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News Article | May 22, 2017
Site: www.eurekalert.org

A drop of blood on filter paper, allowed to dry and stored for future diagnostic purposes - considerably easier than the present-day, resource-consuming method using frozen blood samples in plastic tubes. In a new study, Uppsala researchers have successfully measured 92 different proteins in millimetre-sized circles punched out of dried samples. They have shown that this method has great potential to save resources, to the benefit of early diagnostics and treatment. Stored blood samples are of utmost importance for finding disease markers that can be used for early detection of diseases, when they are still curable. Today, test tubes holding relatively large volumes (millilitres) of blood plasma are kept in big, energy-guzzling freezers at ?80°C. A patient must first go to a healthcare unit where a trained nurse obtains a venous blood sample, which is sent to a lab for centrifugal separation of plasma. The sample can then be analysed and/or saved in a biobank for future studies. This resource-consuming method means, for example, that Uppsala University Hospital currently saves only 1% of all samples in a biobank, while the rest are discarded after an initial analysis. The new method could change this situation radically and have a crucial value for development of future healthcare. The study shows that very little happens to proteins when they are allowed to dry. In many cases, they remain completely unaltered after 30 years, or change only minimally. Consequently, dried samples could be used for health services' routine checks. These could be performed in the fast-growing laboratory service sector, enabling people to have their state of health investigated without engaging medical and health services. The samples could also be used to set up very large-scale biobanks. Costs in the healthcare sector would plunge, more samples could be analysed and a high proportion of all blood samples taken could be saved. "This has several implications. First, you can prick your own finger and send in a dried blood spot by post. Second, at a minimal cost, it will be possible to build gigantic biobanks of samples obtained on a routine clinical basis. This means that samples can be taken before the clinical debut of a disease, to identify markers of value for early diagnosis, improving the scope for curative treatment," says Ulf Landegren, Professor of Molecular Medicine and head of the Molecular Tools research group. In the present study, the scientists analysed dried blood spots (DBS). Some had been collected recently, while others had been preserved for up to 30 years in biobanks in Sweden and Denmark that store DBS samples taken from all newborn babies for screening of some 20 congenital metabolic disorders. These two biobanks keep their DBS at different temperatures: the Swedish one at +4°C and the Danish one at ?24°C. The samples were used to analyse levels of 92 proteins that are relevant in oncology. Wet plasma samples, kept at ?70°C for corresponding periods of time, were also used. In addition, in order to be able to distinguish the effects of the long-term storage, the researchers examined what happens to protein detection as an effect of the drying process. "Our conclusion is that we can measure levels of 92 proteins with very high precision and sensitivity using PEA technology in the tiny, punched-out discs from a dried blood spot. The actual drying process has a negligible effect on the various proteins and the effect is reproducible, which means that it can be included in the calculation," says Johan Björkesten, a doctoral student at Uppsala University and the first author of the study. Interest in using biobanks to search for proteins or RNA molecules that can dynamically reflect disease progression is growing rapidly. Sample collections comprising many samples taken regularly from the same individuals are very important for identifying biomarkers of this type. This has two advantages. First, over time, individuals can serve as their own controls. Second, after a person has fallen ill, the many samples taken improve the scope for locating patient samples taken before the onset of the disease, in a phase in which early diagnosis can be particularly valuable. One precondition for this is the availability of large numbers of samples, collected regularly from many individuals. This makes it essential for costs of individual samples to be low and the entire process, from sampling to storage, to be very simple and preferably require no healthcare staff to be involved. The use of DBS affords a range of advantages over using "wet" samples. Examples are minimal stress for patients since a tiny, self-administered prick on the finger suffices; costs of collection and storage are low; no highly trained staff are required for the sampling; samples can be sent by letter post; and storage conditions are simple. One of the major limitations of dried samples, on the other hand, has been the small quantity of blood taken, which rules out many traditional analytical methods. Long-term DBS storage affects the detectability of certain proteins more than others. Most proteins remain completely intact after 30 years, or change only minimally, while measured levels of some proteins decrease so that half the quantity remains after a period of between 10 and 50 years. The researchers have also found that a relative low storage temperature is preferable for proteins that are affected by storage. Compared with storing wet plasma at ?70°C, they found that this preserved the proteins better than DBS storage at ?24°C. This part of the analysis was, however, complicated by some confounding factors that made the conclusion less clearcut. The proximity extension assay (PEA) method allows detection of levels of 96 proteins (including 4 controls) from a disc 1.2 mm in diameter punched out of a dried blood spot (DBS) on filter paper. PEA, based on research at Uppsala University, has been developed into a commercial product, Proseek Multiplex, by the Uppsala company Olink. To date, the company has used the method to analyse a quarter of a million wet plasma samples. Reference: Björkesten, et al. Stability of Proteins in Dried Blood Spot Biobanks. Molecular & Cellular Proteomics. DOI. 10.1074/mcp.RA117.000015


