GENERAL PRACTICES can improve clinical outcomes if they employ more nurses, according to newly published work by the national nursing research Unit (NNRU).
Aim
PROMoting THE USE of Studies Within A Trial (PROMETHEUS) aimed to improve the evidence base for recruiting and retaining participants in Randomised Controlled Trials (RCTs) by pump-priming and ...facilitating the start of at least 25 Studies Within A Trial (SWATs) testing recruitment or retention interventions.
Methods
Ten Clinical Trials Units (CTUs) and one Primary Care Research Centre formed a network to conduct randomised SWATs of recruitment and/or retention strategies. We identified promising recruitment and retention interventions from various sources, which were reviewed by patient and public (PPI) partners to generate an initial priority list of seven recruitment and eight retention interventions.
Host trial teams could apply for funding of up to £5000 and receive support from the PROMETHEUS team to design, implement, and report SWATs. We additionally tested the feasibility of undertaking coordinated SWATs across multiple host trials simultaneously.
Results
PROMETHEUS funded 42 SWATs, embedded within 31 host trials, across 12 CTUs. The SWAT cost per SWAT was £3535. Of the 42 SWATs, 12 tested the same SWAT in multiple trials (simultaneous SWAT design) and eight tested a factorial SWAT design. PROMETHEUS will add 18% and 79% more SWATs to the Cochrane systematic review of recruitment strategies and the Cochrane review of retention strategies respectively.
Conclusion
The PROMETHEUS programme substantially increased the evidence base for both recruitment and retention strategies within RCTs. Future research should adopt a systematic approach to identifying and targeting gaps in the evidence base and focus on translating SWAT evidence into recruitment and retention practice.
Genetic studies suggest that the major events of human hair follicle development are similar to those in mice, but detailed analyses of this process are lacking. In mice, hair follicle placode ...“budding” is initiated by invagination of Wnt-induced epithelium into the underlying mesenchyme. Modification of adherens junctions (AJs) is clearly required for budding. Snail-mediated downregulation of AJ component E-cadherin is important for placode budding in mice. Beta-catenin, another AJ component, has been more difficult to study owing to its essential functions in Wnt signaling, a prerequisite for hair follicle placode induction. Here, we show that a subset of human invaginating hair placode cells expresses the stem cell marker CD133 during early morphogenesis. CD133 associates with membrane beta-catenin in early placodes, and its continued expression correlates with loss of beta-catenin and E-cadherin from the cell membrane at a time when E-cadherin transcriptional repressors Snail and Slug are not implicated. Stabilization of CD133 via anti-CD133 antibody treatment of human fetal scalp explants depresses beta-catenin and E-cadherin membrane localization. We discuss this unique correlation and suggest a hypothetical model whereby CD133 promotes morphogenesis in early hair follicle placodes through the localized removal of membrane beta-catenin proteins and subsequent AJ dissolution.
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Overall, the survival with current chemotherapy is only 20-40%, declining steadily with advancing age. Approximately ...30% of AML patients have mutations that constitutively activate the FLT3 gene. The most common FLT3 mutation results in tandem duplications within the juxtamembrane domain, observed in 20-25% of AML patients (internal tandem duplication, ITD), associated with markedly decreased survival. FLT3 kinase domain inhibitors, including SU11248, SU5416, CEP-701 and PKC412 (midostaurin), have been shown to induce partial, and usually brief, remissions in clinical trials of relapsed AML patients when administered as single agents. In a large trial in newly diagnosed patients, however, midostaurin was shown to increase survival when combined with standard chemotherapy.1 This study supports the notion that inhibition of FLT3 may be important, at least in patients with mutations in the FLT3 gene. Since drug resistance develops in some patients with newly diagnosed AML and virtually all patients with advanced disease, additional strategies to target FLT3 would be of value.
