| 1. |
- Block, Keith I., et al.
(författare)
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Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
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Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
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Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
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| 2. |
- Stanaway, Jeffrey D., et al.
(författare)
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Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
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Tidskriftsartikel (refereegranskat)abstract
- Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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| 3. |
- Brugat, Thibaut, et al.
(författare)
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Antibody-independent mechanisms regulate the establishment of chronic Plasmodium infection
- 2017
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Ingår i: Nature Microbiology. - : Macmillan Publishers Ltd.. - 2058-5276. ; 2:4
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Tidskriftsartikel (refereegranskat)abstract
- Malaria is caused by parasites of the genus Plasmodium. All human-infecting Plasmodium species can establish long-lasting chronic infections(1-5), creating an infectious reservoir to sustain transmission(1,6). It is widely accepted that the maintenance of chronic infection involves evasion of adaptive immunity by antigenic variation(7). However, genes involved in this process have been identified in only two of five human-infecting species: Plasmodium falciparum and Plasmodium knowlesi. Furthermore, little is understood about the early events in the establishment of chronic infection in these species. Using a rodent model we demonstrate that from the infecting population, only a minority of parasites, expressing one of several clusters of virulence-associated pir genes, establishes a chronic infection. This process occurs in different species of parasites and in different hosts. Establishment of chronicity is independent of adaptive immunity and therefore different from the mechanism proposed for maintenance of chronic P. falciparum infections(7-9). Furthermore, we show that the proportions of parasites expressing different types of pir genes regulate the time taken to establish a chronic infection. Because pir genes are common to most, if not all, species of Plasmodium(10), this process may be a common way of regulating the establishment of chronic infections.
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| 4. |
- Böhme, Ulrike, et al.
(författare)
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Complete avian malaria parasite genomes reveal features associated with lineage-specific evolution in birds and mammals
- 2018
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory Press (CSHL). - 1088-9051 .- 1549-5469. ; 28:4, s. 547-560
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Tidskriftsartikel (refereegranskat)abstract
- Avian malaria parasites are prevalent around the world and infect a wide diversity of bird species. Here, we report the sequencing and analysis of high-quality draft genome sequences for two avian malaria species, Plasmodium relictum and Plasmodium gallinaceum. We identify 50 genes that are specific to avian malaria, located in an otherwise conserved core of the genome that shares gene synteny with all other sequenced malaria genomes. Phylogenetic analysis suggests that the avian malaria species form an outgroup to the mammalian Plasmodium species, and using amino acid divergence between species, we estimate the avian- and mammalian-infective lineages diverged in the order of 10 million years ago. Consistent with their phylogenetic position, we identify orthologs of genes that had previously appeared to be restricted to the clades of parasites containing Plasmodium falciparum and Plasmodium vivax, the species with the greatest impact on human health. From these orthologs, we explore differential diversifying selection across the genus and show that the avian lineage is remarkable in the extent to which invasion-related genes are evolving. The subtelomeres of the P. relictum and P. gallinaceum genomes contain several novel gene families, including an expanded surf multigene family. We also identify an expansion of reticulocyte binding protein homologs in P. relictum, and within these proteins, we detect distinct regions that are specific to nonhuman primate, humans, rodent, and avian hosts. For the first time in the Plasmodium lineage, we find evidence of transposable elements, including several hundred fragments of LTR-retrotransposons in both species and an apparently complete LTR-retrotransposon in the genome of P. gallinaceum.
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| 5. |
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| 6. |
- Kurien, Matthew, et al.
(författare)
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A nationwide population-based study on the risk of coma, ketoacidosis and hypoglycemia in patients with celiac disease and type 1 diabetes
- 2015
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Ingår i: Acta Diabetologica. - : Springer Milan. - 0940-5429 .- 1432-5233. ; 52:6, s. 1167-1174
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Tidskriftsartikel (refereegranskat)abstract
- Celiac disease (CD) may influence metabolic control in type 1 diabetes (T1D). This work examines whether CD in T1D influences hospital admissions due to coma, ketoacidosis and hypoglycemia.In population-based cohort study, individuals with CD were identified using biopsy data (1969-2008) from Sweden's 28 pathology departments. T1D was defined as a recorded diagnosis of T1D at age a parts per thousand currency sign30 years in the Swedish National Patient Register between 1964 and 2009. In total, 906 individuals had both T1D and CD and were matched for sex, age and calendar period with 4303 reference individuals. Through stratified Cox regression analysis, we modeled CD as a time-dependent covariate and estimated the risk of future coma, ketoacidosis and hypoglycemia, defined by relevant international classification of disease codes among T1D patients with and without CD.During follow-up, patients with both T1D and CD had 49 hospital admissions with diabetic coma, 91 episodes of ketoacidosis and 25 hypoglycemic events. Among patients with T1D, CD did not influence the risk of coma (adjusted HR 0.97; 95 % CI 0.72-1.32), ketoacidosis (adjusted HR 1.08; 95 % CI 0.86-1.34), or hypoglycemia (adjusted HR 1.34; 95 % CI 0.87-2.05). The absolute risk of coma was 621/100,000 person-years in T1D and CD (637 in controls). Corresponding figures for ketoacidosis were 1175/100,000 person-years in T1D and CD (1092 in controls) and for hypoglycemia 316/100,000 person-years (236 in controls). HRs for metabolic emergencies in T1D were similar in the first 5 years after T1D diagnosis as thereafter.Having a diagnosis of CD is unlikely to influence the risk of coma, ketoacidosis and hypoglycemia in T1D patients.
