.360, P<0.001) and increment of insulin secretion (r=0.377, P<0.001) as variables positively associated to [DELTA]CP/GCr. A negative association to [DELTA]CP/GCr was cold ischemia time (r=-0.330, P<0.001). A linear, backward-selection multiple regression was used to obtain a model for the transplanted functional islet mass (TFIM). The TFIM model, composed of islet volume transplanted, increment of insulin secretion, cold ischemia time, and exocrine tissue volume transplanted, accounted for 43% of the variance of the clinical outcome in the islet-after-kidney data set.Conclusion.The TFIM provides a straightforward and potent tool to guide the decision to use a specific islet preparation for clinical transplantation.
|
|
| 16. |
- Gil, Jeovanis, et al.
(författare)
-
Clinical protein science in translational medicine targeting malignant melanoma
- 2019
-
Ingår i: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 35:4, s. 293-332
-
Tidskriftsartikel (refereegranskat)abstract
- Melanoma of the skin is the sixth most common type of cancer in Europe and accounts for 3.4% of all diagnosed cancers. More alarming is the degree of recurrence that occurs with approximately 20% of patients lethally relapsing following treatment. Malignant melanoma is a highly aggressive skin cancer and metastases rapidly extend to the regional lymph nodes (stage 3) and to distal organs (stage 4). Targeted oncotherapy is one of the standard treatment for progressive stage 4 melanoma, and BRAF inhibitors (e.g. vemurafenib, dabrafenib) combined with MEK inhibitor (e.g. trametinib) can effectively counter BRAFV600E-mutated melanomas. Compared to conventional chemotherapy, targeted BRAFV600E inhibition achieves a significantly higher response rate. After a period of cancer control, however, most responsive patients develop resistance to the therapy and lethal progression. The many underlying factors potentially causing resistance to BRAF inhibitors have been extensively studied. Nevertheless, the remaining unsolved clinical questions necessitate alternative research approaches to address the molecular mechanisms underlying metastatic and treatment-resistant melanoma. In broader terms, proteomics can address clinical questions far beyond the reach of genomics, by measuring, i.e. the relative abundance of protein products, post-translational modifications (PTMs), protein localisation, turnover, protein interactions and protein function. More specifically, proteomic analysis of body fluids and tissues in a given medical and clinical setting can aid in the identification of cancer biomarkers and novel therapeutic targets. Achieving this goal requires the development of a robust and reproducible clinical proteomic platform that encompasses automated biobanking of patient samples, tissue sectioning and histological examination, efficient protein extraction, enzymatic digestion, mass spectrometry–based quantitative protein analysis by label-free or labelling technologies and/or enrichment of peptides with specific PTMs. By combining data from, e.g. phosphoproteomics and acetylomics, the protein expression profiles of different melanoma stages can provide a solid framework for understanding the biology and progression of the disease. When complemented by proteogenomics, customised protein sequence databases generated from patient-specific genomic and transcriptomic data aid in interpreting clinical proteomic biomarker data to provide a deeper and more comprehensive molecular characterisation of cellular functions underlying disease progression. In parallel to a streamlined, patient-centric, clinical proteomic pipeline, mass spectrometry–based imaging can aid in interrogating the spatial distribution of drugs and drug metabolites within tissues at single-cell resolution. These developments are an important advancement in studying drug action and efficacy in vivo and will aid in the development of more effective and safer strategies for the treatment of melanoma. A collaborative effort of gargantuan proportions between academia and healthcare professionals has led to the initiation, establishment and development of a cutting-edge cancer research centre with a specialisation in melanoma and lung cancer. The primary research focus of the European Cancer Moonshot Lund Center is to understand the impact that drugs have on cancer at an individualised and personalised level. Simultaneously, the centre increases awareness of the relentless battle against cancer and attracts global interest in the exceptional research performed at the centre.
|
|
| 17. |
- Haugen, Trine B., et al.
(författare)
-
Differences in serum levels of CB-153 and p,p '-DDE, and reproductive parameters between men living south and north in Norway
- 2011
-
Ingår i: Reproductive Toxicology. - : Elsevier BV. - 1873-1708 .- 0890-6238. ; 32:3, s. 261-267
-
Tidskriftsartikel (refereegranskat)abstract
- Arctic is contaminated with persistent organochlorine pollutants (POPs), and exposure to these compounds may differ between south and north in Norway. POPs may have negative impact on male reproductive characteristics. We compared serum levels of the CB-153 and p,p'-DDE in men who were born and had lived most of their lifetime south and north (close to or above the Arctic Circle) in Norway. We found no geographical differences in levels of CB-153 (south: 50 ng/g lipid (mean), north: 59 ng/g lipid; p = 0.27) or sperm parameters. However, the levels of AV-ODE were higher in south than in north (81 ng/g lipid (mean) vs. 66 ng/g lipid; p = 0.02), as were the levels of total and free testosterone. The FSH levels were lowest in south. A strong relationship between the CB-153 and the SHBG levels was observed. The regional differences observed for p,p'-DDE, testosterone and FSH were not reflected in the semen quality. (C) 2011 Elsevier Inc. All rights reserved.
|
|
| 18. |
- Israelsson, Hanna, 1983-, et al.
