341 research outputs found
Intravesical Ty21a vaccine promotes dendritic cells and T cell-mediated tumor regression in the MB49 bladder cancer model
No full textPreclinical data shows that intravesical instillation of Ty21a/Vivotif®, a commercial vaccine against typhoid fever, is an effective alternative option to standard Bacillus-Calmette-Guérin (BCG) immunotherapy for nonmuscle-invasive bladder cancer (NMIBC). Here we characterized the inflammatory effects of Ty21a on the bladder and investigated the immune mechanisms underlying tumor-regression towards the use of this bacterial vaccine in NMIBC patients. MB49 bladder tumor-bearing mice had significantly improved survival after intravesical instillations of Ty21a doses of 106 to 108 colony-forming units. By immunohistochemistry and morphology, both BCG and Ty21a instillations were associated with bladder inflammation, which was decreased with the use of low, but effective, doses of Ty21a. Flow cytometry analysis showed a significant infiltration of T cells, natural killer (NK) cells, and myeloid cells, compared with controls, after a single dose of Ty21a, whereas this was only observed after multiple doses of BCG. The induced myeloid cells were predominantly neutrophils and Ly6C+CD103+ dendritic cells (DC), the latter being significantly more numerous after instillation of Ty21a than BCG. Ex vivo infection of human leukocytes with Ty21a, but not BCG, similarly significantly increased DC frequency. CD4+ and CD8+ T cells, but not NK cells nor neutrophils, were required for effective Ty21a bladder tumor responses. Thus, the generation of antitumor adaptive immunity was identified as a key process underlying Ty21a-mediated treatment efficacy. Altogether, these results demonstrate mechanisms of intravesical Ty21a therapy and suggest its potential as a safe and effective treatment for NMIBC patients
Phosphorylation-dependent dimerization and subcellular localization of islet-brain 1/c-Jun N-terminal kinase-interacting protein 1
No full textIslet-brain 1 [IB1; also termed c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP-1] is involved in the apoptotic signaling cascade of JNK and functions as a scaffold protein. It organizes several MAP kinases and the microtubule-transport motor protein kinesin and relates to other signal-transducing molecules such as the amyloid precursor protein. Here we have identified IB1/JIP-1 using different antibodies that reacted with either a monomeric or a dimeric form of IB1/JIP-1. By immunoelectron microscopy, differences in the subcellular localization were observed. The monomeric form was found in the cytoplasmic compartment and is associated with the cytoskeleton and with membranes, whereas the dimeric form was found in addition in nuclei. After treatment of mouse brain homogenates with alkaline phosphatase, the dimeric form disappeared and the monomeric form decreased its molecular weight, suggesting that an IB1/JIP-1 dimehzation is phosphorylation dependent and that IB1 exists in several phospho- forms. N-methyl-D-aspartate receptor activation induced a dephosphorylation of IB1/JIP-1 in primary cultures of cortical neurons and reduced homodimehzation. In conclusion, these data suggest that IB1/JIP-1 monomers and dimers may differ in compartmental localization and thus function as a scaffold protein of the JNK signaling cascade in the cytoplasm or as a transcription factor in nuclei
C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in beta-cells.
No full textInduction of the C/EBP homologous protein (CHOP) is considered a key event for endoplasmic reticulum (ER) stress-mediated apoptosis. Type 1 diabetes (T1D) is characterized by an autoimmune destruction of the pancreatic β-cells. Pro-inflammatory cytokines are early mediators of β-cell death in T1D. Cytokines induce ER stress and CHOP overexpression in β-cells, but the role for CHOP overexpression in cytokine-induced β-cell apoptosis remains controversial. We presently observed that CHOP knockdown (KD) prevents cytokine-mediated degradation of the anti-apoptotic proteins B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1), thereby decreasing the cleavage of executioner caspases 9 and 3, and apoptosis. Nuclear factor-κB (NF-κB) is a crucial transcription factor regulating β-cell apoptosis and inflammation. CHOP KD resulted in reduced cytokine-induced NF-κB activity and expression of key NF-κB target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF-7, IL-15, CCL5 and CXCL10. This was due to decreased IκB degradation and p65 translocation to the nucleus. The present data suggest that CHOP has a dual role in promoting β-cell death: (1) CHOP directly contributes to cytokine-induced β-cell apoptosis by promoting cytokine-induced mitochondrial pathways of apoptosis; and (2) by supporting the NF-κB activation and subsequent cytokine/chemokine expression, CHOP may contribute to apoptosis and the chemo attraction of mononuclear cells to the islets during insulitis.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe
Enhancing Business Model Efficiency through Digital Alignment and Strategic flexibility: Evidence from Italy
No full textThe digital age has brought about significant changes to both innovative and more traditional sectors, leading many firms to develop digital business models to leverage new digital technologies to improve their value creation and capture mechanisms (Baden-Fuller and Haefliger, 2013; Volberda et al., 2021). In this perspective, SMEs have been particularly challenged to adapt to the digital age, as they often face size-related disadvantages such as lack of resources and expertise (Eggers, 2020). Achieving enhanced digital alignment, the joint support of strategic decision-making and operational activities, can help SMEs overcome these challenges and improve their business model efficiency (Pati et al., 2018; Tai et al., 2018).
Despite the importance of digital alignment and business model efficiency, many questions remain open, as the concept of business model efficiency itself has received relatively little attention in the existing literature. Therefore, it is crucial for scholars to focus more on the study of business model efficiency and its influence on value creation and value capture in digital business models (Pati et al., 2018; Zott and Amit, 2010). The present study also deepens the importance of strategic flexibility in adapting to changes and responding to crises (Zhou and Wu, 2010). Building on these premises, the proposed research aims to address the gap in literature by investigating the impact of digital alignment and strategic flexibility on business model efficiency
Immunotherapies for uro-genital cancers
No full textLes cancers du col utérin et de la vessie prennent tous deux leur origine dans les sites muqueux et peuvent évoluer lentement de lésions superficielles (lésions squameuses intra-épithéliales de bas à haut grade (HSIL) et carcinomes in situ du col utérin (CIS); ou tumeurs non musculo-invasives de la vessie (NMIBC)) à des cancers invasifs plus avancés. L'éthiologie de ces deux cancers est néanmoins très différente.
Le cancer du col utérin est, à l'échelle mondiale, le deuxième cancer le plus mortel chez la femme. Ce cancer résulte de l'infection des cellules basales de l'épithélium stratifié du col utérin par le papillomavirus humain à haut risque (HPV). Les vaccins prophylactiques récemment développés contre le HPV (Gardasil® et Cervarix®) sont des moyens de prévention efficaces lorsqu'ils sont administrés chez les jeunes filles qui ne sont pas encore sexuellement actives; cependant ces vaccins ne permettent pas la régression des lésions déjà existantes. Malgré un développement actif, les vaccins thérapeutiques ciblant les oncogènes viraux E6/E7 n'ont montré qu'une faible efficacité clinique jusqu'à présent. Nous avons récemment démontré qu'une immunisation sous-cutanée (s.c.) était capable de faire régresser les petites tumeurs génitales chez 90% des souris, mais chez seulement 20% des souris présentant de plus grandes tumeurs. Dans cette étude, nous avons développé une nouvelle stratégie où la vaccination est associée à une application locale (intra-vaginale (IVAG)) d'agonistes de TLR. Celle-ci induit une augmentation des cellules T CD8 totales ainsi que T CD8 spécifiques au vaccin, mais pas des cellules T CD4. L'attraction sélective des cellules T CD8 est permise par leur expression des récepteurs de chemokines CCR5 et CXCR3 ainsi que par les ligants E-selectin. La vaccination, suivie de l'application IVAG de CpG, a conduit, chez 75% des souris, à la régression de grandes tumeurs établies.
Le cancer de la vessie est le deuxième cancer urologique le plus fréquente. La plupart des tumeurs sont diagnostiquées comme NMIBC et sont restreintes à la muqueuse de la vessie, avec une forte propension à la récurrence et/ou progression après une résection locale. Afin de développer des vaccins contre les antigènes associés à la tumeur (TAA), il est nécessaire de trouver un moyen d'induire une réponse immunitaire CD8 spécifique dans la vessie. Pour ce faire, nous avons comparé différentes voies d'immunisation, en utilisant un vaccin composé d'adjuvants et de l'oncogène de HPV (E7) comme modèle. Les vaccinations s.c. et IVAG ont toutes deux induit un nombre similaire de cellules T CD8 spécifiques du vaccin dans la vessie, alors que l'immunisation intra-nasale fut inefficace. Les voies s.c. et IVAG ont induit des cellules T CD8 spécifiques du vaccin exprimant principalement aL-, a4- et le ligand d'E-selectin, suggérant que ces intégrines/sélectines sont responsables de la relocalisation des cellules T dans la vessie. Une unique immunisation avec E7 a permis une protection tumorale complète lors d'une étude prophylactique, indépendemment de la voie d'immunisation. Dans une étude thérapeutique, seules les vaccinations s.c. et IVAG ont efficacement conduit, chez environ 50% des souris, à la régression de tumeurs de la vessie établies, alors que l'immunisation intra-nasale n'a eu aucun effet. La régression de la tumeur est correlée avec l'infiltration dans la tumeur des cellules T CD8 spécifiques au vaccin et la diminution des cellules T régulatrices (Tregs).
Afin d'augmenter l'efficacité de l'immunisation avec le TAA, nous avons testé une vaccination suivie de l'instillation d'agonistes de TLR3 et TLR9, ou d'un vaccin Salmonella Typhi (Ty21a). Cette stratégie a entraîné une augmentation des cellules T CD8 effectrices spécifiques du vaccin dans la vessie, bien qu'à différentes échelles. Ty21a étant l'immunostimulant le plus efficace, il mérite d'être étudié de manière plus approfondie dans le contexte du NMIBC.
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Both cervical and bladder cancer originates in mucosal sites and can slowly progress from superficial lesions (low to high-grade squamous intra-epithelial lesions (HSIL) and carcinoma in situ (CIS) in the cervix; or non-muscle invasive tumors in the bladder (NMIBC)), to more advanced invasive cancers. The etiology of these two cancers is however very different.
Cervical cancer is the second most common cause of cancer death in women worldwide. This cancer results from the infection of the basal cells of the stratified epithelium of the cervix by high-risk human papillomavirus (HPV). The recent availability of prophylactic vaccines (Gardasil® and Cervarix®) against HPV is an effective strategy to prevent this cancer when administered to young girls before sexual activity; however, these vaccines do not induce regression of established lesions. Despite active development, therapeutic vaccines targeting viral oncogenes E6/E7 had limited clinical efficacy to date. We recently reported that subcutaneous (s.c.) immunization was able to regress small genital tumors in 90% of the mice, but only 20% of mice had regression of larger tumors. Here, we developed a new strategy where vaccination is combined with the local (intravaginal (IVAG)) application of TLR agonists. This new strategy induced an increase of both total and vaccine-specific CD8 T cells in cervix-vagina, but not CD4 T cells. The selective attraction of CD8 T cells is mediated by the expression of CCR5 and CXCR3 chemokine receptors and E-selectin ligands in these cells. Vaccination followed by IVAG application of CpG resulted in tumor regression of large established tumors in 75% of the mice.
Bladder cancer is the second most common urological malignancy. Most tumors are diagnosed as NMIBC, and are restricted to the mucosal bladder with a high propensity to recur and/or progress after local resection. Aiming to develop vaccines against tumor associated antigens (TAA) it is necessary to investigate how to target vaccine-specific T-cell immune responses to the bladder. Here we thus compared using an adjuvanted HPV oncogene (E7) vaccine, as a model, different routes of immunization. Both s.c. and IVAG vaccination induced similar number of vaccine-specific CD8 T-cells in the bladder, whereas intranasal (i.n.) immunization was ineffective. S.c. and IVAG routes induced predominantly aL-, a4- and E-selectin ligand-expressing vaccine-specific CD8 T-cells suggesting that these integrin/selectin are responsible for T-cell homing to the bladder. A single E7 immunization conferred full tumor protection in a prophylactic setting, irrespective of the immunization route. In a therapeutic setting, only ivag and s.c. vaccination efficiently regressed established bladder-tumors in ca. 50 % of mice, whereas i.n. immunization had no effect. Tumor regression correlated with vaccine- specific CD8 T cell tumor-infiltration and decrease of regulatory T cells (Tregs).
To increase efficacy of TAA immunization, we tested vaccination followed by the local instillation of TLR3 or TLR9 agonist or of a Salmonella Typhi vaccine (Ty21a). This strategy resulted in an increase of vaccine-specific effector CD8 T cells in the bladder, although at different magnitudes. Ty21a being the most efficient, it deserves further investigation in the context of NMIBC.
We further tested another strategy to improve therapies of NMIBC. In the murine MB49 bladder tumor model, we replaced the intravesical (ives) BCG therapy by another vaccine strain the Salmonella Ty21a. Ives Ty21a induced bladder tumor regression at least as efficiently as BCG. Ty21a bacteria did not infect nor survive neither in healthy nor in tumor-bearing bladders, suggesting its safety. Moreover, Ty21a induced a transient inflammatory response in healthy bladders, mainly through infiltration of neutrophils and macrophages that rapidly returned to basal levels, confirming its potential safety. The tumor regression was associated to a robust infiltration of immune cells, and secretion of cytokines in urines. Infection of murine tumor cell lines by Ty21a resulted in cell apoptosis. The infection of both murine and human urothelial cell lines induced secretion of in vitro inflammatory cytokines. Ty21a may be an attractive alternative for the ives treatment of NMIBC after transurethral resection and thus deserves more investigation
Two Dimensions of Product Modularity and Innovation: The Case of R&D Teams
No full textThis study investigates the relationship between product modularity and innovation in 101 R&D teams. The key contribution and the departure from prior empirical work consists in bringing into relation multidimensional operationalizations of these two concepts. Product modularity is composed of standardization and reconfigurability and innovation of novelty and efficiency. Theory provides arguments for both negative and positive relationships between standardization and the two types of innovation, while positive relationships are argued for product reconfigurability. The empirical findings corroborate most of the theorizing, although negative relationships are found for standardization. This study contributes to the literature by unpacking the understanding of the concept of product modularity in R&D organizations since the multidimensional approach resolves some of the ambiguity from previous studies. The modularity literature long called for studies to empirically investigate product modularity in more than one dimension implying a number of theoretical implications discussed here
Orientations of Open Strategy: From Resistance to Transformation
No full textFour basic orientations capture open strategy-as-practice that are not only transparent to but also inclusive of an outside community: resist, share, join, and transform. By building upon works in innovation studies, I argue and illustrate that the most exciting cases of open strategy are driven, long-term, by insiders as well as outsiders to the organization and I attend to the idea of orientations of open strategy by formulating an agenda for strategy research that looks at the practices through the lenses of business model design, technologyin-use, and organizational regulation. A key challenge when opening up strategizing at the intersection of multiple networks is the important quest for the organizational purpose
Rapport De Stage
No full textContents I Feuilletages de vari'et'es 2 I.1 D'efinitions : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 2 I.2 Champs de plans et feuilletages : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 2 I.3 R'esultats pr'eliminaires : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 3 II Le th'eor`eme de Haefliger 4 III Fibr'e et ensemble minimal 9 III.1 Ensemble minimal d'un feuilletage : : : : : : : : : : : : : : : : : : : : : : : : : : : : 9 III.2 L'exemple de Denjoy : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 10 III.3 Fibr'es et exemple de Sacksteder : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 10 Le but de ce stage est d"etudier quelques notions concernant les feuilletages de vari'et'es diff'erentiables et analytiques r'eelles. Ceci passe par l"etude de la topologie des feuilles, des groupes d'holonomie, pour aboutir au th'eor`eme de Haefliger et `a la notion d'ensemble minimal
Morphisms between complete Riemannian pseudogroups
No full textAbstractWe introduce the concept of morphism of pseudogroups generalizing the étalé morphisms of Haefliger. With our definition, any continuous foliated map induces a morphism between the corresponding holonomy pseudogroups. The main theorem states that any morphism between complete Riemannian pseudogroups is complete, has a closure and its maps are C∞ along the orbit closures. Here, completeness and closure are versions for morphisms of concepts introduced by Haefliger for pseudogroups. This result is applied to approximate foliated maps by smooth ones in the case of transversely complete Riemannian foliations, yielding the foliated homotopy invariance of their spectral sequence. This generalizes the topological invariance of their basic cohomology, shown by El Kacimi-Alaoui–Nicolau. A different proof of the spectral sequence invariance was also given by the second author
The rational classification of links of codimension > 2
No full textLet m and p1,.,pr < m - 2 be positive integers. The set of links of codimension > 2, Em(∐k=1 rSPk), is the set of smooth isotopy classes of smooth embeddings ∐k=1 rSPk → Sm. Haefliger showed that Em(∐k=1 rSPk) is a finitely generated abelian group with respect to embedded connected summation and computed its rank in the case of knots, i.e. r = 1. For r > 1 and for restrictions on p1,.,pr the rank of this group can be computed using results of Haefliger or Nezhinsky. Our main result determines the rank of the group Em(∐k=1 rSPk) in general. In particular we determine precisely when Em(∐k=1 rSPk) is finite. We also accomplish these tasks for framed links. Our proofs are based on the Haefliger exact sequence for groups of links and the theory of Lie algebras. © de Gruyter 2014.The third author was supported in part by INTAS grant 06-1000014-6277, Moebius Contest Foundation for Young Scientists and Euler Foundation
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