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| 7. |
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| 8. |
- Kurien, Matthew, et al.
(författare)
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Celiac Disease Increases Risk of Thyroid Disease in Patients With Type 1 Diabetes : A Nationwide Cohort Study
- 2016
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Ingår i: Diabetes Care. - Alexandria, USA : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 39:3, s. 371-375
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Both type 1 diabetes (T1D) and celiac disease (CD) have been linked to autoimmune thyroid disease (ATD). We examined if individuals with both T1D and CD were at a higher risk of ATD than those with only T1D.Research design and methods: This study was a nationwide population-based cohort study. We defined T1D as having an inpatient or a hospital-based outpatient diagnosis of T1D at age ≤30 years in the Swedish National Patient Register between 1964 and 2009. Data on CD were obtained through small intestinal biopsy reports showing villous atrophy (Marsh histopathology grade III) between 1969 and 2008 at any of the 28 pathology departments in Sweden. ATD included hyperthyreosis and hypothyreosis, defined according to the Swedish National Patient Register. We identified 947 individuals with T1D and biopsy-verified CD. These were matched to 4,584 control subjects with T1D but no CD diagnosis. Cox regression then estimated the risk of ATD.Results: Among T1D, CD was a risk factor for later ATD. During follow-up, 90 T1D+CD patients developed ATD (expected n = 54). Adjusting for sex, age, and calendar period, this corresponded to a hazard ratio (HR) of 1.67 (95% CI 1.32-2.11; P < 0.001). This excess risk was highest in those who had CD for 10 years or more (HR 2.22 [95% CI 1.49-3.23]). Risk increases were seen in both males and females. CD was a risk factor for both hypothyreosis (HR 1.66 [95% CI 1.30-2.12]) and hyperthyreosis (HR 1.72 [95% CI 0.95-3.11]).Conclusions: Among patients with T1D, CD is a risk factor for the later development of ATD.
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| 9. |
- Kurien, Matthew, et al.
(författare)
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Increased rate of abdominal surgery both before and after diagnosis of celiac disease
- 2017
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Ingår i: Digestive and Liver Disease. - : Elsevier. - 1590-8658 .- 1878-3562. ; 49:2, s. 147-151
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Tidskriftsartikel (refereegranskat)abstract
- Background: The detection of celiac disease (CD) is suboptimal.Aims: We hypothesized that misdiagnosis is leading to diagnostic delays, and examine this assertion by determining if patients have increased risk of abdominal surgery before CD diagnosis.Methods: Through biopsy reports from Sweden's 28 pathology departments we identified all individuals with CD (Marsh stage 3; n=29,096). Using hospital-based data on inpatient and outpatient surgery recorded in the Swedish Patient Register, we compared abdominal surgery (appendectomy, laparotomy, biliary tract surgery, and uterine surgery) with that in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression estimated odds ratios (ORs).Results: 4064 (14.0%) individuals with CD and 15,760 (10.9%) controls had a record of earlier abdominal surgery (OR=1.36, 95% CI=1.31-1.42). Risk estimates were highest in the first year after surgery (OR=2.00; 95% CI=1.79-2.22). Appendectomy, laparotomy, biliary tract surgery, and uterine surgery were all associated with having a later CD diagnosis. Of note, abdominal surgery was also more common after CD diagnosis (hazard ratio=1.34; 95% CI=1.29-1.39).Conclusions: There is an increased risk of abdominal surgery both before and after CD diagnosis. Surgical complications associated with CD may best explain these outcomes. Medical nihilism and lack of CD awareness may be contributing to outcomes.
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| 10. |
- Kurien, Matthew, et al.
(författare)
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Persistent mucosal damage and the risk of epilepsy in people with celiac disease
- 2018
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Ingår i: European Journal of Neurology. - : John Wiley & Sons. - 1351-5101 .- 1468-1331. ; 25:3, s. 592-e38
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Celiac disease (CD) is associated with an increased risk of developing epilepsy, a risk that persists after CD diagnosis. A significant proportion of CD patients have persistent villous atrophy (VA) on follow-up biopsy. This study's objective was to determine whether persistent VA on follow-up biopsy affects long-term epilepsy risk and epilepsy-related hospital emergency admissions.METHODS: Nationwide Cohort Study. We identified all people in Sweden with histological evidence of CD who underwent a follow-up small intestinal biopsy (1969-2008). We compared those with persistent VA to those who showed histological improvement, assessing the development of epilepsy and related emergency hospital admissions (defined according to relevant ICD codes in the Swedish Patient Register). Cox regression analysis was used to assess outcome measures.RESULTS: Of 7590 people with CD who had a follow-up biopsy, VA was present in 43%. The presence of persistent VA was significantly associated with a reduced risk of developing newly-diagnosed epilepsy (hazard ratio [HR] 0.61; 95% confidence interval [CI] 0.38-0.98). On stratified analysis this effect was primarily amongst males (HR 0.35; 95 CI 0.15-0.80). Among the 58 CD patients with a prior diagnosis of epilepsy, those with persistent VA were less likely to visit an emergency department with epilepsy (HR 0.37; 95%CI 0.09-1.09).CONCLUSIONS: In a population-based study of CD individuals, persisting VA on follow up biopsy was associated with reduced future risk of developing epilepsy but did not influence emergency epilepsy-related hospital admissions. Mechanisms as to why persistent VA confers this benefit requires further exploration. This article is protected by copyright. All rights reserved.
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