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- Tobias, Deirdre K, et al.
(författare)
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Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine
- 2023
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Ingår i: Nature Medicine. - 1546-170X. ; 29:10, s. 2438-2457
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Forskningsöversikt (refereegranskat)abstract
- Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
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- Mustafa, A, et al.
(författare)
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Decreased plasma insulin-like growth factor-I level in familial Alzheimer's disease patients carrying the Swedish APP 670/671 mutation
- 1999
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Ingår i: Dementia and geriatric cognitive disorders. - : S. Karger AG. - 1420-8008 .- 1421-9824. ; 10:6, s. 446-451
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Tidskriftsartikel (refereegranskat)abstract
- The plasma insulin-like growth factor I (IGF-I) level was determined in family members carrying the Swedish amyloid precursor protein (APP) 670/671 mutation with or without Alzheimer’s disease (AD) and in age-matched controls from the same family. Plasma growth hormone (GH) and prolactin (PRL) levels were also determined. Measurement of the plasma IGF-I level by radioimmunoassay revealed a significant reduction only in the family members with AD compared to age-matched controls. However, there was no significant difference in the levels of GH and PRL between the mutation carriers with or without AD and their respective age-matched controls. These findings indicate that the mechanism(s) regulating GH and PRL were preserved and those regulating IGF-I levels might be affected in AD patients with the Swedish APP 670/671 mutation.
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- Al Shemaili, Jasem, et al.
(författare)
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Frondoside A enhances the antiproliferative effects of gemcitabine in pancreatic cancer
- 2014
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 50:7, s. 1391-1398
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic cancer has a very poor prognosis. While gemcitabine is the mainstay of therapy and improves quality of life, it has little impact on survival. More effective treatments are desperately needed for this disease. Frondoside A is a triterpenoid glycoside isolated from the Atlantic sea cucumber, Cucumaria frondosa. Frondoside A potently inhibits pancreatic cancer cell growth and induces apoptosis in vitro and in vivo. The aim of the present study was to investigate whether frondoside A could enhance the anti-cancer effects of gemcitabine. Effects of frondoside A and gemcitabine alone and in combination on proliferation were investigated in two human pancreatic cancer cell lines, AsPC-1 and S2013. To investigate possible synergistic effects, combinations of low concentrations of the two drugs were used for a 72 h treatment period in vitro. Growth inhibition was significantly greater with the drug combinations than their additive effects. Combinations of frondoside A and gemcitabine were tested in vivo using the athymic mouse model. Xenografts of AsPC-1 and S2013 cells were allowed to form tumours prior to treatment with the drugs alone or in combination for 30 days. Tumours grew rapidly in placebo-treated animals. Tumour growth was significantly reduced in all treatment groups. At the lowest dose tested, gemcitabine (4 mg/kg/dose), combined with frondoside A (100 mu g/kg/day) was significantly more effective than with either drug alone. To conclude: The present data suggest that combinations of frondoside A and gemcitabine may provide clinical benefit for patients with pancreatic cancer.
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| 17. |
- Al Shemaili, Jasem, et al.
(författare)
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Pharmacokinetics in Mouse and Comparative Effects of Frondosides in Pancreatic Cancer
- 2016
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Ingår i: Marine Drugs. - : MDPI AG. - 1660-3397. ; 14:6
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Tidskriftsartikel (refereegranskat)abstract
- The frondosides are triterpenoid glycosides from the Atlantic sea cucumber Cucumaria frondosa. Frondoside A inhibits growth, invasion, metastases and angiogenesis and induces apoptosis in diverse cancer types, including pancreatic cancer. We compared the growth inhibitory effects of three frondosides and their aglycone and related this to the pharmocokinetics and route of administration. Frondoside A potently inhibited growth of pancreatic cancer cells with an EC50 of similar to 1 mu M. Frondoside B was less potent (EC50 similar to 2.5 mu M). Frondoside C and the aglycone had no effect. At 100 mu g/kg, frondoside A administered to CD2F1 mice as an i.v. bolus, the Cp-max was 129 nM, Cl-tb was 6.35 mL/min/m(2), and half-life was 510 min. With i.p. administration the Cp-max was 18.3 nM, Cl-tb was 127 mL/min/m(2) and half-life was 840 min. Oral dosing was ineffective. Frondoside A (100 mu g/kg/day i.p.) markedly inhibited growth cancer xenografts in nude mice. The same dose delivered by oral gavage had no effect. No evidence of acute toxicity was seen with frondoside A. Frondoside A is more potent inhibitor of cancer growth than other frondosides. The glycoside component is essential for bioactivity. Frondoside A is only effective when administered systemically. Based on the current and previous studies, frondoside A appears safe and may be valuable in the treatment of cancer.
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- Ali, M Al Haj, et al.