Use of the erectile dysfunction drug Viagra does not cause the development of melanoma, a deadly form of skin cancer. This is the main finding of new research led by investigators at NYU Langone Medical Center and its Perlmutter Cancer Center and published online May 19 in the Journal of the National Cancer Institute. While the researchers found an overall 11 percent increase in the risk of developing melanoma among erection medication users, they found no evidence that erectile dysfunction medicines cause melanoma. Instead, the study authors attribute the risk to "detection bias," where the group of patients likely to take erection medicines also happens to be more health conscious, more likely to see a doctor, and so more likely to get diagnosed with melanoma than other men of similar age. "Physicians should still screen for melanoma risk, but they do not need to add the use of Viagra and similar drugs to the list of screening criteria specifically," says urologist Stacy Loeb, MD, MSc, an assistant professor at NYU Langone. "In general, men should continue to be careful about the risk of any kind of skin cancer from excessive sun exposure and use sun protection." In 2016, the U.S. Food and Drug Administration placed Viagra and other erectile dysfunction drugs collectively known as phosphodiesterase type 5 (PDE5) inhibitors on its watch list of medications with possible safety issues. The FDA action followed a 2014 report in the Journal of the American Medical Association (JAMA) that linked an increased risk of melanoma with Viagra use. Loeb's team, in 2015, published a detailed analysis in JAMA of the medical records of 20,000 men in Sweden that found no evidence that Viagra or similar medicines cause melanoma. In response to the FDA's action, Loeb and her colleagues analyzed data from five large-scale studies of erectile medication users and melanoma published between 2014 and 2016, which included a total of 866,049 men, of whom 41,874 were diagnosed with melanoma. The researchers found an overall increase in melanoma risk among men who used PDE5 inhibitors, but they hypothesized that if a cause and effect exists, higher use of erection medications would be associated with higher risk of developing the disease. Loeb and her colleagues found the opposite: there was an increase in risk among men who had a small amount of exposure to these medications, and men who took larger amounts of erectile dysfunction medications had no significant increase in melanoma risk. The researchers also reasoned that if erectile dysfunction medications cause melanoma, they would expect to find more aggressive disease among people who take the medications, but that was not the case. They did find an increased risk of early stage melanoma among erection medicine users, but those who took such medications were at a lower risk for aggressive melanoma than non-users. "Overall, Viagra and other PDE5 inhibitors are safe medications as long as men are not taking nitrates, which carry a risk of reducing blood pressure," Loeb said. "Physicians and patients should not be concerned about taking these medications on account of worry about melanoma." Loeb's co-authors are Eugenio Ventimiglia, MD, and Andrea Salonia, MD, at Università Vita-Salute San Raffaele, Milan, Italy; Yasin Folkvaljon, MD, at Uppsala University Hospital in Uppsala, Sweden; and P?r Stattin MD, PhD, at Uppsala University Hospital and Umea University in Umea, Sweden. The research was supported by grants from The Swedish Cancer Society, the Louis Feil Charitable Lead Trust, and the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center.