(författare)
-
Vascular risk factors contribute to idiopathic normal pressure hydrocephalus : the INPH-CRasH Study
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- ObjectiveThe objective was to determine the complete modern vascular risk factor (VRF) profile of idiopathic normal pressure hydrocephalus (INPH) using a large sample of representative INPH-patients and population-based controls, in order to confirm the impact of vascular disease on INPH pathophysiology. MethodsAll shunted INPH-patients in Sweden 2008-2010 were compared to age- and gender-matched population-based controls. Inclusion criteria: 60-85 years and mini mental state estimation ³23. The ten most important modern VRFs as well as cerebrovascular and peripheral vascular disease were prospectively assessed through blood samples, by-protocol clinical examinations and standardized questionnaires. Investigated VRFs: hypertension, hyperlipidemia, diabetes, obesity, psychosocial factors, smoking, diet, alcohol intake, cardiac disease and, physical activity. Results After exclusion, 176 INPH-patients and 368 controls participated. Using multivariable logistic regression, hyperlipidemia (OR: 2.380, 95%CI: 1.434-3.950), diabetes (OR: 2.169, 95%CI: 1.195-3.938), obesity (OR: 5.428, 95%CI: 2.502-11.772) and, psychosocial factors (OR: 5.343, 95%CI: 3.219-8.868) were independently associated with INPH. Hypertension, physical inactivity, cerebrovascular and peripheral vascular disease were overrepresented in INPH, although not independently. The protective factors: moderate alcohol intake and physical activity were overrepresented among the controls. The population attributable risk percentage was 24%. ConclusionsOur findings confirm that INPH-patients have a more dangerous VRF-profile and lack the protective factors present in the population. Almost one quarter of INPH could be explained by VRF, suggesting that INPH possibly may be a subgroup of vascular dementia. Targeted interventions against modifiable VRF are likely to have beneficial effects in INPH.
|
|
| 19. |
- Israelsson, Hanna, et al.
(författare)
-
Vascular risk factors in INPH A prospective case- control study (the INPH-CRasH study)
- 2017
-
Ingår i: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 88:6, s. 577-585
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: To assess the complete vascular risk factor (VRF) profile of idiopathic normal pressure hydrocephalus (INPH) using a large sample of representative patients with INPH and populationbased controls to determine the extent to which vascular disease influences INPH pathophysiology. Methods: All patients with INPH who underwent shunting in Sweden in 2008-2010 were compared to age-and sex-matched population-based controls. Inclusion criteria were age 60-85 years and no dementia. The 10 most important VRFs and cerebrovascular and peripheral vascular disease were prospectively assessed using blood samples, clinical examinations, and standardized questionnaires. Assessed VRFs were hypertension, hyperlipidemia, diabetes, obesity, psychosocial factors, smoking habits, diet, alcohol intake, cardiac disease, and physical activity. Results: In total, 176 patients with INPH and 368 controls participated. Multivariable logistic regression analysis indicated that hyperlipidemia (odds ratio [OR] 2.380; 95% confidence interval [CI] 1.434-3.950), diabetes (OR 2.169; 95% CI 1.195-3.938), obesity (OR 5.428; 95% CI 2.502-11.772), and psychosocial factors (OR 5.343; 95% CI 3.219-8.868) were independently associated with INPH. Hypertension, physical inactivity, and cerebrovascular and peripheral vascular disease were also overrepresented in INPH. Moderate alcohol intake and physical activity were overrepresented among the controls. The population-attributable risk percentage was 24%. Conclusions: Our findings confirm that patients with INPH have more VRFs and lack the protective factors present in the general population. Almost 25% of cases of INPH may be explained by VRFs. This suggests that INPH may be a subtype of vascular dementia. Targeted interventions against modifiable VRFs are likely to have beneficial effects on INPH.
|
|
| 20. |
- Ivarsson, Bo, et al.
(författare)
-
Consumer satisfaction, quality of life and distress with regard to social funcion and gender in severe mental illness.
