Impairments across multiple domains are a disabling consequence of multiple sclerosis (MS). Originating from preventive medical strategies, the “time matters”-perspective has become a focal point ...when treating MS. In particular, early detection of physical and cognitive deficits, along with deficits in patient-reported outcomes seems crucial to further optimize both pharmacological and non-pharmacological MS treatment strategies. Therefore, this topical review investigates the level of impairments across multiple domains (physical function, cognitive function, and patient-reported outcomes) in the early stage of MS (⩽5 years since diagnosis, including clinically isolated syndrome (CIS)), when compared to matched healthy controls. Even at early disease stages, studies show impairments corresponding to 8%–34% and small-to-large numerical effect sizes (0.35–2.85) in MS/CIS patients across domains. This evidence call for early screening programs along with early interventions targeting the multiple impaired domains. This further highlights the importance of preventive initiatives preserving and/or restoring physical and cognitive reserve capacity if possible.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
No studies have synthesized the literature regarding mechanical muscle function (ie, strength, power, rate of force development RFD) in people with Parkinson disease (PD). Here, we aimed to expand ...our understanding of mechanical muscle function in people with PD (PwPD) by systematically reviewing (1) the psychometric properties of isokinetic/isometric dynamometry in PD, (2) the literature comparing mechanical muscle function in PwPD with healthy controls (HC), and (3) reported associations between muscle mechanical muscle function and functional capacity and/or disease severity.
Systematic literature search in 6 databases. Included studies had to (1) enroll and report data on PwPD, (2) include assessment(s) of psychometric properties (ie, validity, reliability, responsiveness) of isokinetic/isometric dynamometry in PD, and/or (3) assess mechanical muscle function in both PwPD and HC using isokinetic/isometric dynamometry.
A total of 40 studies were included. Aim 1 studies (n = 2) showed high reliability for isometric dynamometry (hip-abductor/dorsiflexor/trunk flexor-extensor/handgrip: intraclass correlations coefficients range = 0.92-0.98). Aim 2 studies (n = 40) showed impaired mechanical muscle function (ie, strength, power, RFD) in PwPD compared with HC (effect sizes range = 0.52-1.89). Aim 3 studies (n = 11) showed weak-to-strong associations between overall and lower extremities muscle strength and functional capacity and/or disease severity outcomes (ie, Unified Parkinson Disease Rating Scale).
Sparse methodological evidence suggests high reliability when using dynamometry in PwPD. Muscle strength, power, and RFD are impaired in PwPD compared with HC. Muscle strength is associated with functional capacity and disease severity.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A403 ).
Oligonucleotides containing Locked Nucleic Acids (LNA) to various extents and at various positions were evaluated for antisense activity, RNase H recruitment, nuclease stability and thermal affinity. ...In this work, two different diastereoisomers of LNA were studied: the beta‐d‐LNA and the alpha‐l‐LNA (abbreviated as β‐d‐LNA and α‐l‐LNA). Our findings show that the best antisense activity with 16mer gapmers containing β‐d‐LNA (oligonucleotides containing consecutive segments of LNA and DNA with a central DNA stretch flanked by two LNA segments, LNA–DNA–LNA) is found with gap sizes between 7 and 10 nt. The optimal gap size is motif‐dependent, and requires the right balance between gap size and affinity. Compared to β‐d‐LNA, α‐l‐LNA shows superior stability against a 3′‐exonuclease. The design possibilities of α‐l‐LNA were explored for different gapmers and other designs, collectively called chimeras. The placement of α‐l‐LNA in the junctions or in the flanks resulted in potent antisense oligonucleotides. Moreover, different chimeras with an alternate composition of DNA, α‐l‐LNA and β‐d‐LNA were evaluated in terms of antisense activity and RNase H recruitment. Chimeras with an interrupted DNA stretch with α‐l‐LNA still recruit RNase H and show good levels of antisense activity, while the same design with β‐d‐LNA results in a drop in antisense potency. Our findings indicate that α‐l‐LNA is a powerful and versatile nucleotide analogue for designing potent antisense oligonucleotides.