While the researchers found an overall 11 percent increase in the risk of developing melanoma among erection medication users, they found no evidence that erectile dysfunction medicines cause melanoma. Instead, the study authors attribute the risk to "detection bias," where the group of patients likely to take erection medicines also happens to be more health conscious, more likely to see a doctor, and so more likely to get diagnosed with melanoma than other men of similar age. "Physicians should still screen for melanoma risk, but they do not need to add the use of Viagra and similar drugs to the list of screening criteria specifically," says urologist Stacy Loeb, MD, MSc, an assistant professor at NYU Langone. "In general, men should continue to be careful about the risk of any kind of skin cancer from excessive sun exposure and use sun protection." In 2016, the U.S. Food and Drug Administration placed Viagra and other erectile dysfunction drugs collectively known as phosphodiesterase type 5 (PDE5) inhibitors on its watch list of medications with possible safety issues. The FDA action followed a 2014 report in the Journal of the American Medical Association (JAMA) that linked an increased risk of melanoma with Viagra use. Loeb's team, in 2015, published a detailed analysis in JAMA of the medical records of 20,000 men in Sweden that found no evidence that Viagra or similar medicines cause melanoma. In response to the FDA's action, Loeb and her colleagues analyzed data from five large-scale studies of erectile medication users and melanoma published between 2014 and 2016, which included a total of 866,049 men, of whom 41,874 were diagnosed with melanoma. The researchers found an overall increase in melanoma risk among men who used PDE5 inhibitors, but they hypothesized that if a cause and effect exists, higher use of erection medications would be associated with higher risk of developing the disease. Loeb and her colleagues found the opposite: there was an increase in risk among men who had a small amount of exposure to these medications, and men who took larger amounts of erectile dysfunction medications had no significant increase in melanoma risk. The researchers also reasoned that if erectile dysfunction medications cause melanoma, they would expect to find more aggressive disease among people who take the medications, but that was not the case. They did find an increased risk of early stage melanoma among erection medicine users, but those who took such medications were at a lower risk for aggressive melanoma than non-users. "Overall, Viagra and other PDE5 inhibitors are safe medications as long as men are not taking nitrates, which carry a risk of reducing blood pressure," Loeb said. "Physicians and patients should not be concerned about taking these medications on account of worry about melanoma." Loeb's co-authors are Eugenio Ventimiglia, MD, and Andrea Salonia, MD, at Università Vita-Salute San Raffaele, Milan, Italy; Yasin Folkvaljon, MD, at Uppsala University Hospital in Uppsala, Sweden; and Pӓr Stattin MD, PhD, at Uppsala University Hospital and Umea University in Umea, Sweden. The research was supported by grants from The Swedish Cancer Society, the Louis Feil Charitable Lead Trust, and the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/erectile-dysfunction-medicines-do-not-cause-melanoma-analysis-of-large-studies-finds-300457921.html