- 2011
-
Ingår i: Open Journal of Psychiatry. - : Scientific Research Publishing, Inc.. - 2161-7325 .- 2161-7333. ; 1:3, s. 88-97
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE The relationships between subjective satisfaction, distress and quality of life for severely mental ill patients with different functional levels and gender was investigated in a multi-center cohort, using a balanced mix of subjective and clinician ratings in an outcome-informed model for a clinical management based on shared decision making, "The Quality star". METHODS Naturalistic data for 2552 persons, mainly with schizophrenia diagnoses, in long-term treatment and rehabilitation, were analyzed in a cross-sectional study. RESULTS With increasing Social Function, rated with the split-GAF Disability/Functioning scale, the better were patients' Satisfaction, subjective Quality of life and Perceived Global Distress. Women were more satisfied with the care but also more distressed. CONCLUSION Main findings were in line with other studies. However, the gender differences are in line with some, but not with other, studies. This poses questions how patient factors, instrument constructs, and treatment, especially shared decision making, influence subjective reports.
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
- Ivarsson, Bo, et al.
(författare)
-
The self-assessment Global Quality of Life scale : Reliability and construct validity
- 2010
-
Ingår i: International journal of psychiatry in clinical practice (Print). - : Informa UK Limited. - 1365-1501 .- 1471-1788. ; 14:4, s. 287-297
-
Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim was to establish psychometric properties of the Global Quality of Life Scale (GQL) for people with severe mental illness. Methods. GQL is a stand-alone visual analogue scale included in "The Quality Star", a minimal platform for clinical follow-up and efficiency documentation of mental health services in eight dimensions widely used in Sweden. Validating instruments included MANSA, Inventory of Problem and Solutions, Consumer Satisfaction Rating Scale, Perceived Global Distress, health screening using UKU-Side Effect Rating Scale, GAF, and Perceived Global Burden (for next of kin). Test-retest reliability of the GQL was examined between ratings at quarterly intervals during 1 year. Results. There were three main results: test-retest reliability at quarterly intervals was very satisfactory, concurrent validity with the initial item of life satisfaction scale of MANSA, "Life as a whole", was demonstrated and finally content validity was clarified by associations with a number of validating measures from several contexts in three studies. Conclusion. GQL have acceptable psychometric properties and is valid for serious mental ill persons. Its use as easy-to-use instrument for screening of perceived global quality of life was supported.
|
|
| 24. |
|
|
| 25. |
- Kim, Yonghyo, et al.
(författare)
-
Protein Expression in Metastatic Melanoma and the Link to Disease Presentation in a Range of Tumor Phenotypes
- 2020
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 12:3
-
Forskningsöversikt (refereegranskat)abstract
- Malignant melanoma is among the most aggressive skin cancers and it has among the highest metastatic potentials. Although surgery to remove the primary tumor is the gold standard treatment, once melanoma progresses and metastasizes to the lymph nodes and distal organs, i.e., metastatic melanoma (MM), the usual outcome is decreased survival. To improve survival rates and life span, advanced treatments have focused on the success of targeted therapies in the MAPK pathway that are based on BRAF (BRAF V600E) and MEK. The majority of patients with tumors that have higher expression of BRAF V600E show poorer prognosis than patients with a lower level of the mutated protein. Based on the molecular basis of melanoma, these findings are supported by distinct tumor phenotypes determined from differences in tumor heterogeneity and protein expression profiles. With these aspects in mind, continued challenges are to: (1) deconvolute the complexity and heterogeneity of MM; (2) identify the signaling pathways involved; and (3) determine protein expression to develop targeted therapies. Here, we provide an overview of the results from protein expression in MM and the link to disease presentation in a variety of tumor phenotypes and how these will overcome the challenges of clinical problems and suggest new promising approaches in metastatic melanoma and cancer therapy.
|
|
| 26. |
- Kwon, Ho Jeong, et al.