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Background: SPC2968 is a short (16-mer), oligonucleotide antagonist of Hif-1α mRNA in which potency has been enhanced through incorporation of Locked Nucleic Acid. Over-expression ...of Hif-1α has been correlated with increased vascularisation, metastatic potential and poor clinical outcome in a variety of malignancies, including Renal Cell Carcinoma (RCC) of clear cell aetiology, where Hif-1α dysregulation, brought about by mutations in the von Hippel Lindau gene, appears to play a major pathogenic role. Methods: In vitro, human cancer and endothelial cells grown under hypoxic conditions were used to evaluate the effect of SPC2968 on mRNA and protein to Hif-1α as well as phenotypic effects, measured by quantitative polymerase chain reaction (QPCR), Western blotting and biochemical/cellular assays. QPCR was also used to measure mRNA levels in SPC2968-treated mice, while the effects of the drug on tumour growth and vascularisation were evaluated in xenografts. To assess biodistribution in vivo, tritium-labelled SPC2968 was injected intravenously. Results: In vitro, SPC2968 at 1nM reduced both mRNA and protein levels of Hif-1α in cancer cell lines and downregulated two downstream targets of Hif-1, VEGF and MMP-2.Treatment also induced apoptosis in tumour cells and prevented tube formation by endothelial cells in vitro. Parenteral administration of SPC2968 in mice yielded potent inhibition of Hif-1α and VEGF mRNA in several tissues, including kidney, liver, and colon. Radioactively labelled SPC2968 distributed to kidney, liver, colon, bone marrow, lymph nodes and skin. Preclinical studies investigating acute and sub-acute toxicity and safety pharmacology of SPC2968 are completed, and SPC2968 was well tolerated. Conclusions: SPC2968 is an effective suppressor of Hif-1α mRNA and Hif-1α-regulated genes in vitro and in vivo and has shown good tissue biostability and biodistribution in rodents. Preclinical safety studies have been completed, and SPC2968 is ready for clinical testing. A phase I/II, dose-escalating study of SPC2968 in clear cell RCC in the US and the EU is planned to be submitted by mid 2006.
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Background: Bcl-2 protein is a critical regulator of programmed cell death and contributes to apoptosis resistance in many cancers, including chronic lymphocytic leukemia (CLL). ...The novel RNA antagonist, SPC2996, is a 16-mer oligonucleotide incorporating Locked Nucleic Acid (LNA) with unique high-affinity binding to Bcl-2 mRNA and enhanced resistance to nuclease digestion. We report the pharmacological properties of this new investigational drug and are currently evaluating clinical safety and initial efficacy in CLL patients. Methods: In vitro, the effects of SPC2996 on Bcl-2 mRNA and protein levels and phenotypic responses were evaluated in human cancer cell lines by quantitative polymerase chain reaction, Western blotting and biochemical assays. In vivo bio-distribution in rodents was assessed with tritium-labelled SPC2996 given intravenously. Anti-tumour efficacy was assessed in human prostate (PC3) and melanoma (518A2 and 607B) tumour cell line xenografts in immunodeficient mice. Preclinical toxicology and safety pharmacology were evaluated after intravenous treatment in rats and primates and tissue uptake measured by HPLC. Results: In vitro, low nanomolar concentrations of SPC2996 substantially reduced intracellular levels of Bcl-2 mRNA and protein and induced apoptosis in a dose-dependant manner. In vivo, systemically administered SPC2996 accumulated in liver, kidney, bone marrow, and lymph nodes. Repeated dosing at 10mg/kg inhibited growth of human xenografts in mice. Substantial down-regulation of Bcl-2 mRNA was observed in primate tissues after intravenous administration of SPC2996 at 3 and 6mg/kg. No acute toxicity was encountered on systemic bolus dosing of substantially higher doses in primates. An international phase I/II dose-escalating study in 42 patients with relapsed or refractory CLL is currently recruiting in the USA, UK, Denmark and France. Conclusions: SPC2996 is the first member of a new generation of specific RNA antagonising oligonucleotides with enhanced properties derived from LNA. SPC2996 has the potential to lower Bcl-2 levels in CLL cells without significant toxicity and with less frequent dosing than required with previous drugs.