News Article | May 22, 2017
Site: phys.org

Stored blood samples are of utmost importance for finding disease markers that can be used for early detection of diseases, when they are still curable. Today, test tubes holding relatively large volumes (millilitres) of blood plasma are kept in big, energy-guzzling freezers at −80°C. A patient must first go to a healthcare unit where a trained nurse obtains a venous blood sample, which is sent to a lab for centrifugal separation of plasma. The sample can then be analysed and/or saved in a biobank for future studies. This resource-consuming method means, for example, that Uppsala University Hospital currently saves only 1% of all samples in a biobank, while the rest are discarded after an initial analysis. The new method could change this situation radically and have a crucial value for development of future healthcare. The study shows that very little happens to proteins when they are allowed to dry. In many cases, they remain completely unaltered after 30 years, or change only minimally. Consequently, dried samples could be used for health services' routine checks. These could be performed in the fast-growing laboratory service sector, enabling people to have their state of health investigated without engaging medical and health services. The samples could also be used to set up very large-scale biobanks. Costs in the healthcare sector would plunge, more samples could be analysed and a high proportion of all blood samples taken could be saved. "This has several implications. First, you can prick your own finger and send in a dried blood spot by post. Second, at a minimal cost, it will be possible to build gigantic biobanks of samples obtained on a routine clinical basis. This means that samples can be taken before the clinical debut of a disease, to identify markers of value for early diagnosis, improving the scope for curative treatment," says Ulf Landegren, Professor of Molecular Medicine and head of the Molecular Tools research group. In the present study, the scientists analysed dried blood spots (DBS). Some had been collected recently, while others had been preserved for up to 30 years in biobanks in Sweden and Denmark that store DBS samples taken from all newborn babies for screening of some 20 congenital metabolic disorders. These two biobanks keep their DBS at different temperatures: the Swedish one at +4°C and the Danish one at −24°C. The samples were used to analyse levels of 92 proteins that are relevant in oncology. Wet plasma samples, kept at −70°C for corresponding periods of time, were also used. In addition, in order to be able to distinguish the effects of the long-term storage, the researchers examined what happens to protein detection as an effect of the drying process. "Our conclusion is that we can measure levels of 92 proteins with very high precision and sensitivity using PEA technology in the tiny, punched-out discs from a dried blood spot. The actual drying process has a negligible effect on the various proteins and the effect is reproducible, which means that it can be included in the calculation," says Johan Björkesten, a doctoral student at Uppsala University and the first author of the study. Interest in using biobanks to search for proteins or RNA molecules that can dynamically reflect disease progression is growing rapidly. Sample collections comprising many samples taken regularly from the same individuals are very important for identifying biomarkers of this type. This has two advantages. First, over time, individuals can serve as their own controls. Second, after a person has fallen ill, the many samples taken improve the scope for locating patient samples taken before the onset of the disease, in a phase in which early diagnosis can be particularly valuable. One precondition for this is the availability of large numbers of samples, collected regularly from many individuals. This makes it essential for costs of individual samples to be low and the entire process, from sampling to storage, to be very simple and preferably require no healthcare staff to be involved. The use of DBS affords a range of advantages over using "wet" samples. Examples are minimal stress for patients since a tiny, self-administered prick on the finger suffices; costs of collection and storage are low; no highly trained staff are required for the sampling; samples can be sent by letter post; and storage conditions are simple. One of the major limitations of dried samples, on the other hand, has been the small quantity of blood taken, which rules out many traditional analytical methods. Long-term DBS storage affects the detectability of certain proteins more than others. Most proteins remain completely intact after 30 years, or change only minimally, while measured levels of some proteins decrease so that half the quantity remains after a period of between 10 and 50 years. The researchers have also found that a relative low storage temperature is preferable for proteins that are affected by storage. Compared with storing wet plasma at −70°C, they found that this preserved the proteins better than DBS storage at −24°C. This part of the analysis was, however, complicated by some confounding factors that made the conclusion less clearcut. The proximity extension assay (PEA) method allows detection of levels of 96 proteins (including 4 controls) from a disc 1.2 mm in diameter punched out of a dried blood spot (DBS) on filter paper. PEA, based on research at Uppsala University, has been developed into a commercial product, Proseek Multiplex, by the Uppsala company Olink. To date, the company has used the method to analyse a quarter of a million wet plasma samples. Explore further: Biobank storage time as important as age More information: Johan Björkesten et al. Stability of Proteins in Dried Blood Spot Biobanks, Molecular & Cellular Proteomics (2017). DOI: 10.1074/mcp.RA117.000015