(författare)
-
Drug Compound Characterization by Mass Spectrometry Imaging in Cancer Tissue
- 2015
-
Ingår i: Archives of Pharmacal Research. - : Springer Science and Business Media LLC. - 1976-3786 .- 0253-6269. ; 38:9, s. 1718-1727
-
Forskningsöversikt (refereegranskat)abstract
- MALDI Mass spectrometry imaging (MSI) provides a technology platform that allows the accurate visualization of unlabeled small molecules within the two-dimensional spaces of tissue samples. MSI has proven to be a powerful tool-box concept in the development of new drugs. MSI allows unlabeled drug compounds and drug metabolites to be detected and identified and quantified according to their mass-to-charge ratios (m/z) at high resolution in complex tissue environments. Such drug characterization in situ, by both spatial and temporal behaviors within tissue compartments, provide new understandings of the dynamic processes impacting drug uptake and metabolism at the local sites targeted by therapy. Further, MSI in combination with histology and immunohistochemistry, provides the added value of defining the context of cell biology present at the sites of drug localization thus providing invaluable information relating to treatment efficacy. In this report we provide mass spectrometry imaging data within various cancers such as malignant melanoma in patients administered with Vemurafenib, a protein kinase inhibitor that is targeting both the BRAF, and ERK mutated target proteins and that has shown significant efficacy in restraining disease progression. We also provide an overview of other examples of the new generation of targeted drugs, and demonstrate the data on personalized medicine drugs localization within tumor compartments within in vivo models. In these cancer models we provide detailed data on drug and target protein co-localization of YCG185 and Sunitinib. These drugs are targeting VEGFR2 within the angiogenesis mechanism. Our ability to resolve drug uptake at targeted sites of directed therapy provides important opportunities for increasing our understanding about the mode of action of drug activity within the environment of disease.
|
|
| 27. |
|
|
| 28. |
- Lundkvist, Bo, et al.
(författare)
-
Cerebrospinal fluid dynamics and long-term survival of the Strata(®) valve in idiopathic normal pressure hydrocephalus.
- 2011
-
Ingår i: Acta Neurologica Scandinavica. - : Wiley. - 0001-6314 .- 1600-0404. ; 124:2, s. 115-121
-
Tidskriftsartikel (refereegranskat)abstract
- Objective - Cerebrospinal fluid (CSF) dynamics and long-term shunt survival of the Strata(®) CSF shunt were evaluated in patients with idiopathic normal pressure hydrocephalus (INPH). Subjects and methods - Seventy-two patients with INPH received a Strata(®) valve. A CSF infusion test, neuroimaging and video recording of gait were performed at baseline and at 6 months (n = 68) after surgery. Long-term shunt survivals were obtained from patient records. Results - The shunt survival at 1 year was 94% and at 3 years 92.5%. Forty-nine patients (72%) had an improved gait. Two patients were improved despite non-functioning shunts, indicating a possible placebo response. Nineteen patients were not improved at the 6-month follow-up. The shunt tests revealed a functioning shunt in 12; thus, unnecessary shunt revisions could be avoided. Seventeen patients showed a siphoning effect. Shunt revisions were made in six patients. Eight hygromas/subdural hematomas were found. Conclusions - The long-term survival of the Strata(®) valves was good, and a concern of complications is not a reason to exclude elderly with INPH from shunt surgery. Studies are needed to evaluate pros and cons of the anti-siphon device. Using a CSF shunt test, unnecessary shunt revisions may be avoided.
|
|
| 29. |
- Malm, Arvid, 1979-
(författare)
-
The Absent Entrepreneur : Exploring the Role of the Entrepreneur in Economics
- 2018
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Economics as an academic discipline has often found it difficult to formally model the Entrepreneur. As Baumol (1968) noted, “The theoretical firm is entrepreneurless—the prince of Denmark has been expunged from the discussion of Hamlet.”This dissertation first examines if the entrepreneur is still absent from economics and then seeks to apply the concept of the entrepreneur to some contemporary economic discussions. Finally, I examine a concept closely associated with entrepreneurship: Philanthropy.The first and second article examine the presence of the entrepreneur and the family firm in the current economic “canon” in economics PhD programs. We find that the entrepreneur remains scarce in economics, but that some recent included works attempt to model entrepreneurship. The family firm is entirely absent from the surveyed literature.The third article examines the impact of a major Swedish educational reform that lengthened mandatory education on self-employment outcomes. I find that reform participants are less likely to operate marginal businesses.The fourth article examines income inequality in the United States in relation to entrepreneurship. Using the “Supermanager” hypothesis of Thomas Piketty as a starting point, we argue that entrepreneurs and managers in closely held firms play an important role in rising income inequality.Finally, the fifth article examines the state of Swedish philanthropy, a field usually fueled by successful entrepreneurship. We examine the productivity of philanthropic funding of research relative to other R&D funding and conclude that the main predictor of publication and patent output appears to be overall funding, not funding structure.
