Abstract Background/purpose Despite conventional immunosuppressants, active and steroid-dependent systemic lupus erythematosus (SLE) represents a therapeutic challenge. Only one biologic, belimumab, ...has been approved, but other biologics are sometimes used off-label. Given the lack of evidence-based data in some clinical situations encountered in real life, we developed expert recommendations for the use of biologics for SLE. Methods The recommendations were developed by a formal consensus method. This method aims to formalize the degree of agreement among experts by identifying, through iterative ratings with feedback, the points on which experts agree, disagree or are undecided. Hence, the recommendations are based on the agreed-upon points. We gathered the opinion of 59 French-speaking SLE experts from 3 clinical networks dedicated to systemic autoimmune diseases (FLEUR, IMIDIATE, FAI2R) from Algeria, Belgium, France, Italy, Morocco, Switzerland and Tunisia. Represented medical specialities were internal medicine (49%), rheumatology (34%), nephrology (7%), dermatology (5%), pediatrics (3%) and cardiology (2%). Two methodologists and 3 strictly independent SLE expert groups contributed to developing these recommendations: a steering group (SG) ( n = 9), an evaluation group (EG) ( n = 28) and a reading group (RG) ( n = 22). Preliminary recommendations were drafted by the SG, then proposed to the EG. Each EG member rated the degree of agreement from 1 to 9 (1: lowest; 9: strongest) for each recommendation. After 2 rating rounds, the SG submitted a new version of the recommendations to the RG. With comments from the RG, the SG finalised the recommendations. Results A total of 17 final recommendations were formulated by the SG, considering all agreement scores and comments by the EG and RG members and the two methodologists. These recommendations define the subset of patients who require a biologic; the type of biologics to use (belimumab, rituximab, etc. ) depending on the organ involvement and associated co-treatments; what information should be given to patients; and how to evaluate treatment efficacy and when to consider discontinuation. Conclusion Overall, 17 recommendations for the good use of biologics in SLE were formulated by a large panel of SLE experts to provide guidance for clinicians in daily practice. These recommendations will be regularly updated according to the results of new randomized trials and increasing real life experience.
Myotonic dystrophy type 1 (DM1) is characterized by an unstable expansion of a CTG repeat resulting in altered mRNA biogenesis. Benign or malignant tumours are increasingly reported. The aim of the ...study was to evaluate the risk of tumor in a cohort of patients DM1.We retrospectively reviewed the medical records of every DM1 patient admitted in our neuromuscular center. Diagnoses of cancer and age at diagnosis were noted. The relative risk of a selected cancer was calculated using the data of the cancer registry obtained from the French "Institut de Veille Sanitaire".A total of 109 French DM1 patients, aged 44.1±13.0 years, were studied, and 14 malignant tumours were observed, with a significant relative risk (RR) of thymoma, of gynaecologic cancers, of lung cancers.While this cohort is small, our findings nevertheless suggest an increased risk of particular cancers in DM1. The toxic effects of mutant RNA may possibly affect oncogene expression or growth factor signalling pathways in cells. Clinical practice should include cancer screening and prevention of risk factors in DM1 patients.
Myotonic dystrophy type 1 (DM1) is characterized by an unstable expansion of a CTG repeat resulting in altered mRNA biogenesis. Benign or malignant tumours are increasingly reported. The aim of the ...study was to evaluate the risk of tumor in a cohort of patients DM1.
We retrospectively reviewed the medical records of every DM1 patient admitted in our neuromuscular center. Diagnoses of cancer and age at diagnosis were noted. The relative risk of a selected cancer was calculated using the data of the cancer registry obtained from the French “Institut de Veille Sanitaire”.
A total of 109 French DM1 patients, aged 44.1±13.0 years, were studied, and 14 malignant tumours were observed, with a significant relative risk (RR) of thymoma, of gynaecologic cancers, of lung cancers.
While this cohort is small, our findings nevertheless suggest an increased risk of particular cancers in DM1. The toxic effects of mutant RNA may possibly affect oncogene expression or growth factor signalling pathways in cells. Clinical practice should include cancer screening and prevention of risk factors in DM1 patients.
La dystrophie myotonique de type 1 (DM1) est caractérisée par une expansion instable de triplets nucéotidiques CTG entraînant des troubles de la biogenèse des ARNm. De nombreuses publications ont suggéré une augmentation du risque tumoral chez les patients DM1. Le but de ce travail était d’estimer ce risque dans une cohorte de patients DM1 suivis dans un centre spécialisé.
