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1.
Osteoarthr Cartil Open ; 6(2): 100474, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38737983

ABSTRACT

Objective: The aim of this study was to compare the magnitude and the predictors of the placebo response in an internet versus onsite randomised controlled trials (RCTs) in people with hand osteoarthritis (HOA). Method: This study is a post-hoc analysis based on one internet RCT (RADIANT) and previously published onsite RCTs for HOA identified through a rigorous searching and selection strategy. The magnitude of the placebo response in the two different types of RCTs were compared using heterogeneity statistics and forest plots visualisation. Classic placebo predictors as well as a combined model, defined with data from onsite RCTs, were tested to predict the placebo response. Results: We analysed the dataset from RADIANT and fourteen previously published onsite RCTs. None of the analyses showed a significant difference between the placebo response for the internet versus onsite RCTs. The "classic" placebo predictors combined in a multivariate predictive model correlated significantly with the placebo response measured in RADIANT study. Conclusion: Despite the absence of face-to-face interactions with the study personnel, there is no evidence that either the magnitude or the predictors of the placebo response of this internet RCT differ from those of onsite RCTs. This analysis is considered as a first step towards evaluating the difference between these designs and strengthens the argument that internet RCTs remain an acceptable alternative way to assess the efficacy of an active treatment in comparison to a placebo.

2.
Proc Natl Acad Sci U S A ; 111(21): 7723-8, 2014 May 27.
Article in English | MEDLINE | ID: mdl-24812125

ABSTRACT

Outcome of TGFß1 signaling is context dependent and differs between individuals due to germ-line genetic variation. To explore innate genetic variants that determine differential outcome of reduced TGFß1 signaling, we dissected the modifier locus Tgfbm3, on mouse chromosome 12. On a NIH/OlaHsd genetic background, the Tgfbm3b(C57) haplotype suppresses prenatal lethality of Tgfb1(-/-) embryos and enhances nuclear accumulation of mothers against decapentaplegic homolog 2 (Smad2) in embryonic cells. Amino acid polymorphisms within a disintegrin and metalloprotease 17 (Adam17) can account, at least in part, for this Tgfbm3b effect. ADAM17 is known to down-regulate Smad2 signaling by shedding the extracellular domain of TGFßRI, and we show that the C57 variant is hypomorphic for down-regulation of Smad2/3-driven transcription. Genetic variation at Tgfbm3 or pharmacological inhibition of ADAM17, modulates postnatal circulating endothelial progenitor cell (CEPC) numbers via effects on TGFßRI activity. Because CEPC numbers correlate with angiogenic potential, this suggests that variant Adam17 is an innate modifier of adult angiogenesis, acting through TGFßR1. To determine whether human ADAM17 is also polymorphic and interacts with TGFß signaling in human vascular disease, we investigated hereditary hemorrhagic telangiectasia (HHT), which is caused by mutations in TGFß/bone morphogenetic protein receptor genes, ENG, encoding endoglin (HHT1), or ACVRL1 encoding ALK1 (HHT2), and considered a disease of excessive abnormal angiogenesis. HHT manifests highly variable incidence and severity of clinical features, ranging from small mucocutaneous telangiectases to life-threatening visceral and cerebral arteriovenous malformations (AVMs). We show that ADAM17 SNPs associate with the presence of pulmonary AVM in HHT1 but not HHT2, indicating genetic variation in ADAM17 can potentiate a TGFß-regulated vascular disease.


Subject(s)
ADAM Proteins/genetics , ADAM Proteins/metabolism , Blood Vessels/pathology , Gene Expression Regulation/physiology , Genetic Variation , Signal Transduction/physiology , Transforming Growth Factor beta/metabolism , ADAM17 Protein , Animals , Gene Expression Regulation/genetics , Humans , Immunohistochemistry , Luciferases , Mice , Mice, Inbred C57BL , NIH 3T3 Cells , Signal Transduction/genetics , Smad2 Protein/metabolism , Transforming Growth Factor beta1/genetics
3.
Proc Natl Acad Sci U S A ; 109(44): 18042-7, 2012 Oct 30.
Article in English | MEDLINE | ID: mdl-23064636