News Article | May 24, 2017
Site: www.gizmag.com

Blood samples are one of medicine's most powerful diagnostic tools, but taking and storing liquid blood samples is expensive and time consuming. To bring down costs and broaden the use of samples, researchers at Uppsala University are studying the potential for using millimeter-wide drops of dried blood on filter paper as an alternative means of collecting and storing samples. Go in for a medical exam and odds are that the doctor will at some point order a blood draw because the bloodstream is a treasure trove of medical data. By looking at various protein or RNA biomarkers, for example, physicians can find early signs of illnesses that can be treated before they even produce symptoms. Ideally, if enough samples can be taken at frequent intervals, doctors would have a baseline of a patient's normal state of health, a record of the progression of a disease, and a better understanding of how to treat it. The problem is taking and storing blood samples is expensive, time consuming, and requires skilled technicians. Collecting a blood sample involves going to an office or clinic where it will be taken by a trained nurse. The venous blood must then be sent to a lab for centrifuging and analysis or stored in a special freezer at a temperature of -80° C (-112° F). Because of all this, institutions like the Uppsala University Hospital often save only about one percent of blood samples taken in its biobank after analysis, and sampling isn't nearly as frequent as diagnosticians and researchers would like. The Uppsala scientists are looking at dried blood spots (DBS) as an alternative. To do this, they looked at blood spots that were collected from newborn babies in routine screening for congenital metabolic disorders. These samples were preserved for up to 30 years in biobanks in Sweden and Denmark at temperatures from -24° C (-11° F) to 4° C (39° F) and were compared against wet plasma samples stored at -70° C (-94° F) for about the same period of time. The researchers looked at levels of 92 proteins that are relevant in cancer diagnosis by means of proximity extension assay, which uses matched pairs of antibodies linked to unique oligonucleotides that bond to specific proteins. In addition, they measured the effects of long-term storage and the effect of drying on protein detection. What they found was that, even after being dried for decades, most samples remained almost completely unaltered. However, some proteins showed signs of losing up to half their quantity after 10 to 50 years. They also discovered that in comparison to wet blood plasma that needs to be stored at temperatures of -70° C (-94° F), dried samples do well at -24° C (-11° F). "Our conclusion is that we can measure levels of 92 proteins with very high precision and sensitivity using [proximity extension assay] technology in the tiny, punched-out discs from a dried blood spot," says Johan Björkesten, a doctoral student at Uppsala University. "The actual drying process has a negligible effect on the various proteins and the effect is reproducible, which means that it can be included in the calculation." According to the team, the use of dried samples would allow blood samples to be used more often for routine health checks. Because there's no need for taking venous blood to get a few drops, patients can take their own samples by pricking their fingers, and instead of visiting a clinic they can post the papers to their healthcare provider. In addition, because the large, expensive medical freezers aren't needed, and more dried samples can be kept for longer periods of time, which would provide doctors and researchers with much larger bio-databases. "This has several implications," says Ulf Landegren, Professor of Molecular Medicine and head of the Molecular Tools research group. "First, you can prick your own finger and send in a dried blood spot by post. Second, at a minimal cost, it will be possible to build gigantic biobanks of samples obtained on a routine clinical basis. This means that samples can be taken before the clinical debut of a disease, to identify markers of value for early diagnosis, improving the scope for curative treatment." The research was published in Molecular & Cellular Proteomics.