|
|
| 30. |
- Malm, Bo, 1953-
(författare)
-
Cell motility : on the biochemical properties of profilin and the profilactin complex
- 1985
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Actin is a 42 000 Mw globular protein which is known to play an essential role in muscle contraction and which is suggested to have an equally important function in non-muscle cell motility. In isotonic solutions actin polymerizes to form double-stranded helixes with lengths of several microns. These filaments are the functional form of actin in the muscle sarcomere. Also in non-muscle cells actin filaments, originally described as microfilaments, seem to be a functional unit in the motility apparatus.From non-muscle tissues actin can be purified in complex with a 15 000 Mw protein called profilin. The complex is called profilactin and is suggested to be the precursor to actin filaments. In the "Induced filament formation model of cell motility" actin is polymerized and depolymerized in a reversible manner with profilin acting as the regulator of actin polymerizability.There is evidence for the co-existence of a monomeric and a polymerized form of actin in several non-muscle cell types. In blood platelets there is evidence for a conversion of actin from profilactin to filamentous actin as a result of stimulation. If profilactin is the precursor to actin filaments the dissociation of profilin from actin would be the primary event in the formation of microfilaments.The work presented in this thesis demonstrates the decisive importance of the C-terminal part of actin for its interaction with profilin. In the case of profilin the C-terminus is suggested to have a considerable influence on the stability of the molecule although it seems to be of relatively little importance for the formation of the profilactin complex. The results presented here also indicate hydrophobic properties of profilin induced by the oxidation of the molecule which might be of significance to its functioning in vivo.
|
|
| 31. |
- Malm, Carl Johan, et al.
(författare)
-
Small calibre biosynthetic bacterial cellulose blood vessels: 13-months patency in a sheep model.
- 2012
-
Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1651-2006 .- 1401-7431. ; 46:1, s. 57-62
-
Tidskriftsartikel (refereegranskat)abstract
- Abstract Objectives. Many patients in need of bypass surgery lack graft material and current synthetic alternatives have poor performance. A 4 mm vascular graft composed of bacterial cellulose (BC) was developed and tested in pilot study in a large animal model. Design. BC is a biopolymer made by the bacteria acetobacter xylinum. BC grafts (n = 16) with 4 cm length and 4 mm internal diameter were implanted bilaterally in the carotid arteries of eight sheep. No long-term antithrombotic therapy was administered. Patency was assessed with ultrasound. Histology, immunohistochemistry, and electron microscopy were performed after explantation. Results. Fifty percent of the grafts occluded within two weeks. One animal died with patent grafts after 14 days. In the three remaining animals 5/6 grafts were patent after nine months. Two animals were followed 13 months after implantation with 3/4 grafts patent at explantation. All patent grafts had confluent endothelial-like cells. Conclusions. Biosynthetic small calibre vascular grafts made from BC can be patent for up to 13 months in sheep carotid arteries. BC is a potential material for small calibre grafts but patency in animal models needs to be improved before clinical studies can be planned.
|
|
| 32. |
- Malm, Dan, et al.
(författare)
-
Reducing the prevalence of catheter-related infections by quality improvement : Six-year follow-up study
- 2016
-
Ingår i: Open Journal of Nursing. - : Scientific Research Publishing, Inc.. - 2162-5336 .- 2162-5344. ; 6:2, s. 79-87
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral venous catheter (PVC) insertion is a crucial nursing action during life support. Several factors that increase the risk of thrombophlebitis associated with PVCs have been reported. Objective: We wish to evaluate the impact of a quality improvement regarding PVC treatment for patients with coronary heart diseases.Method: A longitudinal, quantitative observational study was carried out in 2008 and 2013 in a hospital in southern Sweden with 360 consecutive patients suffering from acute chest pain. New routines for PVC treatment were included in the hospital with daily inspection according to a checklist. A structured observation protocol was used to survey the prevalence of thrombophlebitis between 2008 and 2013. Also, we examined the relationship between the location and luminal diameters of PVCs.Results: The student’s t-test showed significant differences between 2008 and 2013 with respect to luminal diameter of PVCs (p = 0.002), prevalence of thrombophlebitis (p = 0.003) and number of days with PVC left in situ (p < 0.001).Conclusion: These findings emphasize the value of using systematic daily inspections and checklists to achieve quality and safety in patients with acute chest pain having PVC-based treatment.
|
|
| 33. |
- Malm, Jan, Professor, 1957-, et al.
(författare)
-
Influence of comorbidities in idiopathic normal pressure hydrocephalus - research and clinical care : A report of the ISHCSF task force on comorbidities in INPH
- 2013
-
Ingår i: Fluids and Barriers of the CNS. - : BioMed Central (BMC). - 2045-8118. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Idiopathic normal pressure hydrocephalus (INPH) is a syndrome of ventriculomegaly, gait impairment, cognitive decline and incontinence that occurs in an elderly population prone to many types of comorbidities. Identification of the comorbidities is thus an important part of the clinical management of INPH patients. In 2011, a task force was appointed by the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders (ISHCSF) with the objective to compile an evidence-based expert analysis of what we know and what we need to know regarding comorbidities in INPH. This article is the final report of the task force. The expert panel conducted a comprehensive review of the literature. After weighing the evidence, the various proposals were discussed and the final document was approved by all the task force members and represents a consensus of expert opinions. Recommendations regarding the following topics are given: I. Musculoskeletal conditions; II. Urinary problems; III. Vascular disease including risk factors, Binswanger disease, and white matter hyperintensities; IV. Mild cognitive impairment and Alzheimer disease including biopsies; V. Other dementias (frontotemporal dementia, Lewy body, Parkinson); VI. Psychiatric and behavioral disorders; VII. Brain imaging; VIII. How to investigate and quantify. The task force concluded that comorbidity can be an important predictor of prognosis and post-operative outcome in INPH. Reported differences in outcomes among various INPH cohorts may be partly explained by variation in the rate and types of comorbidities at different hydrocephalus centers. Identification of comorbidities should thus be a central part of the clinical management of INPH where a detailed history, physical examination, and targeted investigations are the basis for diagnosis and grading. Future INPH research should focus on the contribution of comorbidity to overall morbidity, mortality and long-term outcomes.
|
|
| 34. |
- Qvarlander, Sara, et al.
(författare)
-
Pulsatility in CSF dynamics : pathophysiology of idiopathic normal pressure hydrocephalus
- 2013
-
Ingår i: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ Publishing Group. - 0022-3050 .- 1468-330X. ; 84:7, s. 735-741
-
Tidskriftsartikel (refereegranskat)abstract
- Background: It is suggested that disturbed CSF dynamics are involved in the pathophysiology of idiopathic normal pressure hydrocephalus (INPH). The pulsatility curve describes the relationship between intracranial pressure (ICP) and the amplitude of cardiac related ICP pulsations. The position of baseline ICP on the curve provides information about the physiological state of the CSF dynamic system. The objective of the study was to investigate if shunt surgery modifies the pulsatility curve and the baseline position on the curve, and how this relates to gait improvement in INPH.Methods: 51 INPH patients were investigated with lumbar CSF dynamic investigations preoperatively and 5 months after shunt surgery. During the investigation, ICP was measured at baseline, and then a CSF sample was removed, resulting in pressure reduction. After this, ICP was regulated with an automated infusion protocol, with a maximum increase of 24 mm Hg above baseline. The pulsatility curve was thus determined in a wide range of ICP values. Gait improvement was defined as a gait speed increase >= 0.1 m/s.Results: The pulsatility curve was unaltered by shunting. Baseline ICP and amplitude were reduced (-3.0 +/- 2.9 mm Hg; -1.1 +/- 1.5 mm Hg; p < 0.05, n = 51). Amplitude reduction was larger for gait improvers (-1.2 +/- 1.6 mm Hg, n = 42) than non-improvers (-0.2 +/- 0.5 mm Hg, n = 9) (p < 0.05) although mean ICP reduction did not differ.Conclusions: The pulsatility curve was not modified by shunt surgery, while the baseline position was shifted along the curve. Observed differences between gait improvers and non-improvers support cardiac related ICP pulsations as a component of INPH pathophysiology.
|
|
| 35. |
- Sanchez, Aniel, et al.
(författare)
-
Novel functional proteins coded by the human genome discovered in metastases of melanoma patients
- 2020
-
Ingår i: Cell Biology and Toxicology. - : Springer Science and Business Media LLC. - 0742-2091 .- 1573-6822. ; 36:3, s. 261-272
-
Tidskriftsartikel (refereegranskat)abstract
- In the advanced stages, malignant melanoma (MM) has a very poor prognosis. Due to tremendous efforts in cancer research over the last 10 years, and the introduction of novel therapies such as targeted therapies and immunomodulators, the rather dark horizon of the median survival has dramatically changed from under 1 year to several years. With the advent of proteomics, deep-mining studies can reach low-abundant expression levels. The complexity of the proteome, however, still surpasses the dynamic range capabilities of current analytical techniques. Consequently, many predicted protein products with potential biological functions have not yet been verified in experimental proteomic data. This category of ‘missing proteins’ (MP) is comprised of all proteins that have been predicted but are currently unverified. As part of the initiative launched in 2016 in the USA, the European Cancer Moonshot Center has performed numerous deep proteomics analyses on samples from MM patients. In this study, nine MPs were clearly identified by mass spectrometry in MM metastases. Some MPs significantly correlated with proteins that possess identical PFAM structural domains; and other MPs were significantly associated with cancer-related proteins. This is the first study to our knowledge, where unknown and novel proteins have been annotated in metastatic melanoma tumour tissue.
|
|
| 36. |
- Sugihara, Yutaka, et al.
(författare)
-
Endogenous expression mapping of malignant melanoma by mass spectrometry imaging
- 2018
-
Ingår i: Clinical and Translational Medicine. - : Wiley. - 2001-1326. ; 7, s. 1-9
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Currently, only a limited number of molecular biomarkers for malignant melanoma exist. This is the case for both diagnosing the disease, staging, and efficiently measuring the response to therapy by tracing the progression of disease development and drug impact. There is a great need to identify novel landmarks of disease progression and alterations.METHODS: Matrix-assisted laser desorption ionisation mass spectrometry imaging (MALDI-MSI) has been developed within our group to study drug localisation within micro-environmental tissue compartments. Here, we expand further on this technology development and introduce for the first time melanoma tumour tissues to map metabolite localisation utilising high resolution mass spectrometry. MALDI-MSI can measure and localise the distribution pattern of a number of small molecule metabolites within tissue compartments of tumours isolated from melanoma patients. Data on direct measurements of metabolite identities attained at the local sites in tissue compartments has not been readily available as a measure of a clinical index for most cancer diseases. The current development on the mapping of endogenous molecular expression melanoma tumours by mass spectrometry imaging focuses on the establishment of a cancer tissue preparation process whereby a matrix crystal formation is homogenously built on the tissue surface, providing uniform molecular mapping. We apply this micro-preparation technology to disease presentation by mapping the molecular signatures from patient tumour sections.RESULTS: We have automated the process with a micro-technological dispensing platform. This provides the basis for thin film generation of the cancer patient tissues prior to imaging screening. Compartmentalisation of the tumour regions are displayed within the image analysis interfaced with histopathological grading and characterisation.CONCLUSIONS: This enables site localisation within the tumour with image mapping to disease target areas such as melanoma cells, macrophages, and lymphocytes.
|
|
| 37. |
- Szadai, Leticia, et al.
(författare)
-
Deep proteomic analysis on biobanked paraffine-archived melanoma with prognostic/predictive biomarker read-out
- 2021
-
Ingår i: Cancers. - : MDPI AG. - 2072-6694. ; 13:23
-
Tidskriftsartikel (refereegranskat)abstract
- The discovery of novel protein biomarkers in melanoma is crucial. Our introduction of formalin-fixed paraffin-embedded (FFPE) tumor protocol provides new opportunities to understand the progression of melanoma and open the possibility to screen thousands of FFPE samples deposited in tumor biobanks and available at hospital pathology departments. In our retrospective biobank pilot study, 90 FFPE samples from 77 patients were processed. Protein quantitation was performed by high-resolution mass spectrometry and validated by histopathologic analysis. The global protein expression formed six sample clusters. Proteins such as TRAF6 and ARMC10 were upregulated in clusters with enrichment for shorter survival, and proteins such as AIFI1 were upregulated in clusters with enrichment for longer survival. The cohort’s heterogeneity was addressed by comparing primary and metastasis samples, as well comparing clinical stages. Within immunotherapy and targeted therapy subgroups, the upregulation of the VEGFA-VEGFR2 pathway, RNA splicing, increased activity of immune cells, extracellular matrix, and metabolic pathways were positively associated with patient outcome. To summarize, we were able to (i) link global protein expression profiles to survival, and they proved to be an independent prognostic indicator, as well as (ii) identify proteins that are potential predictors of a patient’s response to immunotherapy and targeted therapy, suggesting new opportunities for precision medicine developments.
|
|
| 38. |
- Thomas, Richard D., et al.
(författare)
-
The double electrostatic ion ring experiment : A unique cryogenic electrostatic storage ring for merged ion-beams studies
- 2011
-
Ingår i: Review of Scientific Instruments. - : AIP Publishing. - 0034-6748 .- 1089-7623. ; 82:6, s. 065112-
-
Tidskriftsartikel (refereegranskat)abstract
- We describe the design of a novel type of storage device currently under construction at Stockholm University, Sweden, using purely electrostatic focussing and deflection elements, in which ion beams of opposite charges are confined under extreme high vacuum cryogenic conditions in separate rings and merged over a common straight section. The construction of this double electrostatic ion ring experiment uniquely allows for studies of interactions between cations and anions at low and well-defined internal temperatures and centre-of-mass collision energies down to about 10 K and 10 meV, respectively. Position sensitive multi-hit detector systems have been extensively tested and proven to work in cryogenic environments and these will be used to measure correlations between reaction products in, for example, electron-transfer processes. The technical advantages of using purely electrostatic ion storage devices over magnetic ones are many, but the most relevant are: electrostatic elements which are more compact and easier to construct; remanent fields, hysteresis, and eddy-currents, which are of concern in magnetic devices, are no longer relevant; and electrical fields required to control the orbit of the ions are not only much easier to create and control than the corresponding magnetic fields, they also set no upper mass limit on the ions that can be stored. These technical differences are a boon to new areas of fundamental experimental research, not only in atomic and molecular physics but also in the boundaries of these fields with chemistry and biology. For examples, studies of interactions with internally cold molecular ions will be particular useful for applications in astrophysics, while studies of solvated ionic clusters will be of relevance to aeronomy and biology.
