Increased dissolution rates of tranilast solid dispersions extruded with inorganic excipients

The purpose of this study was to evaluate the performance of Neusilin® (NEU) a synthetic magnesium aluminometasilicate as inorganic drug carrier co-processed with the hydrophilic surfactants Labrasol and Labrafil to develop Tranilast (TLT) based solid dispersions using continuous melt extrusion (HME) processing. Twin – screw extrusion was optimized to develop various TLT/excipient/surfactant formulations followed by continuous capsule filling in the absence of any downstream equipment. Physicochemical characterisation showed the existence of TLT in partially crystalline state in the porous network of inorganic NEU for all extruded formulations. Furthermore, the in line NIR studies revealed a possible intermolecular H–bonding formation between the drug and carrier resulting in the increase of dissolution of TLT. The capsules containing TLT extruded solid dispersions showed enhanced dissolution rates and compared with the marketed Rizaben® product

Good practice recommendations for the use of time-lapse technology†

STUDY QUESTION: What recommendations can be provided on the approach to and use of time-lapse technology (TLT) in an IVF laboratory?SUMMARY ANSWER: The present ESHRE document provides 11 recommendations on how to introduce TLT in the IVF laboratory. WHAT IS KNOWN ALREADY: Studies have been published on the use of TLT in clinical embryology. However, a systematic assessmentof how to approach and introduce this technology is currently missing.STUDY DESIGN, SIZE, DURATION: A working group of members of the Steering Committee of the ESHRE Special Interest Group in Embryology and selected ESHRE members was formed in order to write recommendations on the practical aspects of TLT for the IVF laboratory.PARTICIPANTS/MATERIALS, SETTING, METHODS: The working group included 11 members of different nationalities with internationally recognized experience in clinical embryology and basic science embryology, in addition to TLT. This document is developed according to the manual for development of ESHRE recommendations for good practice. Where possible, the statements are supported by studies retrieved from a PUBMED literature search on ‘time-lapse’ and ART.MAIN RESULTS AND THE ROLE OF CHANCE: A clear clinical benefit of the use of TLT, i.e. an increase in IVF success rates, remains to be proven. Meanwhile, TLT systems are being introduced in IVF laboratories. The working group listed 11 recommendations on what to do before introducing TLT in the lab. These statements include an assessment of the pros and cons of acquiring a TLT system, selection of relevant morphokinetic parameters, selection of an appropriate TLT system with technical and customer support, development of an internal checklist and education of staff. All these aspects are explained further here, based on the current literature and expert opinion.LIMITATIONS, REASONS FOR CAUTION: Owing to the limited evidence available, recommendations are mostly based on clinical and technical expertise. The paper provides technical advice, but leaves any decision on whether or not to use TLT to the individual centres.WIDER IMPLICATIONS OF THE FINDINGS: This document is expected to have a significant impact on future developments of clinical embryology, considering the increasing role and impact of TLT

Tertiary Lymphoid Tissue in Colorectal Cancer: A Key Player in the Tumour Immune Microenvironment

Tumour infiltrating lymphocytes influence colorectal cancer (CRC) progression. However, lymphocyte infiltration comes in different flavours and evidence has been provided that the spatial distribution of immune cells within the tumour tissue is an important immunological feature. The aim of this thesis was to investigate how the dual localization of tumour infiltrating lymphocytes (TILs) can affect their function in the tumour microenvironment. The project started with the analysis of the CD3 compartment, as CD3+ T cell infiltration (CD3-TILs) is a recognized positive prognostic factor for CRC patients. Results here presented show that CD3+ tumour-infiltrating lymphocytes are present both interspersed in the tumour tissue or scattered throughout the stroma (CD3-TILs) and also aggregated in lymphoid structures showing features of tertiary lymphoid tissue (CD3-TLT). Tumour-associated TLT had a peculiar compartmentalization, with CD3+ T cells and CD20+ B lymphocytes holding complementary positions and with distinct types of dendritic cell populations among them. The presence of HEVs (High Endothelial Venules) suggests a role for TLT in T cell recruitment at the tumour site. To test this hypothesis in human cancer, I performed a whole tissue analysis of the CD3+ infiltrate on CRC sections and found a positive correlation between CD3-TIL and CD3-TLT densities. I further confirmed the hypothesis in vivo in a murine model of colitis-associated cancer (AOM/DSS). AOM/DSS treated mice had expanded TLT compared to control mice. Intravenously injected GFP+ splenocytes localised in TLT of tumour-bearing mice more than in control mice. I then investigated the clinical significance of CD3-TLT in relationship with CD3-TILs in a cohort of 351 CRC patients. In patients with node-negative (without lymph node metastasis, stage II) CRC, a high density of CD3-TLT and CD3-TILs associated to a better prognosis, while in patients with node-positive (presence of lymph node metastasis, stage III) CRC, TLT and TIL density were irrelevant in predicting patient prognosis, thus behaving as biomarkers only for early stage CRC patients. In the second part of my thesis, I analysed the distribution of B cells in colorectal cancer and their possible contribution to disease progression. Despite still controversial, increasing evidence that B cells play a role in cancer progression has been provided, bringing up the hypothesis that also B-cell responses should be considered as targets of immunotherapeutic approaches. Similarly to CD3+ cells, I showed that, both in human and in preclinical models of CRC, B cells display a dual geographical distribution, either within tertiary lymphoid tissue (CD20-TLT) or dispersed at the tumour invasive margin (CD20-TILs). Therefore, I evaluated the role of B cells according to their localization in the microenvironment. I found that CD20-TLT associated to better prognosis, while CD20-TILs did not. Interestingly, CD20-TLT correlated with CD20-TILs only among patients who experienced cancer recurrence. This result suggests that, when located within a lymphoid site, B cells might have a protective anti-tumour function, participating in an antitumour immune response. Conversely, the distribution of B cells scattered in the microenvironment is likely to reflect a non-specific pro-tumour inflammatory reaction. To confirm the hypothesis in vivo and attempt to dissect the dual function of B cells, I took advantage of two CRC preclinical models in which B cells present a distinct geographical distribution in the tumour microenvironment. In the first model, B cells mainly localise within TLT, while in the second one B cells diffusely infiltrate the mucosa, without forming aggregates. I found that in a model in which B cells localize primarily within TLT, the genetic deficiency of B cells significantly increased tumour formation, suggesting that B cells within TLT might exert an important anti-tumour function. In contrast, in a model in which B cells only localize within the tissue, genetic deficiency of B cells reduces tumour growth, suggesting that infiltrating B-TILs might have a pro-tumour role. Therefore, the occurrence of TLT is associated with lymphocyte infiltration in CRC, contributing to recruitment of CD3-TILs. TLT and TILs work together to set up an anti-tumour immune response in patients with low-risk early-stage colorectal cancer. Thus, TLT represents a novel prognostic biomarker for CRC. As to the B cell compartment, their differential distribution in the tumour site corresponds to distinct prognostic functions. This evidence suggests that the design of novel immunotherapeutic drugs depleting B cells should take into account their ability to selectively targeting CD20-TILs but not C20-TLT