ABSTRACT

TGFß activation and signaling have been extensively studied in experimental models of allergen-induced asthma as potential therapeutic targets during chronic or acute phases of the disease. Outcomes of experimental manipulation of TGFß activity have been variable, in part due to use of different model systems. Using an ovalbumin (OVA)-induced mouse model of asthma, we here show that innate variation within TGFß1 genetic modifier loci, Tgfbm2 and Tgfbm3, alters disease susceptibility. Specifically, Tgfbm2(129) and Tgfbm3(C57) synergize to reverse accentuated airway hyperresponsiveness (AHR) caused by low TGFß1 levels in Tgfb1(+/-) mice of the NIH/OlaHsd strain. Moreover, epistatic interaction between Tgfbm2(129) and Tgfbm3(C57) uncouples the inflammatory response to ovalbumin from those of airway remodeling and airway hyperresponsiveness, illustrating independent genetic control of these responses. We conclude that differential inheritance of genetic variants of Tgfbm genes alters biological responses to reduced TGFß1 signaling in an experimental asthma model. TGFß antagonists for treatment of lung diseases might therefore give diverse outcomes, dependent on genetic variation.


Subject(s)
Asthma/genetics , Epistasis, Genetic , Transforming Growth Factor beta1/genetics , Animals , Genetic Predisposition to Disease , Mice , Mice, Inbred C57BL , Mice, Transgenic
4.
Nat Cell Biol ; 14(9): 958-65, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22864477

ABSTRACT

Synthetic lethality is a promising strategy for specific targeting of cancer cells that carry mutations that are absent in normal cells. This approach may help overcome the challenge associated with targeting dysfunctional tumour suppressors, such as p53 and Rb (refs 1, 2). Here we show that Dicer1 targeting prevents retinoblastoma formation in mice by synthetic lethality with combined inactivation of p53 and Rb. Although Dicer1 functions as a haploinsufficient tumour suppressor, its complete loss of function is selected against during tumorigenesis(3-5). We show that Dicer1 deficiency is tolerated in Rb-deficient retinal progenitor cells harbouring an intact p53 pathway, but not in the absence of p53. This synthetic lethality is mediated by the oncogenic miR-17-92 cluster because its deletion phenocopies Dicer1 loss in this context. miR-17-92 inactivation suppresses retinoblastoma formation in mice and co-silencing of miR-17/20a and p53 cooperatively decreases the viability of human retinoblastoma cells. These data provide an explanation for the selective pressure against loss of Dicer1 during tumorigenesis and a proof-of-concept that targeting miRNAs may potentially represent a general approach for synthetic lethal targeting of cancer cells that harbour specific cancer-inducing genotypes.


Subject(s)
DEAD-box RNA Helicases/genetics , MicroRNAs/genetics , Retinal Neoplasms/genetics , Retinoblastoma Protein/genetics , Retinoblastoma/genetics , Ribonuclease III/genetics , Tumor Suppressor Protein p53/genetics , Animals , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/metabolism , DEAD-box RNA Helicases/metabolism , Female , Genes, Tumor Suppressor , Humans , Male , Mice , Mice, Inbred C57BL , MicroRNAs/metabolism , Mutation , Retinal Neoplasms/metabolism , Retinoblastoma/metabolism , Retinoblastoma Protein/metabolism , Ribonuclease III/metabolism , Tumor Suppressor Protein p53/metabolism
6.
Nat Commun ; 3: 616, 2012 Jan 10.
Article in English | MEDLINE | ID: mdl-22233626

ABSTRACT

Hereditary haemorrhagic telangiectasia (HHT) [corrected] is a vascular dysplasia syndrome caused by mutations in transforming growth factor-ß/bone morphogenetic protein pathway genes, ENG and ACVRL1. HHT [corrected] shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng(+/-) and Tgfb1(-/-) mice provides further support for genetic modification of transforming growth factor-ß pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1(-/-) mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HHT, [corrected] as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HHT [corrected] in particular and to angiogenesis in general.