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PurposeMerkel cell carcinoma (MCC) is a highly aggressive skin cancer with strong evidence for viral carcinogenesis. The association of MCC with the Merkel cell polyomavirus (MCPyV) may explain the ...explicit immunogenicity of MCC. Indeed, MCPyV-encoded proteins are likely targets for cytotoxic immune responses to MCC as they are both foreign to the host and necessary to maintain the oncogenic phenotype. However, to date only a single MCPyV-derived CD8 T-cell epitope have been described, thus impeding specific monitoring of T-cell responses to MCC.MethodTo overcome this limitation, we scanned the MCPyV oncoproteins large T and small T antigen and the virus-capsid protein VP1 for potential T-cell epitopes, and tested for major histocompatibility complex (MHC) class I affinity. We confirmed the relevance of these epitopes using a high-throughput platform for T-cell enrichment and combinatorial encoding of MHC class I multimers.ResultsIn peripheral blood from 38 MCC patients and 30 healthy donors we identified 53 MCPyV-directed CD8+ T-cell responses against 35 different peptide sequences. Strikingly, T-cell responses against oncoproteins were exclusively present in MCC patients, but not in healthy donors. We further demonstrate both the processing and presentation of the oncoprotein-derived epitopes, as well as the lytic activity of oncoprotein-specific T cells towards MHC-matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumour infiltrating lymphocytes ex vivo further substantiated the relevance of the identified epitopes.ConclusionThese T-cell epitopes represent ideal targets for antigen specific immune therapy of MCC, and enables tracking and characterisation of MCPyV specific immune responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
8.
Antisense Knockdown of PKC-α Using LNA-Oligos Hansen, Jens Bo; Westergaard, Majken; Albaek Thrue, Charlotte ...
Nucleosides, nucleotides & nucleic acids,
10/1/2003, Volume:
22, Issue:
5-8
Journal Article
Peer reviewed
Full-length and 4 nucleotides truncated
L
ocked
N
ucleic
A
cid (LNA) modifications of ISIS 3521 were compared for antisense properties in a cellular assay. ISIS 3521 is a 20-mer phosphorothioate ...designed to hybridise to human protein kinase C-
α
(PKC-
α
) mRNA and is currently submitted to clinical trials against cancer. We report that LNA can potentate this antisense oligo and retain the antisense potential with shorter oligos.
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BFBNIB, DOBA, GIS, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with strong evidence of viral carcinogenesis. The association of MCC with the Merkel cell polyomavirus (MCPyV) may explain the explicit ...immunogenicity of MCC. Indeed, MCPyV-encoded proteins are likely targets for cytotoxic immune responses to MCC as they are both foreign to the host and necessary to maintain the oncogenic phenotype. However, to date only a single MCPyV-derived CD8 T-cell epitope has been described, thus impeding specific monitoring of T-cell responses to MCC.
To overcome this limitation, we scanned the MCPyV oncoprotein large T and small T antigens and the virus capsid protein VP1 for potential T-cell epitopes, and tested for MHC class I affinity. We confirmed the relevance of these epitopes using a high-throughput platform for T-cell enrichment and combinatorial encoding of MHC class I multimers.
In peripheral blood from 38 patients with MCC and 30 healthy donors, we identified 53 MCPyV-directed CD8 T-cell responses against 35 different peptide sequences. Strikingly, T-cell responses against oncoproteins were exclusively present in patients with MCC, but not in healthy donors. We further demonstrate both the processing and presentation of the oncoprotein-derived epitopes, as well as the lytic activity of oncoprotein-specific T cells toward MHC-matched MCC cells. Demonstrating the presence of oncoprotein-specific T cells among tumor-infiltrating lymphocytes further substantiated the relevance of the identified epitopes.
These T-cell epitopes represent ideal targets for antigen-specific immune therapy of MCC, and enable tracking and characterization of MCPyV-specific immune responses.
What has Alexander the Great to do with Jesus Christ? Or the legendary king's conquest of the Persian Empire (335-23 BCE) to do with the prophecies of the Old Testament? In many ways, the early ...Christian writings on Alexander and his legacy provide a lens through which it is possible to view the shaping of the literature and thought of the early church in the Greek East and the Latin West. This book articulates that fascinating discourse for the first time by focusing on the early Christian use of Alexander. Delving into an impressively deep pool of patristic literature written between 130-313 CE, Christian Thrue Djurslev offers original interpretations of various important authors, from the learned lawyer Tertullian to the 'Christian Cicero' Lactantius, and from the apologist Tatian to the first church historian Eusebius. He demonstrates that the early Christian adaptations of the Alexandrian myths created a new tradition that has continued to develop and expand ever since. This innovative work of reception studies is important reading for all scholars of Alexander the Great and early church history.
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