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- 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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| 4. |
- Forlenza, O. V., et al.
(författare)
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Cerebrospinal fluid biomarkers in Alzheimer's disease: Diagnostic accuracy and prediction of dementia
- 2015
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Ingår i: Alzheimer's & Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 1:4, s. 455-463
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Guidelines for the use of cerebrospinal fluid (CSF) biomarkers in the diagnosis of Alzheimer's disease (AD) establish that each laboratory must use internally qualified cutoff values. We determined the concentrations of biomarkers that discriminate cases from controls and combinations that predict the progression to dementia in a Brazilian cohort. Methods: Concentrations of amyloid-beta peptide (Aβ1-42), total tau (T-tau), and 181Thr-phosphorylated-tau (P-tau) were determined in CSF samples from 184 older adults (68 mild cognitive impairment, 41 AD, 34 non-AD cognitive impairment, and 41 controls) by the INNO-BIA AlzBio3 assay. Results: Cutoff values discriminating AD from controls are as follows: Aβ1-42: 416.0 pg/mL (sensitivity [SE]: 83%, specificity (SP): 70%); T-tau: 76.7 pg/mL (SE: 82%, SP: 67%); P-tau: 36.1 pg/mL (SE: 83%, SP: 49%); Aβ1-42/P-tau <9.53 (SE: 88%, SP: 78%); and Aβ1-42/T-tau <4.13 (SE: 80%; SP: 80%). Combining values Aβ1-42 <416.5 pg/mL and Aβ1-42/P-tau <9.5 best predicted the conversion in 2 years (Cox regression: hazard ratio 7.24 [2.09-25.06], P =.002, SE: 74%, Sp: 73%). Discussion: Our findings are in line with most of the available evidence in this field; yet, our cutoff values are different from those derived from other laboratories. © 2015 The Authors.
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| 6. |
- Mattsson, Niklas, 1979, et al.
(författare)
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The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
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| 7. |
- Palmer, Nathan, et al.
(författare)
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A novel function for CDK2 activity at meiotic crossover sites
- 2020
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Ingår i: PLoS Biology. - : Public Library of Science (PLoS). - 1545-7885. ; 18:10
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Tidskriftsartikel (refereegranskat)abstract
- Genetic diversity in offspring is induced by meiotic recombination, which is initiated between homologs at >200 sites originating from meiotic double-strand breaks (DSBs). Of this initial pool, only 1-2 DSBs per homolog pair will be designated to form meiotic crossovers (COs), where reciprocal genetic exchange occurs between parental chromosomes. Cyclin-dependent kinase 2 (CDK2) is known to localize to so-called "late recombination nodules" (LRNs) marking incipient CO sites. However, the role of CDK2 kinase activity in the process of CO formation remains uncertain. Here, we describe the phenotype of 2 Cdk2 point mutants with elevated or decreased activity, respectively. Elevated CDK2 activity was associated with increased numbers of LRN-associated proteins, including CDK2 itself and the MutL homolog 1 (MLH1) component of the MutLγ complex, but did not lead to increased numbers of COs. In contrast, reduced CDK2 activity leads to the complete absence of CO formation during meiotic prophase I. Our data suggest an important role for CDK2 in regulating MLH1 focus numbers and that the activity of this kinase is a key regulatory factor in the formation of meiotic COs.
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| 8. |
- Palmer, Nathan, et al.
(författare)
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Diverse roles for CDK-associated activity during spermatogenesis
- 2019
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Ingår i: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 593:20, s. 2925-2949
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Forskningsöversikt (refereegranskat)abstract
- The primary function of cyclin-dependent kinases (CDKs) in complex with their activating cyclin partners, is to promote mitotic division in somatic cells. This canonical cell cycle-associated activity is also crucial for fertility as it allows the proliferation and differentiation of stem cells within the reproductive organs to generate meiotically competent cells. Intriguingly several CDKs exhibit meiosis-specific functions and are essential for the completion of the two reductional meiotic divisions required to generate haploid gametes. These meiosis-specific functions are mediated by both known CDK/cyclin complexes and meiosis-specific CDK-regulators and are important for a variety of processes during meiotic prophase. The majority of meiotic defects observed upon deletion of these proteins occur during the extended prophase I of the first meiotic division. Importantly a lack of redundancy is seen within the meiotic arrest phenotypes described for many of these proteins suggesting intricate layers of cell cycle control are required for normal meiotic progression. Using the process of male germ cell development (spermatogenesis) as a reference, this review seeks to highlight the diverse roles of selected CDKs their activators, and their regulators during gametogenesis.
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| 9. |
- Palmer, Nathan, et al.
(författare)
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Identification PMS1 and PMS2 as potential meiotic substrates of CDK2 activity
- 2023
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 18:3
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Tidskriftsartikel (refereegranskat)abstract
- Cyclin dependent-kinase 2 (CDK2) plays important functions during the mitotic cell cycle and also facilitates several key events during germ cell development. The majority of CDK2's known meiotic functions occur during prophase of the first meiotic division. Here, CDK2 is involved in the regulation of meiotic transcription, the pairing of homologous chromosomes, and the maturation of meiotic crossover sites. Despite that some of the CDK2 substrates are known, few of them display functions in meiosis. Here, we investigate potential meiotic CDK2 substrates using in silico and in vitro approaches. We find that CDK2 phosphorylates PMS2 at Thr337, PMS1 at Thr331, and MLH1 in vitro. Phosphorylation of PMS2 affects its interaction with MLH1 to some degree. In testis extracts from mice lacking Cdk2, there are changes in expression of PMS2, MSH2, and HEI10, which may be reflective of the loss of CDK2 phosphorylation. Our work has uncovered a few CDK2 substrates with meiotic functions, which will have to be verified in vivo. A better understanding of the CDK2 substrates will help us to gain deeper insight into the functions of this universal kinase.
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