Subject(s)
Protein Tyrosine Phosphatases, Non-Receptor/physiology , Telangiectasia, Hereditary Hemorrhagic/genetics , Activin Receptors, Type I/metabolism , Activin Receptors, Type II/metabolism , Animals , Chromosome Mapping , Ephrin-B2/metabolism , Exons , Female , Genetic Variation , Haplotypes , Humans , Male , Mice , Mice, Congenic , Mice, Inbred C57BL , Mice, Transgenic , Models, Genetic , Mutation , Phenotype , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Species Specificity , Transforming Growth Factor beta/metabolism
7.
Clin Cancer Res ; 15(16): 5101-7, 2009 Aug 15.
Article in English | MEDLINE | ID: mdl-19671862

ABSTRACT

PURPOSE: Nonmelanoma skin cancer incidence is enhanced >50-fold in patients taking antirejection drugs (ARD) following organ transplantation. Preclinical studies suggest that ARD treatment increases transforming growth factor-beta1 (TGF-beta1) levels, which contribute to enhanced tumor susceptibility independent of the immunosuppressive effects of ARDs. This study investigates whether TGF-beta signaling is elevated in transplant patients. EXPERIMENTAL DESIGN: Immunohistochemical tissue microarray analysis was used to determine the levels of TGF-beta1, TGF-beta2, TGF-beta3, TbetaRII, and activated P-Smad2/3 and P-Smad1/5/8, which are phosphorylated directly by distinct TGF-beta/BMP receptor complexes. We analyzed >200 cutaneous lesions and adjacent nonlesional skin samples from 87 organ transplant recipients, and 184 cutaneous lesions and adjacent skin samples from 184 individuals who had never received ARDs. RESULTS: We found significantly higher levels of P-Smad2 in both nonlesional and lesional tissue from transplant recipients compared with those not exposed to ARDs (P < or = 0.001). In contrast, P-Smad1/5/8, a marker of activation of the bone morphogenetic protein signaling pathway, was generally not expressed at higher levels in patients taking ARDs, including analysis of nonlesional skin, actinic keratoses, carcinoma in situ, or squamous cell carcinoma but was differentially expressed between keratoacanthoma from transplant recipients compared with those from non-transplant recipients (P < or = 0.005). CONCLUSIONS: Observation of elevated P-Smad2 levels in transplant recipients is consistent with the notion that elevated TGF-beta signaling may contribute to malignancy in organ transplant recipients. Disparate P-Smad1/5/8 expression levels between keratoacanthoma from the two patient groups might reflect the distinct BMP-responsive cell of origin for this hair follicle-derived lesion.


Subject(s)
Carcinoma, Squamous Cell/metabolism , Disease Susceptibility/metabolism , Skin Neoplasms/metabolism , Skin/metabolism , Smad Proteins/metabolism , Transplants , Age Factors , Bone Morphogenetic Proteins/metabolism , Carcinoma, Squamous Cell/etiology , Disease Susceptibility/etiology , Female , Humans , Immunosuppression Therapy/adverse effects , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/pharmacology , Immunosuppressive Agents/therapeutic use , Male , Protein Serine-Threonine Kinases/metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta/metabolism , Sex Characteristics , Signal Transduction/drug effects , Skin/pathology , Skin Neoplasms/etiology , Tissue Array Analysis , Transforming Growth Factor beta1/metabolism , Up-Regulation/drug effects
8.
J Cell Biochem ; 104(4): 1161-71, 2008 Jul 01.
Article in English | MEDLINE | ID: mdl-18465786

ABSTRACT

We were looking by a proteomic approach for new phospho-proteins involved during the early steps of the TNF + cycloheximide (CHX)-induced apoptosis-preceding mitochondrial membrane permeabilization-of endothelial cells (BAEC). In the present study, we observed on the autoradiography from 2D gel of (32)P-labeled samples a string of proteins undergoing a complete dephosphorylation after 1 h of stimulation with TNF + CHX-while mitochondrial membrane permeabilization was observed after 3 h-identified the different spots by mass spectrometry as one and only protein, HDGF, and confirmed the identity by western blot. The intensity of the 2D phosphorylation pattern of HDGF was correlated with the amount of apoptosis induced by TNF + CHX and TNF or CHX alone and this event was inhibited by the Caspase specific inhibitor zVADfmk. Moreover the TNF + CHX-treatment did not affect the nuclear localization of GFP-HDGF. Taken together, our data suggest an involvement of HDGF during the initiation phase of the apoptotic process downstream from an initiator Caspase and a regulation of this protein by phosphorylation in the nucleus.