Revue de livre : Understanding and Promoting Transformative Learning (2e édition)

This book is a well-crafted guide to Transformative Learning Theory (TLT). Cranton first distills the components of TLT and its evolution. She then shifts focus to the learner’s perspective and individual’s psychological differences. The subsequent chapters look at educator roles to empower learners and lastly how educators can self-reflect and support learners through their own transformative journey.  Ce livre est un guide bien conçu de la théorie de l’apprentissage transformateur (TLT). Cranton distille d’abord les composants du TLT et son évolution. Elle se concentre ensuite sur le point de vue de l’apprenant et les différences psychologiques de l’individu. Les chapitres suivants examinent les rôles des éducateurs pour responsabiliser les apprenants et enfin comment les éducateurs peuvent réfléchir et soutenir les apprenants à travers leur propre parcours de transformation. 

Simulation and performance assessment of a modified throttled load balancing algorithm in cloud computing environment

Load balancing is crucial to ensure scalability, reliability, minimize response time, and processing time and maximize resource utilization in cloud computing. However, the load fluctuation accompanied with the distribution of a huge number of requests among a set of virtual machines (VMs) is challenging and needs effective and practical load balancers. In this work, a two listed throttled load balancer (TLT-LB) algorithm is proposed and further simulated using the CloudAnalyst simulator. The TLT-LB algorithm is based on the modification of the conventional TLB algorithm to improve the distribution of the tasks between different VMs. The performance of the TLT-LB algorithm compared to the TLB, round robin (RR), and active monitoring load balancer (AMLB) algorithms has been evaluated using two different configurations. Interestingly, the TLT-LB significantly balances the load between the VMs by reducing the loading gap between the heaviest loaded and the lightest loaded VMs to be 6.45% compared to 68.55% for the TLB and AMLB algorithms. Furthermore, the TLT-LB algorithm considerably reduces the average response time and processing time compared to the TLB, RR, and AMLB algorithms

Immune Responses Elicited in Tertiary Lymphoid Tissues Display Distinctive Features

During chronic inflammation, immune effectors progressively organize themselves into a functional tertiary lymphoid tissue (TLT) within the targeted organ. TLT has been observed in a wide range of chronic inflammatory conditions but its pathophysiological significance remains unknown. We used the rat aortic interposition model in which a TLT has been evidenced in the adventitia of chronically rejected allografts one month after transplantation. The immune responses elicited in adventitial TLT and those taking place in spleen and draining lymph nodes (LN) were compared in terms of antibody production, T cell activation and repertoire perturbations. The anti-MHC humoral response was more intense and more diverse in TLT. This difference was associated with an increased percentage of activated CD4+ T cells and a symmetric reduction of regulatory T cell subsets. Moreover, TCR repertoire perturbations in TLT were not only increased and different from the common pattern observed in spleen and LN but also “stochastic,” since each recipient displayed a specific pattern. We propose that the abnormal activation of CD4+ T cells promotes the development of an exaggerated pathogenic immune humoral response in TLT. Preliminary findings suggest that this phenomenon i) is due to a defective immune regulation in this non-professional inflammatory-induced lymphoid tissue, and ii) also occurs in human chronically rejected grafts

Beyond personal transformation: Engaging students as agents for social change.

Although Transformative Learning Theory (TLT) has been around for more than 40 years, few studies empirically engage critical theoretical frameworks to move beyond personal learning to identify the impacts of transformation on society. The purpose of this article is to discuss academic literature that expands TLT in the direction of societal transformation rather than merely personal change. Moreover, this article appeals for empirical studies that inform TLT through various socially constructed variables of race, class, (trans)gender, (a)sexuality, (dis)ability, and culture. The author titles this post-modern, intersectional approach critical social transformative learning theory