Molekular- und zellbiologische Untersuchungen zur effektiven Suppression des onkogenen Fusionsproteins BCR-Abl

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Crystal Structure of the Hexamerization Domain of N-ethylmaleimide–Sensitive Fusion Protein

AbstractN-ethylmaleimide–sensitive fusion protein (NSF) is a cytosolic ATPase required for many intracellular vesicle fusion reactions. NSF consists of an amino-terminal region that interacts with other components of the vesicle trafficking machinery, followed by two homologous ATP-binding cassettes, designated D1 and D2, that possess essential ATPase and hexamerization activities, respectively. The crystal structure of D2 bound to Mg2PLUSPUSSIGN-AMPPNP has been determined at 1.75 Å resolution. The structure consists of a nucleotide-binding and a helical domain, and it is unexpectedly similar to the first two domains of the clamp-loading subunit δ′ of E. coli DNA polymerase III. The structure suggests several regions responsible for coupling of ATP hydrolysis to structural changes in full-length NSF

Familial X-linked cardiomyopathy (Danon disease): diagnostic confirmation by mutation analysis of the LAMP2 gene

A boy presented at age 2.5 years with mild left ventricular hypertrophy and mild myopathy. Hypertrophic cardiomyopathy progressed relentlessly, leading to death at age 16 years shortly before planned heart transplantation. During the course of the disease, his mother developed severe dilated cardiomyopathy and died of its complications at 46 years of age. The combination of myopathy and cardiomyopathy, the biochemical and electron microscopy findings in a muscle biopsy, and the pedigree suggested Danon disease (MIM 300257), an X-linked lysosomal storage disorder caused by deficiency of lysosome-associated membrane protein-2 (LAMP2). The diagnosis was confirmed by the identification of a novel mutation, G138A, in the LAMP2gene, leading to the premature stop codon W46X. Conclusion:Early diagnosis of Danon disease is important for genetic counselling and timely cardiac transplantation, the only effective therapeutic optio

Redefining value: a discourse analysis on value-based health care

__Background__ Today’s remarkable popularity of value-based health care (VBHC) is accompanied by considerable ambiguity concerning the very meaning of the concept. This is evident within academic publications, and mirrored in fragmented and diversified implementation efforts, both within and across countries. __Method__ This article builds on discourse analysis in order to map the ambiguity surrounding VBHC. We conducted a document analysis of publicly accessible, official publications (n = 22) by actors and organizations that monitor and influence the quality of care in the Netherlands. Additionally, between March and July 2019, we conducted a series of semi-structured interviews (n = 23) with national stakeholders. __Results__ Our research revealed four discourses, each with their own perception regarding the main purpose of VBHC. Firstly, we identified a Patient Empowerment discourse in which VBHC is a framework for strengthening the position of patients regarding their medical decisions. Secondly, in the Governance discourse, VBHC is a toolkit to incentivize providers. Thirdly, within the Professionalism discourse, VBHC is a methodology for healthcare delivery. Fourthly, in the Critique discourse, VBHC is rebuked as a dogma of manufacturability. We also show, however, that these diverging lines of reasoning find common ground: they perceive shared decision-making to be a key component of VBHC. Strikingly, this common perception contrasts with the pioneering literature on VBHC. __Conclusions__ The four discourses will profoundly shape the diverse manners in which VBHC moves from an abstract concept to the practical provision and administration of health care. Moreover, our study reveals that VBHC’s conceptual ambiguity largely arises from differing and often deeply rooted presuppositions, which underlie these discourses, and which frame different perceptions on value in health care. The meaning of VBHC – including its perceived implications for action – thus depends greatly on the frame of reference an actor or organization brings to bear as they aim for more value for patients. Recognizing this is a vital concern when studying, implementing and evaluating VBHC

Expert consensus on moving towards a value-based healthcare system in the Netherlands

Objectives: While the uptake of value-based health care (VBHC) is remarkable, uncertainty prevails regarding the most important actions and practices in establishing a value-based healthcare system. In this paper, we generate expert consensus on the most important aspects of VBHC. Design: The Delphi technique was used to reach consensus on the most important practices in moving towards a value-based healthcare system. Setting and participants: A Dutch expert panel consisting of nine members participated in a two-round survey. Primary and secondary outcome measures: We developed 39 initial items based on the pioneering literature on VBHC and recent health policies in the Netherlands. Experts rated the importance of each item on a 4-point Likert scale. Experts could change items or add new ones as they saw fit. We retained items that were rated (very) important by ≥80% of the panel. Results: After two survey rounds, 32 items (72%) were included through expert consensus. Experts unanimously agree on the importance of shared decision-making, with this item uniquely obtaining the maximum score. Experts also reached consensus on the importance of outcome measurements, a focus on medical conditions, and full cycles of care. No consensus was reached on the importance of benchmarking. Conclusion: This paper provides new insight into the most important actions and practices for establishing a value-based healthcare system in the Netherlands. Interestingly, several of our findings contrast with the pioneering literature on VBHC. This raises the question whether VBHC’s widespread international uptake indicates its actual implementation, or rather that the original concept primaril

Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy (CIPN) with Non-Pharmacological Interventions: Clinical Recommendations from a Systematic Scoping Review and an Expert Consensus Process

Background: Most individuals affected by cancer who are treated with certain chemotherapies suffer of CIPN. Therefore, there is a high patient and provider interest in complementary non-pharmacological therapies, but its evidence base has not yet been clearly pointed out in the context of CIPN. Methods: The results of a scoping review overviewing the published clinical evidence on the application of complementary therapies for improving the complex CIPN symptomatology are synthesized with the recommendations of an expert consensus process aiming to draw attention to supportive strategies for CIPN. The scoping review, registered at PROSPERO 2020 (CRD 42020165851), followed the PRISMA-ScR and JBI guidelines. Relevant studies published in Pubmed/MEDLINE, PsycINFO, PEDro, Cochrane CENTRAL, and CINAHL between 2000 and 2021 were included. CASP was used to evaluate the methodologic quality of the studies. Results: Seventy-five studies with mixed study quality met the inclusion criteria. Manipulative therapies (including massage, reflexology, therapeutic touch), rhythmical embrocations, movement and mind–body therapies, acupuncture/acupressure, and TENS/Scrambler therapy were the most frequently analyzed in research and may be effective treatment options for CIPN. The expert panel approved 17 supportive interventions, most of them were phytotherapeutic interventions including external applications and cryotherapy, hydrotherapy, and tactile stimulation. More than two-thirds of the consented interventions were rated with moderate to high perceived clinical effectiveness in therapeutic use. Conclusions: The evidence of both the review and the expert panel supports a variety of complementary procedures regarding the supportive treatment of CIPN; however, the application on patients should be individually weighed in each case. Based on this meta-synthesis, interprofessional healthcare teams may open up a dialogue with patients interested in non-pharmacological treatment options to tailor complementary counselling and treatments to their needs

Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases

Background: Recently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information. Methods: From 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months. Results: At 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival. Conclusions: Moderate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information

Prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN) with non-pharmacological interventions : clinical recommendations from a systematic scoping review and an expert consensus process

Background: Most individuals affected by cancer who are treated with certain chemotherapies suffer of CIPN. Therefore, there is a high patient and provider interest in complementary non-pharmacological therapies, but its evidence base has not yet been clearly pointed out in the context of CIPN. Methods: The results of a scoping review overviewing the published clinical evidence on the application of complementary therapies for improving the complex CIPN symptomatology are synthesized with the recommendations of an expert consensus process aiming to draw attention to supportive strategies for CIPN. The scoping review, registered at PROSPERO 2020 (CRD 42020165851), followed the PRISMA-ScR and JBI guidelines. Relevant studies published in Pubmed/MEDLINE, PsycINFO, PEDro, Cochrane CENTRAL, and CINAHL between 2000 and 2021 were included. CASP was used to evaluate the methodologic quality of the studies. Results: Seventy-five studies with mixed study quality met the inclusion criteria. Manipulative therapies (including massage, reflexology, therapeutic touch), rhythmical embrocations, movement and mind-body therapies, acupuncture/acupressure, and TENS/Scrambler therapy were the most frequently analyzed in research and may be effective treatment options for CIPN. The expert panel approved 17 supportive interventions, most of them were phytotherapeutic interventions including external applications and cryotherapy, hydrotherapy, and tactile stimulation. More than two-thirds of the consented interventions were rated with moderate to high perceived clinical effectiveness in therapeutic use. Conclusions: The evidence of both the review and the expert panel supports a variety of complementary procedures regarding the supportive treatment of CIPN; however, the application on patients should be individually weighed in each case. Based on this meta-synthesis, interprofessional healthcare teams may open up a dialogue with patients interested in non-pharmacological treatment options to tailor complementary counselling and treatments to their needs

A cohort of 17 patients with kyphoscoliotic Ehlers-Danlos syndrome caused by biallelic mutations in FKBP14: expansion of the clinical and mutational spectrum and description of the natural history.

PurposeIn 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.MethodsWe report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.ResultsBased on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.ConclusionOur data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS