Tyrosine kinase inhibitors for the therapy of anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is often incurable so new therapeutic approaches are needed. Tyrosine kinases inhibitors (such as imanitib, sunitinib or sorafenib) are under evaluation for the treatment of ATC. Other vascular disrupting agents, such as combretastatin A4 phosphate, and antiangiogenic agents, such as aplidin, PTK787/ZK222584 and human VEGF monoclonal antibodies (bevacizumab, cetuximab), have been evaluated. Small-molecule adenosine triphosphate competitive inhibitors directed intracellularly at EGFRs tyrosine kinase, such as erlotinib or gefitinib, are also studied. Furthermore, new molecules have been shown to be active against ATC, such as CLM94 and CLM3. However, more research is needed to finally identify therapies able to control and to cure this disease

Impact of Subthalamic Deep Brain Stimulation Frequency on Upper Limb Motor Function in Parkinson's Disease

BACKGROUND: Whilst changes in the frequency of subthalamic deep brain stimulation (STN-DBS) have been proposed to improve control of tremor or axial motor features in Parkinson's disease (PD), little is known about the effects of frequency changes on upper limb motor function, particularly bradykinesia. OBJECTIVE: To investigate the acute effects of various STN-DBS frequencies (40-160 Hz, 40 Hz intervals) on upper limb motor function. METHODS: We carried out a randomised, double-blind study on 20 PD patients with chronic STN-DBS using the Simple and Assembly components of the Purdue Pegboard (PP) test and a modified upper limb version of the UPDRS-III (UL-UPDRS-III). RESULTS: There was no significant effect of frequency on bradykinesia on the Simple PP task or the UL-UPDRS-III. There was an effect of frequency on the Assembly PP score when comparing all frequencies (p = 0.019) and between 80 Hz and 130 Hz (p = 0.007), with lower frequencies yielding a better performance. Rigidity and Tremor scores were significantly reduced with higher (>80 Hz) compared to lower (40 Hz) frequencies. CONCLUSIONS: Our findings suggest that a wide range of frequencies are efficacious in improving acute upper-limb motor function. Reducing the frequency of stimulation down to 80 Hz is safe and has a similar clinical effect to higher frequencies. Therefore, a wider range of frequencies are available when it comes adjusting patients' acute settings without the risk of worsening bradykinesia

The Emergence and Progression of Motor Dysfunction in Individuals at Risk of Parkinson's Disease

BACKGROUNDL: PREDICT-PD is a United Kingdom population-based study aiming to stratify individuals for future Parkinson's disease (PD) using a risk algorithm. METHODS: A randomly selected, representative sample of participants in PREDICT-PD were examined using several motor assessments, including the motor section of the Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)-III, at baseline (2012) and after an average of 6 years of follow-up. We checked for new PD diagnoses in participants seen at baseline and examined the association between risk scores and incident sub-threshold parkinsonism, motor decline (increasing ≥5 points in MDS-UPDRS-III) and single motor domains in the MDS-UPDRS-III. We replicated analyses in two independent datasets (Bruneck and Parkinson's Progression Markers Initiative [PPMI]). RESULTS: After 6 years of follow-up, the PREDICT-PD higher-risk group (n = 33) had a greater motor decline compared with the lower-risk group (n = 95) (30% vs. 12.5%, P = 0.031). Two participants (both considered higher risk at baseline) were given a diagnosis of PD during follow-up, with motor signs emerging between 2 and 5 years before diagnosis. A meta-analysis of data from PREDICT-PD, Bruneck, and PPMI showed an association between PD risk estimates and incident sub-threshold parkinsonism (odds ratio [OR], 2.01 [95% confidence interval (CI), 1.55–2.61]), as well as new onset bradykinesia (OR, 1.69 [95% CI, 1.33–2.16]) and action tremor (OR, 1.61 [95% CI, 1.30–1.98]). CONCLUSIONS: Risk estimates using the PREDICT-PD algorithm were associated with the occurrence of sub-threshold parkinsonism, including bradykinesia and action tremor. The algorithm could also identify individuals whose motor examination experience a decline over time

Inanspruchnahme von Angebotsuntersuchungen in der arbeitsmedizinischen Vorsorge

In den vergangenen zehn Jahren wurde die arbeitsmedizinische Vorsorge zu einem individuellen Arbeitsschutzinstrument weiterentwickelt, das der Aufklärung und Beratung der Beschäftigten über die Wechselwirkungen zwischen Arbeit und Gesundheit dient und bei dem die Selbstbestimmungs- und Datenschutzrechte zu achten sind. In dem vorliegenden Forschungsprojekt hat das Institut für Arbeitsmedizin, Sozialmedizin und Versorgungsforschung der Universitätsklinik Tübingen exemplarisch untersucht, welche Faktoren für die erfolgreiche Durchführung von Angebotsuntersuchungen bedeutsam sind. Die Studie bedient sich hierfür eines multimodularen Ansatzes mit qualitativen und quantitativen Anteilen. Im Ergebnis wird sichtbar, dass die Verordnung zur arbeitsmedizinischen Vorsorge (ArbMedVV) in der Praxis angekommen ist. Zum Teil werden arbeitsmedizinische Vorsorge und Eignungsuntersuchungen jedoch nicht adäquat unterschieden. Mit der Änderung der ArbMedVV Ende Oktober 2013 konnten bereits wichtige Klarstellungen erreicht werden. Unsicherheiten bestehen auch im Zusammenhang mit den so genannten Berufsgenossenschaftlichen Grundsätzen, die teilweise irrtümlich als verbindlich verstanden werden. Hier besteht noch Änderungs- und Klarstellungsbedarf. Übergreifend zeigt die Studie, dass die Inanspruchnahme der arbeitsmedizinischen Vorsorge maßgeblich vom Kenntnisstand aller Beteiligten zur Rechtslage abhängt und das Vertrauensverhältnis zum Betriebsarzt für die Beschäftigten von besonderer Bedeutung ist. Aufklärungsarbeit spielt deshalb auch weiterhin eine wichtige Rolle

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-ß signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-ß-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-ß, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-ß induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-ß induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-ß-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-ß-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-ß. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-ß and for the subsequent gene induction dependent on these signalling pathways

Designing stem-cell-based dopamine cell replacement trials for Parkinson's disease

Clinical studies of Parkinson’s disease (PD) using a dopamine cell replacment strategy have been tried for more than 30 years. The outcomes following transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years and others not responding and/or developing significant side effects, including graft-induced dyskinesia. This led to a re-appraisal of the best way to do such trials, which resulted in a new European-Union-funded allograft trial with fetal dopamine cells across several centers in Europe. This new trial, TRANSEURO (NCT01898390), is an open-label study in which some individuals in a large observational cohort of patients with mild PD who were undergoing identical assessments were randomly selected to receive transplants of hfVM. The TRANSEURO trial is currently ongoing as researchers have completed both recruitment into a large multicenter observational study of younger onset early-stage PD and transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with the lessons we have learned along the way, can help inform researchers and facilitate planning of transplants of dopamine-producing cells derived from human pluripotent stem cells for future clinical trials

Application of a Simple Parkinson's Disease Risk Score in a Longitudinal Population-Based Cohort.

BACKGROUND: Identifying individuals at risk of developing Parkinson's disease (PD) is critical to define target populations for future neuroprotective trials. OBJECTIVE: The objective of this study was to apply the PREDICT-PD algorithm of risk indicators for PD in a prospective community-based study (the Bruneck study), representative of the general elderly population. METHODS: PREDICT-PD risk scores were calculated based on risk factor assessments obtained at baseline (2005, n = 574 participants). Cases of incident PD were identified at 5-year and 10-year follow-ups. Participants with PD or secondary parkinsonism at baseline were excluded (n = 35). We analyzed the association of log-transformed risk scores with the presence of well-established markers as surrogates for PD risk at baseline and with incident PD at follow-up. RESULTS: A total of 20 participants with incident PD were identified during follow-up (11 after 5 years and 9 after 10 years). Baseline PREDICT-PD risk scores were associated with incident PD with odds ratios of 2.09 (95% confidence interval, 1.35-3.25; P = 0.001) after 5 years and of 1.95 (1.36-2.79; P < 0.001) after 10 years of follow-up per doubling of risk scores. In addition, higher PREDICT-PD scores were significantly correlated with established PD risk markers (olfactory dysfunction, signs of rapid eye movement sleep behavior disorder and motor deficits) and significantly associated with higher probability for prodromal PD according to the Movement Disorder Society research criteria at baseline. CONCLUSIONS: The PREDICT-PD score was associated with an increased risk for incident PD in our sample and may represent a useful first screening step in future algorithms aiming to identify cases of prodromal PD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Inhibition of ER stress-mediated apoptosis in macrophages by nuclear-cytoplasmic relocalization of eEF1A by the HIV-1 Nef protein

HIV-1 Nef protein has key roles at almost all stages of the viral life cycle. We assessed the role of the Nef/eEF1A (eukaryotic translation elongation factor 1-alpha) complex in nucleocytoplasmic shuttling in primary human macrophages. Nuclear retention experiments and inhibition of the exportin-t (Exp-t) pathway suggested that cytoplasmic relocalization of eEF1A, mediated by Exp-t, occurs in Nef-treated monocyte-derived macrophages (MDMs). We observed the presence of tRNA in the Nef/eEF1A complexes. Nucleocytoplasmic relocalization of the Nef/eEF1A complexes prevented stress-induced apoptosis of MDMs treated with brefeldin-A. Blockade of stress-induced apoptosis of MDMs treated with HIV-1 Nef resulted from enhanced nucleocytoplasmic transport of eEF1A with decreased release of mitochondrial cytochrome c, and from increased tRNA binding to cytochrome c, ultimately leading to an inhibition of caspase activation. Our results indicate that HIV-1 Nef, through the nucleocytoplasmic relocalization of eEF1A and tRNAs, enhances resistance to stress-induced apoptosis in primary human macrophages

Effect of Low versus High Frequency Subthalamic Deep Brain Stimulation on Speech Intelligibility and Verbal Fluency in Parkinson’s Disease: A Double-Blind Study

BACKGROUND: Subthalamic deep brain stimulation (STN-DBS) is an established treatment for late stage Parkinson's disease (PD). Speech intelligibility (SI) and verbal fluency (VF) have been shown to deteriorate following chronic STN-DBS. It has been suggested that speech might respond favourably to low frequency stimulation (LFS). OBJECTIVE: We examined how speech intelligibility, perceptual speech characteristics, phonemic and semantic VF and processes underlying it (clustering and switching) respond to LFS of 60 and 80 Hz in comparison to high frequency stimulation (HFS) (110, 130 and 200 Hz). METHODS: In this double-blind study, 15 STN-DBS PD patients (mean age 65, SD = 5.8, 14 right handed, three females), were assessed at five stimulation frequencies: 60 Hz, 80 Hz, 110 Hz, 130 Hz and 200 Hz. In addition to the clinical neurological assessment of speech, VF and SI were assessed. RESULTS: Speech intelligibility and in particular articulation, respiration, phonation and prosody improved with LFS (all p <  0.05). Phonemic VF switching improved with LFS (p = 0.005) but this did not translate to an improved phonemic VF score. A trend for improved semantic VF was found. A negative correlation was found between perceptual characteristics of speech and duration of chronic stimulation (all p <  0.05). CONCLUSIONS: These findings highlight the need for meticulous programming of frequency to maximise speech intelligibility in chronic STN-DBS. The findings further implicate stimulation frequency in changes to specific processes underlying VF, namely phonemic switching and demonstrate the potential to address such deficits through advanced adjustment of stimulation parameters