Oberg K.,Uppsala University Hospital
Seminars in Oncology | Year: 2010

Pancreatic endocrine tumors have been steadily growing in incidence and prevalence during the last two decades, showing an incidence of 45/1,000,000 population. They represent a heterogeneous group with very varying tumor biology and prognosis. About half of the patients present clinical symptoms and syndromes related to substances released from the tumors (Zollinger-Ellison syndrome, insulinoma, glucagonoma, etc) and the other half are so-called nonfunctioning tumors mainly presenting with symptoms such as obstruction, jaundice, bleeding, and abdominal mass. Ten percent to 15% of the pancreatic endocrine tumors are part of an inherited syndrome such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau (VHL), neurofibromatosis, or tuberousclerosis. The diagnosis is based on histopathology demonstrating neuroendocrine features such as positive staining for chromogranin A and specific hormones such as gastrin, proinsulin, and glucagon. Moreover, the biochemical diagnosis includes measurement of chromogranins A and B or specific hormones such as gastrin, insulin, glucagon, and vasoactive intestinal polypeptide (VIP) in the circulation. In addition to standard localization procedures, radiology (computed tomography [CT] scan, magnetic resonance imaging [MRI], ultrasound [US]), somatostatin receptor scintigraphy, and most recently positron emission tomography with specific isotopes such as 11C-5 hydroxytryptamin (11C-5-HTP), fluorodopa and 68Ga-1,4,7, 10-tetra-azacyclododecane-N,N′,N″,N‴-tetra-acetic acid (DOTA)-octreotate are performed. Surgery is still one of the cornerstones in the management of pancreatic endocrine tumors, but curative surgery is rarely obtained in most cases because of metastatic disease. Debulking and other cytoreductive procedures might facilitate systemic treatment. Cytotoxic drugs, biological agents, such as somatostatin analogs, alpha interferons, mammalian target of rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors are routinely used. Tumor-targeted radioactive treatment is available in many centres in Europe and is effective in patients with tumors that express high content of somatostatin receptors type 2 and 5. In the future, treatment will be based on tumor biology and molecular genetics with the aim of so-called personalized medicine. © 2010 Elsevier Inc. All rights reserved.


Background We aimed to investigate whether the benefits of blood pressure-lowering drugs are proportional to baseline cardiovascular risk, to establish whether absolute risk could be used to inform treatment decisions for blood pressure-lowering therapy, as is recommended for lipid-lowering therapy. Methods This meta-analysis included individual participant data from trials that randomly assigned patients to either blood pressure-lowering drugs or placebo, or to more intensive or less intensive blood pressure-lowering regimens. The primary outcome was total major cardiovascular events, consisting of stroke, heart attack, heart failure, or cardiovascular death. Participants were separated into four categories of baseline 5-year major cardiovascular risk using a risk prediction equation developed from the placebo groups of the included trials (<11%, 11-15%, 15-21%, >21%). Findings 11 trials and 26 randomised groups met the inclusion criteria, and included 67 475 individuals, of whom 51 917 had available data for the calculation of the risk equations. 4167 (8%) had a cardiovascular event during a median of 4·0 years (IQR 3·4-4·4) of follow-up. The mean estimated baseline levels of 5-year cardiovascular risk for each of the four risk groups were 6·0% (SD 2·0), 12·1% (1·5), 17·7% (1·7), and 26·8% (5·4). In each consecutive higher risk group, blood pressure-lowering treatment reduced the risk of cardiovascular events relatively by 18% (95% CI 7-27), 15% (4-25), 13% (2-22), and 15% (5-24), respectively (p=0·30 for trend). However, in absolute terms, treating 1000 patients in each group with blood pressure-lowering treatment for 5 years would prevent 14 (95% CI 8-21), 20 (8-31), 24 (8-40), and 38 (16-61) cardiovascular events, respectively (p=0·04 for trend). Interpretation Lowering blood pressure provides similar relative protection at all levels of baseline cardiovascular risk, but progressively greater absolute risk reductions as baseline risk increases. These results support the use of predicted baseline cardiovascular disease risk equations to inform blood pressure-lowering treatment decisions. Funding None. © 2014 Elsevier Ltd.