We discovered that the deubiquitinating enzyme (DUB) ubiquitin specific protease 10 (USP10) removes a degradative ubiquitin tag from mutant FLT3 thereby contributing to high levels of the oncogenic protein in AML (Fig 1a). Screening of our preclinical DUB inhibitor library for ability to selectively kill growth factor-independent FLT3-ITD-positive Ba/F3 cells over IL-3-dependent parental Ba/F3 cells identified HBX19818, a reported USP7 inhibitor, as the top hit. The effects are not unique to the Ba/F3 system: when profiled against a panel of 7 leukemia cell lines, HBX19818 conferred a substantial growth suppressive effect only to those expressing the FLT3-ITD oncoprotein (Fig 1b). As an initial assessment of the mechanism of HBX19818 we confirmed that it does promote ubiquitin-mediated degradation of FLT3-ITD (Fig 1c) and that the effect is selective as HBX19818 does not impact protein levels of wt FLT3. HBX19818 is published as an irreversible USP7 inhibitor,2 however DUBome selectivity profiling data we generated identifies USP10 as the most potently inhibited DUB of the compound (USP10 IC50 = 14 µM). We went on to validate USP10 as the DUB that stabilizes FLT3-ITD using a combination of small molecule and genetic experiments. Notably, HBX19818 binds and inhibits USP10 in cells (data not shown), small hairpin knockdown of USP10 phenocopies the antiproliferative and FLT3 degradation effects of HBX19818 (Figure 1d and data not shown), and a direct interaction between USP10 and FLT3-ITD is observed in co-immunoprecipitation experiments (Fig 1e). Additionally, SAR studies reveal correlation among USP10 IC50, FLT3-ITD degradation and anti-proliferative effects for the HBX19818 chemical series, and we identified a second chemotype that phenocopies its effects. In support of the translational potential of USP10 inhibition for FLT3 mutant AML, we observed that both USP10 inhibitor series synergize with FLT3 kinase inhibitors, suppress growth of mutant FLT3-expressing primary AML cells and primagraft AML cells and, importantly, display the ability to overcome the FLT3 inhibitor-resistant mutant FLT3-ITD-F691L among other FLT3 kinase inhibitor-resistant mutants (Fig. 1f and data not shown).
Overall, our data strongly support degradation of mutant FLT3 as an alternative approach to therapeutically target FLT3. This approach, which focuses on targeting USP10, could prove more efficacious than kinase inhibitors by simultaneously blocking both enzymatic and scaffolding functions of FLT3, and blocking compensatory increases in FLT3 protein or resistant point mutations associated with some kinase inhibitors. Importantly, this is the first demonstration of stabilization of an AML mutant driver protein by a DUB enzyme and introduces a novel therapy for FLT3 mutant-positive AML.
References:
1. Stone, R.M., ASH, 2015.
2. Reverdy, C., et al., Chem Biol, 2012. 19, 467-77.
Display omitted
Weisberg:novartis: Research Funding. Weinstock:Novartis: Consultancy, Research Funding. Stone:Celator: Consultancy; Pfizer: Consultancy; Xenetic Biosciences: Consultancy; Novartis: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Amgen: Consultancy; ONO: Consultancy; Xenetic Biosciences: Consultancy; Sunesis Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Karyopharm: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Agios: Consultancy; Jansen: Consultancy. Gray:Gatekeeper: Equity Ownership; Petra: Consultancy, Equity Ownership; C4: Consultancy, Equity Ownership; Syros: Consultancy, Equity Ownership. Griffin:Janssen: Research Funding; Novartis: Consultancy, Research Funding.
How Do I Examine Rigidity and Spasticity? Fearon, Conor; Doherty, Laura; Lynch, Tim
Movement disorders clinical practice (Hoboken, N.J.),
June 2015, Letnik:
2, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Examination of tone (increased resistance to the passive movement of a joint) is a clinically useful and occasionally neglected part of the neurological examination. Rigidity and spasticity are two ...distinct types of hypertonia that arise from distinct anatomical pathways. The ability to differentiate between these two entities therefore gives important information regarding localization. Whereas spasticity arises as a result of damage to the corticoreticulospinal (pyramidal) tracts, rigidity is caused by dysfunction of extrapyramidal pathways, most commonly the basal ganglia, but also as a result of lesions of the mesencephalon and spinal cord. Spasticity is characterized by abnormally high muscle tone, which often asymmetrically affects antagonistic muscle groups. It is both amplitude and velocity dependent and is therefore best assessed using rapid movements of the relevant joint to effect abrupt stretching of the muscle group involved. When a threshold velocity, angle, or amplitude is reached, a sudden increase in tone can be detected as a characteristic “catch.” Rigidity differs from spasticity in that the increased tone remains constant throughout the range of movement of the joint. It is independent of velocity and should even be detectable with very slow movements. It is present in flexors and extensor muscle groups equally, giving rise to a uniform quality in all directions often described as “lead pipe” rigidity. Given that rigidity frequently arises in diseases of the basal ganglia, a tremor can coexist, giving rise to an interrupted “cogwheeling” effect. We herein describe an approach to the examination of patients with rigidity and spasticity.
PDF