|
|
| 39. |
|
|
| 40. |
- Welinder, Charlotte, et al.
(författare)
-
Correlation of histopathologic characteristics to protein expression and function in malignant melanoma
- 2017
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:4
-
Tidskriftsartikel (refereegranskat)abstract
- Background Metastatic melanoma is still one of the most prevalent skin cancers, which upon progression has neither a prognostic marker nor a specific and lasting treatment. Proteomic analysis is a versatile approach with high throughput data and results that can be used for characterizing tissue samples. However, such analysis is hampered by the complexity of the disease, heterogeneity of patients, tumors, and samples themselves. With the long term aim of quest for better diagnostics biomarkers, as well as predictive and prognostic markers, we focused on relating high resolution proteomics data to careful histopathological evaluation of the tumor samples and patient survival information. Patients and methods Regional lymph node metastases obtained from ten patients with metastatic melanoma (stage III) were analyzed by histopathology and proteomics using mass spectrometry. Out of the ten patients, six had clinical follow-up data. The protein deep mining mass spectrometry data was related to the histopathology tumor tissue sections adjacent to the area used for deep-mining. Clinical follow-up data provided information on disease progression which could be linked to protein expression aiming to identify tissue-based specific protein markers for metastatic melanoma and prognostic factors for prediction of progression of stage III disease.Results In this feasibility study, several proteins were identified that positively correlated to tumor tissue content including IF6, ARF4, MUC18, UBC12, CSPG4, PCNA, PMEL and MAGD2. The study also identified MYC, HNF4A and TGFB1 as top upstream regulators correlating to tumor tissue content. Other proteins were inversely correlated to tumor tissue content, the most significant being; TENX, EHD2, ZA2G, AOC3, FETUA and THRB. A number of proteins were significantly related to clinical outcome, among these, HEXB, PKM and GPNMB stood out, as hallmarks of processes involved in progression from stage III to stage IV disease and poor survival. Conclusion In this feasibility study, promising results show the feasibility of relating proteomics to histopathology and clinical outcome, and insight thus can be gained into the molecular processes driving the disease. The combined analysis of histological features including the sample cellular composition with protein expression of each metastasis enabled the identification of novel, differentially expressed proteins. Further studies are necessary to determine whether these putative biomarkers can be utilized in diagnostics and prognostic prediction of metastatic melanoma.
|
|
| 41. |
- Zarrinkoob, Laleh, et al.
(författare)
-
Aging alters the dampening of pulsatile blood flow in cerebral arteries
- 2016
-
Ingår i: Journal of Cerebral Blood Flow and Metabolism. - 0271-678X .- 1559-7016. ; 36:9, s. 1519-1527
-
Tidskriftsartikel (refereegranskat)abstract
- Excessive pulsatile flow caused by aortic stiffness is thought to be a contributing factor for several cerebrovascular diseases. The main purpose of this study was to describe the dampening of the pulsatile flow from the proximal to the distal cerebral arteries, the effect of aging and sex, and its correlation to aortic stiffness. Forty-five healthy elderly (mean age 71 years) and 49 healthy young (mean age 25 years) were included. Phase-contrast magnetic resonance imaging was used for measuring blood flow pulsatility index and dampening factor (proximal artery pulsatility index/distal artery pulsatility index) in 21 cerebral and extra-cerebral arteries. Aortic stiffness was measured as aortic pulse wave velocity. Cerebral arterial pulsatility index increased due to aging and this was more pronounced in distal segments of cerebral arteries. There was no difference in pulsatility index between women and men. Dampening of pulsatility index was observed in all cerebral arteries in both age groups but was significantly higher in young subjects than in elderly. Pulse wave velocity was not correlated with cerebral arterial pulsatility index. The increased pulsatile flow in elderly together with reduced dampening supports the pulse wave encephalopathy theory, since it implies that a higher pulsatile flow is reaching distal arterial segments in older subjects.
|
|