Friberg L.,Danderyd Hospital | Skeppholm M.,Danderyd Hospital | Terent A.,Uppsala University Hospital
Journal of the American College of Cardiology | Year: 2015

Background Patients with atrial fibrillation (AF) and ≥1 point on the stroke risk scheme CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) are considered at increased risk for future stroke, but the risk associated with a score of 1 differs markedly between studies. Objectives The goal of this study was to assess AF-related stroke risk among patients with a score of 1 on the CHA2DS2-VASc. Methods We conducted this retrospective study of 140,420 patients with AF in Swedish nationwide health registries on the basis of varying definitions of "stroke events." Results Using a wide "stroke" diagnosis (including hospital discharge diagnoses of ischemic stroke as well as unspecified stroke, transient ischemic attack, and pulmonary embolism) yielded a 44% higher annual risk than if only ischemic strokes were counted. Including stroke events in conjunction with the index hospitalization for AF doubled the long-term risk beyond the first 4 weeks. For women, annual stroke rates varied between 0.1% and 0.2% depending on which event definition was used; for men, the corresponding rates were 0.5% and 0.7%. Conclusions The risk of ischemic stroke in patients with AF and a CHA2DS2-VASc score of 1 seems to be lower than previously reported. © 2015 American College of Cardiology Foundation.


Andersen K.,Uppsala University Hospital
Circulation. Heart failure | Year: 2014

BACKGROUND: The nature of the association between levels of physical activity and risk of heart failure is little known. We investigated nonlinear associations of total and leisure time physical activity with risk of heart failure.METHODS AND RESULTS: In 1997, 39 805 persons without heart failure completed a questionnaire of lifestyle factors and medical history. We used Cox regression models to investigate total (adjusting for education and previous myocardial infarction) and direct (multivariable-adjusted) effects of self-reported total and leisure time physical activity on risk of heart failure of any cause and heart failure of nonischemic origin. Heart failure diagnoses were obtained until December 31, 2010. Higher leisure time physical activity was associated with lower risk of heart failure of any cause; hazard ratio of the total effect of leisure time physical activity was for fifth versus first quintile 0.54; 95% confidence interval was 0.44 to 0.66. The direct effect was similar. High total daily physical activity level was associated with lower risk of heart failure, although the effect was less pronounced than for leisure time physical activity (total effect hazard ratio, 0.81; 95% confidence interval, 0.69-0.95; fifth versus first quintile). A similar direct effect observed.CONCLUSIONS: Leisure time physical activity was inversely related to risk of developing heart failure in a dose-response fashion. This was reflected in a similar but less pronounced association of total physical activity with risk of heart failure. Only part of the effects appeared to be mediated by traditional risk factors. © 2014 American Heart Association, Inc.


Oberg K.,Uppsala University Hospital
Seminars in Oncology | Year: 2013

Neuroendocrine tumors (NETs) present a wide spectrum of malignant diseases from rather benign to very malignant variants. The majority of these tumors are sporadic, but there are several familial (inherited) syndromes to consider, such as multiple endocrine neoplasia type 1 and type 2 (MEN-1 and MEN-2), von Hippel-Lindau syndrome (VHL), tuberosclerosis, and neurofibromatosis syndromes. The MEN-1 gene is mutated not only in MEN-1 families, but a recent study shows that more than 40% of sporadic pancreatic NETs (PNETs) harbor MEN-1 gene mutations. The same study reported that ATRX/DAXX genes are mutated in a significant number of tumors, as are genes encoding components of the mammalian target of rapamycin (mTOR) signal transduction pathway. These findings have implications for the new therapies that have been approved for the treatment of PNETs, such as the tyrosine kinase inhibitor sunitinib, as well the mTOR inhibitor everolimus. Small intestinal NETs show a less varied mutational pattern in that the majority of genetic alterations are found on chromosome 18. There seem to be no differences between the sporadic and the familiar type of small intestinal NETs (carcinoids). A wide range of genetic alterations have been described for the different subtypes of NETs, but the mechanisms underlying tumor development are essentially unknown except for MEN-2, in which an activating mutation of the RET proto-oncogene drives tumor progression and affords a direct genotype/phenotype correlation. Genome-wide screening of different types of NETs can now be performed for a reasonable price and is likely to generate new insights into the tumor biology and carcinogenesis in various subtypes of NETs. © 2013 Elsevier Inc.

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