(författare)
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Distribution of neuroendocrine cells in the small and large intestines of the one-humped camel (Camelus dromedarius)
- 2007
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Ingår i: Neuropeptides. - : Elsevier BV. - 0143-4179 .- 1532-2785. ; 41:5, s. 293-299
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Tidskriftsartikel (refereegranskat)abstract
- The distribution and relative frequency of neuroendocrine cells in the small and large intestines of one-humped camel were studied using antisera against 5-hydroxytryptamine (5-HT), cholecystokinin (CCK-8), somatostatin (SOM), peptide tyrosine tyrosine (PYY), gastric inhibitory polypeptide (GIP), neuronal nitric oxide synthase (nNOS), gastrin releasing peptide (GRP), substance P (SP), and neurokinin A (NKA). Among these cell types, CCK-8 immunoreactive (IR) cells were uniformly distributed in the mucosa, while others showed varied distribution in the villi or crypts of the small intestine. Immunoreactive cells like 5HT, CCK-8, and SOM showed peak density in the villi and crypts of the small intestine and in the colonic glands of the large intestine, while cells containing SP were discerned predominately in the crypts. 5-HT, CCK-8 and SOM cells were mainly flask-shaped and of the open-variety, while PYY and SP immunoreactive cells were mainly rounded or basket-shaped and of the closed variety. Basically the distribution pattern of the endocrine cells in the duodenum, jejunum and colon of the one-humped camel is similar to that of other mammals. Finally, the distribution of these bioactive agents may give clues as to how these agents aid in the function of the intestinal tract of this desert animal.
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| 19. |
- Ali, M. Al-Haj, et al.
(författare)
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Effect of high-calorie diet on the prevalence of diabetes mellitus in the one-humped camel (Camelus dromedarius)
- 2006
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Ingår i: DIABETES MELLITUS AND ITS COMPLICATIONS - MOLECULAR MECHANISMS, EPIDEMIOLOGY, AND CLINICAL MEDICINE. - : Wiley. - 9781573316354 ; , s. 402-410
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Konferensbidrag (refereegranskat)abstract
- The one-humped camel is a typical desert animal. It has the capability of withstanding the harsh climatic changes and the scarcity of food and water, in addition to the high-ambient temperature. The prevalence of diabetes mellitus in two different groups of the one-humped camel, group (A) control (n = 102) camels and group (B) high-calorie diet-fed camels (n = 103), in Al-Ain region (UAE) was studied using biochemical and radioirnmunoassay techniques. In this article, 7% of the control camels have diabetes mellitus (blood glucose level: >= 140 mg/dL) compared to 21% of the high-calorie-fed camels. Plasma insulin level was significantly (P < 0.05) lower in group B compared to group A. The low insulin level in camels consuming high-caloric diet could be a sign of exhaustion of pancreatic beta cells. The hematological parameters were nearly similar in both groups and no significant differences were seen. Liver and kidney enzymes were normal in both groups. Iron and copper were significantly (P < 0.005) higher in the high-calorie-fed camels compared with the control. Our study indicates that high-caloric feed consumption in camels is associated with the development of disorders in glucose metabolism leading to diabetes mellitus.
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- Diaz, Sandra, et al.
(författare)
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The IPBES Conceptual Framework - connecting nature and people
- 2015
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Ingår i: Current Opinion in Environmental Sustainability. - : Elsevier BV. - 1877-3435 .- 1877-3443. ; 14, s. 1-16
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Tidskriftsartikel (refereegranskat)abstract
- The first public product of the Intergovernmental Platform on Biodiversity and Ecosystem Services (IPBES) is its Conceptual Framework. This conceptual and analytical tool, presented here in detail, will underpin all IPBES functions and provide structure and comparability to the syntheses that IPBES will produce at different spatial scales, on different themes, and in different regions. Salient innovative aspects of the IPBES Conceptual Framework are its transparent and participatory construction process and its explicit consideration of diverse scientific disciplines, stakeholders, and knowledge systems, including indigenous and local knowledge. Because the focus on co-construction of integrative knowledge is shared by an increasing number of initiatives worldwide, this framework should be useful beyond IPBES, for the wider research and knowledge-policy communities working on the links between nature and people, such as natural, social and engineering scientists, policy-makers at different levels, and decision-makers in different sectors of society.
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- Koivula, Robert W., et al.
(författare)
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
- 2019
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
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| 35. |
- Li, Josephine H., et al.
(författare)
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Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
- 2023
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 72:8, s. 1161-1172
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been repli-cated in the Diabetes Prevention Program (DPP). To as-sess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal compo-nents. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes inci-dence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 1029). In the MET arm, rs144322333 near ENOSF1 (minor al-lele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, b = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10212). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, b = 27.55 [95% CI 29.88, 25.22]; P = 3.2 × 10210) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 1024 ]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.
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- Luecken, Malte D., et al.
(författare)
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The discovAIR project : a roadmap towards the Human Lung Cell Atlas
- 2022
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 60:2
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Forskningsöversikt (refereegranskat)abstract
- The Human Cell Atlas (HCA) consortium aims to establish an atlas of all organs in the healthy human body at single-cell resolution to increase our understanding of basic biological processes that govern development, physiology and anatomy, and to accelerate diagnosis and treatment of disease. The Lung Biological Network of the HCA aims to generate the Human Lung Cell Atlas as a reference for the cellular repertoire, molecular cell states and phenotypes, and cell-cell interactions that characterise normal lung homeostasis in healthy lung tissue. Such a reference atlas of the healthy human lung will facilitate mapping the changes in the cellular landscape in disease. The discovAIR project is one of six pilot actions for the HCA funded by the European Commission in the context of the H2020 framework programme. discovAIR aims to establish the first draft of an integrated Human Lung Cell Atlas, combining single-cell transcriptional and epigenetic profiling with spatially resolving techniques on matched tissue samples, as well as including a number of chronic and infectious diseases of the lung. The integrated Human Lung Cell Atlas will be available as a resource for the wider respiratory community, including basic and translational scientists, clinical medicine, and the private sector, as well as for patients with lung disease and the interested lay public. We anticipate that the Human Lung Cell Atlas will be the founding stone for a more detailed understanding of the pathogenesis of lung diseases, guiding the design of novel diagnostics and preventive or curative interventions.
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