Subject(s)
Apoptosis , Caspases/physiology , Endothelial Cells/cytology , Intercellular Signaling Peptides and Proteins/metabolism , Animals , Aorta/cytology , Apoptosis/drug effects , Cattle , Cell Nucleus/metabolism , Cells, Cultured , Cycloheximide/pharmacology , Phosphorylation , Tumor Necrosis Factor-alpha/pharmacology
9.
J Cell Sci ; 119(Pt 4): 759-68, 2006 Feb 15.
Article in English | MEDLINE | ID: mdl-16449320

ABSTRACT

Transforming growth factor beta (TGFbeta) plays an important role in development and maintenance of murine yolk sac vascular development. Targeted deletions of Tgfb1 and other components of this signaling pathway, such as Acvrl1, Tgfbr1 and Tgfbr2, result in abnormal vascular development especially of the yolk sac, leading to embryonic lethality. There are significant differences between murine and primate development that limit interpretation of studies from mouse models. Thus, to examine the role of TGFbeta in early human vascular development we used the model of differentiating human embryonic stem cell-derived embryoid bodies to recapitulate early stages of embryonic development. TGFbeta was applied for different time frames after initiation of embryoid body cultures to assess its effect on differentiation. TGFbeta inhibited the expression of endodermal, endothelial and hematopoietic markers, which contrasts with findings in the mouse in which TGFbeta reduced the level of endodermal markers but increased endothelial marker expression. The inhibition observed was not due to changes in proliferation or apoptosis. This marked contrast between the two species may reflect the different origins of the yolk sac hemangiogenic lineages in mouse and human. TGFbeta effects on the hypoblast, from which these cell lineages are derived in human, would decrease subsequent differentiation of hematopoietic, endothelial and endodermal cells. By contrast, TGFbeta action on murine hypoblast, while affecting endoderm would not affect the hemangiogenic lineages that are epiblast-derived in the mouse. This study highlights important differences between early human and mouse embryonic development and suggests a role of TGFbeta in human hypoblast differentiation.


Subject(s)
Embryonic Development/physiology , Stem Cells/cytology , Stem Cells/physiology , Transforming Growth Factor beta/physiology , Yolk Sac/physiology , Activin Receptors, Type I/antagonists & inhibitors , Activin Receptors, Type I/physiology , Activin Receptors, Type II/antagonists & inhibitors , Activin Receptors, Type II/physiology , Animals , Blood Vessels/embryology , Cell Lineage/physiology , Humans , Mice , Protein Serine-Threonine Kinases , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/physiology , Signal Transduction/physiology , Species Specificity , Transforming Growth Factor beta/antagonists & inhibitors , Yolk Sac/cytology
10.
Cell Signal ; 15(5): 539-46, 2003 May.
Article in English | MEDLINE | ID: mdl-12639717

ABSTRACT

The aim of the present study was to identify biochemical pathways driving the resistance of endothelial cells to apoptosis induced by tumour necrosis factor-alpha (TNF). (1) Although nuclear factor-kappa B (NF-kappaB) was activated by TNF, its inhibition by MG-132 failed to sensitize these cells. (2) The activation of protein kinase C (PKC) by phorbol ester completely abolished the TNF-induced cell death. (3) The phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin (Wo) triggered apoptosis and enhanced the TNF-induced cell death. (4) The MEK inhibitor PD98059 did not affect the TNF-induced apoptotic process. (5) The p38 is activated by TNF and its inhibition by SB203580 sensitized the cells to TNF. This is correlated with the inhibition of phosphorylation of heat-shock protein of 27 kDa (HSP27). These results indicate that TNF activates NF-kappaB, which does not drive any anti-apoptotic response, and p38, which plays an anti-apoptotic function probably through HSP27 phosphorylation. Moreover, PKC and PI3K are involved in the control of survival pathways.


Subject(s)
Apoptosis , Endothelium, Vascular/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Animals , Cattle , Cell Survival , Cells, Cultured , Cytoprotection , DNA Fragmentation , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Enzyme Inhibitors/pharmacology , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase C/antagonists & inhibitors , Signal Transduction
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