Cette étude rétrospective a pris en compte tous les patients DM1 suivis au moins cinq ans dans le centre. Les cas de tumeurs malignes ont été répertoriés et le risque relatif (RR) de développer un type donné de tumeur a été calculé en prenant pour référence le registre des cancers de l’institut de veille sanitaire.
Sur un total de 109 patient âgés de 44,1±13,0ans, 14 ont eu une tumeur. Le RR était significativement plus élevé chez les patients DM1 pour les thymomes, les cancers gynécologiques et le cancer du poumon.
Malgré un effectif faible, les résultats sont en faveur d’une augmentation du risque de tumeur chez les patients DM1. Une cause probable est l’interaction de l’ARN mutant avec la biogenèse d’ARNm impliqués dans l’oncogenèse et la signalisation cellulaire. L’augmentation du risque tumoral implique chez les patients DM1 la surveillance et la correction des éventuels facteurs de risque.
Lupus anticoagulant-hypoprothrombinemia syndrome is a rare condition characterized by the association of acquired factor II deficiency and lupus anticoagulant. Contrary to classical antiphospholipid ...syndrome, it may cause severe life-threatening bleeding (89% of published cases). We report a patient, positive for antidomain I antibodies, with initially primary lupus anticoagulant-hypoprothrombinemia syndrome without previous clinical manifestation or underlying systemic disease. Five years later, he experienced the first systemic lupus erythematous flare. Within a few days, catastrophic antiphospholipid syndrome was diagnosed with heart, liver and kidney involvement. The patient recovered under pulse steroids, intravenous heparin and intravenous immunoglobulins.
Collaborative robots (cobots) have been increasingly adopted in industries to facilitate human–robot collaboration. Despite this, it is challenging to program cobots for collaborative industrial ...tasks as the programming has two distinct elements that are difficult to implement: (1) an intuitive element to ensure that the operations of a cobot can be composed or altered dynamically by an operator, and (2) a human-aware element to support cobots in producing flexible and adaptive behaviours dependent on human partners. In this area, some research works have been carried out recently, but there is a lack of a systematic summary on the subject. In this paper, an overview of collaborative industrial scenarios and programming requirements for cobots to implement effective collaboration is given. Then, detailed reviews on cobot programming, which are categorised into communication, optimisation, and learning, are conducted. Additionally, a significant gap between cobot programming implemented in industry and in research is identified, and research that works towards bridging this gap is pinpointed. Finally, the future directions of cobots for industrial collaborative scenarios are outlined, including potential points of extension and improvement.
•Transfer learning enabled convolutional neural networks (CNNs) is developed to predict the health state of cutting tools.•Benchmarks on the developed approach using several optimization techniques ...are conducted.•Results indicate the developed approach is suitable for estimating the health state of cutting tools.
Effective Prognostics and Health Management (PHM) for cutting tools during Computerized Numerical Control (CNC) processes can significantly reduce downtime and decrease losses throughout manufacturing processes. In recent years, deep learning algorithms have demonstrated great potentials for PHM. However, the algorithms are still hindered by the challenge of the limited amount data available in practical manufacturing situations for effective algorithm training. To address this issue, in this research, a transfer learning enabled Convolutional Neural Networks (CNNs) approach is developed to predict the health state of cutting tools. With the integration of a transfer learning strategy, CNNs can effectively perform tool health state prediction based on a modest number of the relevant images of cutting tools. Quantitative benchmarks and analyses on the performance of the developed approach based on six typical CNNs models using several optimization techniques were conducted. The results indicated the suitability of the developed approach, particularly using ResNet-18, for estimating the wear width of cutting tools. Therefore, by exploiting the integrated design of CNNs and transfer learning, viable PHM strategies for cutting tools can be established to support practical CNC machining applications.
Human clinical trials in type 1 diabetes (T1D) patients using mesenchymal stem cells (MSC) are presently underway without prior validation in a mouse model for the disease. In response to this void, ...we characterized bone marrow-derived murine MSC for their ability to modulate immune responses in the context of T1D, as represented in NOD mice. In comparison to NOD mice, BALB/c-MSC mice were found to express higher levels of the negative costimulatory molecule PD-L1 and to promote a shift toward Th2-like responses in treated NOD mice. In addition, transfer of MSC from resistant strains (i.e., nonobese resistant mice or BALB/c), but not from NOD mice, delayed the onset of diabetes when administered to prediabetic NOD mice. The number of BALB/c-MSC trafficking to the pancreatic lymph nodes of NOD mice was higher than in NOD mice provided autologous NOD-MSC. Administration of BALB/c-MSC temporarily resulted in reversal of hyperglycemia in 90% of NOD mice (p = 0.002). Transfer of autologous NOD-MSC imparted no such therapeutic benefit. We also noted soft tissue and visceral tumors in NOD-MSC-treated mice, which were uniquely observed in this setting (i.e., no tumors were present with BALB/c- or nonobese resistant mice-MSC transfer). The importance of this observation remains to be explored in humans, as inbred mice such as NOD may be more susceptible to tumor formation. These data provide important preclinical data supporting the basis for further development of allogeneic MSC-based therapies for T1D and, potentially, for other autoimmune disorders.
Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes
Paolo Fiorina 1 2 ,
Andrea Vergani 1 2 ,
Shirine Dada 1 ,
Mollie Jurewicz 1 ,
Masie Wong 1 ,
Kenneth Law 3 ,
Erxi Wu 4 ,
Ze Tian 4 ,
...Reza Abdi 1 ,
Indira Guleria 1 ,
Scott Rodig 3 ,
Kyri Dunussi-Joannopoulos 5 ,
Jeffrey Bluestone 6 and
Mohamed H. Sayegh 1
1 Transplantation Research Center, Children's Hospital and Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
2 Department of Medicine, San Raffaele Scientific Institute, Milan, Italy
3 Department of Pathology, Division of Hematopathology, Brigham & Women's Hospital, Harvard Medical School, Boston, Massachusetts
4 Children's Hospital Informatics Program at the Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts
5 Inflammation, Wyeth Research, Cambridge, Massachusetts
6 University of California San Francisco Diabetes Center, San Francisco, California
Corresponding author: Mohamed H. Sayegh, msayegh{at}rics.bwh.harvard.edu
Abstract
OBJECTIVES— To investigate a B-cell–depleting strategy to reverse diabetes in naïve NOD mice.
RESEARCH DESIGN AND METHODS— We targeted the CD22 receptor on B-cells of naïve NOD mice to deplete and reprogram B-cells to effectively reverse autoimmune
diabetes.
RESULTS— Anti-CD22/cal monoclonal antibody (mAb) therapy resulted in early and prolonged B-cell depletion and delayed disease in pre-diabetic
mice. Importantly, when new-onset hyperglycemic mice were treated with the anti-CD22/cal mAb, 100% of B-cell–depleted mice
became normoglycemic by 2 days, and 70% of them maintained a state of long-term normoglycemia. Early therapy after onset of
hyperglycemia and complete B-cell depletion are essential for optimal efficacy. Treated mice showed an increase in percentage
of regulatory T-cells in islets and pancreatic lymph nodes and a diminished immune response to islet peptides in vitro. Transcriptome
analysis of reemerging B-cells showed significant changes of a set of proinflammatory genes. Functionally, reemerging B-cells
failed to present autoantigen and prevented diabetes when cotransferred with autoreactive CD4 + T-cells into NOD.SCID hosts.
CONCLUSIONS— Targeting CD22 depletes and reprograms B-cells and reverses autoimmune diabetes, thereby providing a blueprint for development
of novel therapies to cure autoimmune diabetes.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 8 August 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted July 29, 2008.
Received March 27, 2008.
DIABETES
Acceptance of the fetus expressing allogeneic paternal Ags by the mother is a physiologic model of transplantation tolerance. Various mechanisms contribute to fetal evasion from immune attack by ...maternal leukocytes. We have recently demonstrated that the inhibitory costimulatory molecule PDL1 plays a critical role in fetomaternal tolerance in that PDL1 blockade or deficiency resulted in decreased allogeneic fetal survival rates. CD4(+)CD25(+) T regulatory cells (Tregs) have also been demonstrated to play an important role in fetomaternal tolerance. Since PDL1 is expressed on Tregs, we explored the interactions between PDL1 and Tregs in vivo in a mouse model of fetomaternal tolerance. Depletion of CD25(+) T cells abrogated the effect of anti-PDL1 Ab indicating that the effect of PDL1 is possibly mediated by CD25(+) Tregs. Adoptive transfer of Tregs from wild-type but not PDL1-deficient mice into PDL1-deficient recipients significantly improved fetal survival. The frequency, phenotype and placental trafficking of Tregs from PDL1-deficient mice were similar to those of wild-type controls, but were defective in inhibiting alloreactive Th1 cells in vitro. This is the first report providing evidence for a link between PDL1 and T regulatory cells in mediating fetomaternal tolerance.
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