Targeted oral delivery of a drug via the intestinal lymphatic system (ILS) has the advantages of protecting against hepatic first‐pass metabolism of the drug and improving its pharmacokinetic ...performance. It is also a promising route for the oral delivery of vaccines and therapeutic agents to induce mucosal immune responses and treat lymphatic diseases, respectively. This article describes the anatomical structures and physiological characteristics of the ILS, with an emphasis on enterocytes and microfold (M) cells, which are the main gateways for the transport of particulate delivery vehicles across the intestinal epithelium into the lymphatics. A comprehensive overview of recent advances in the rational engineering of particulate vehicles, along with the challenges and opportunities that they present for improving ILS drug delivery, is provided, and the mechanisms by which such vehicles target and transport through enterocytes or M cells are discussed. The use of naturally sourced materials, such as yeast microcapsules and their derived polymeric β‐glucans, as novel ILS‐targeting delivery vehicles is also reviewed. Such use is the focus of an emerging field of research. Their potential use in the oral delivery of nucleic acids, such as mRNA vaccines, is proposed.
The rational engineering of effective vehicles for lymphatic delivery of drugs, through targeting enterocytes or M cells, prevents their first‐pass metabolism by the liver, markedly increasing the bioavailability of oral drugs. By achieving increased bioavailability, high drug concentrations are attainable at the lesions of interest with beneficial therapeutic effects, making intestinal lymphatic transport a unique modality of drug delivery.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
BCMA targeting chimeric antigen receptor (CAR) T cell therapy has shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of ...resistance remain ill-defined. Here, we perform single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment. We report selection, following initial CAR T cell infusion, of a clone with biallelic loss of BCMA acquired by deletion of one allele and a mutation that creates an early stop codon on the second allele. This loss leads to lack of CAR T cell proliferation following the second infusion and is reflected by lack of soluble BCMA in patient serum. Our analysis suggests the need for careful detection of BCMA gene alterations in multiple myeloma cells from relapse following CAR T cell therapy.
VR technology allows learners to access simulated, immersive and interactive virtual environments to perform authentic learning activities. In particular, VR has emerged as a valuable tool for L2 ...learning. However, VR research has tended to pay more attention to desktop-based VR than to VR via mobile-rendered HMDs, leaving the potentials of VR through mobile-rendered HMDs yet to be investigated. Therefore, this study fills the gap by using a commercial VR app to examine the effect of VR via mobile-rendered HMDs on EFL learners' vocabulary learning. Forty-nine seventh graders in Taiwan were recruited from two intact classes and assigned to either an experimental (VR players) or control (video watchers) group. The VR players interacted with Mondly VR app using mobile-rendered HMDs and took part in conversations with virtual characters. The video watchers watched the walkthrough video signal of the VR player's app via a personal computer. Vocabulary tests, a perception questionnaire, and interviews were used to evaluate the participants' vocabulary learning. The results showed that the VR players' vocabulary learning and retention was significantly higher than the video watchers'. The majority of the VR players felt that VR-mediated vocabulary learning was motivating and beneficial. The VR app contextualized vocabulary learning by providing virtual environments with multimodal support and enhanced learner engagement through real-time interactivity and feedback. The video watchers' feedback revealed mixed feelings. Some felt that the walkthrough video facilitated vocabulary learning by providing word meaning and use in context. Others reported it lacked interactivity and their attention was easily distracted.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical ...advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody-drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.
Willingness to communicate (WTC) is considered to be an important factor contributing to successful foreign language learning. Many studies aim at finding effective tools for enhancing WTC. With the ...support of AI and Automatic Speech Recognition technology, intelligent personal assistants (IPAs) seem to have potentials in improving foreign language learners' WTC. However, few empirical studies focus on the possible impact of IPAs on learners' WTC. This study was conducted to investigate the potentials of an IPA, Google Assistant, for developing adolescent EFL learners' WTC and their perceptions of IPAs for EFL learning. This study recruited 112 eighth-grade EFL learners who engaged in Google-Assistant-language-learning activities for two weeks. Two WTC questionnaires were administered at the beginning and end of the intervention. The results demonstrated that Google Assistant significantly promoted EFL learners' WTC, enhanced communicative confidence, and reduced speaking anxiety. Analyses of interviews revealed that participants enjoyed playing games with Google Assistant and talking to chatbots, which helped them feel less anxious and motivated to use English for real and meaningful communication. The findings indicated that IPA-based interaction provided a less threatening environment, in which learners displayed higher levels of engagement, motivation, confidence, and, in turn, their WTC in the target language.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
We study CD38 levels in immunosuppressive CD4
CD25
Foxp3
regulatory T cells (Treg) and further define immunomodulating effects of a therapeutic CD38 mAb isatuximab/SAR650984 in multiple myeloma.
We ...evaluated percentages of CD38-expressing subsets in Tregs from normal donors and multiple myeloma patients. Peripheral blood mononuclear cells (PBMC) were then treated with isatuximab with or without lenalidomide or pomalidomide to identify their impact on the percentage and immunosuppressive activity of Tregs on CD4
CD25
T cells (Tcons). We investigated the mechanism of increased Tregs in multiple myeloma patients in
cocultures of multiple myeloma cells with PBMCs or Tcons.
CD38 expression is higher on Tregs than Tcons from multiple myeloma patients versus normal donors. CD38 levels and the percentages of CD38
Tregs are increased by lenalidomide and pomalidomide. Isatuximab preferentially decreases Treg and increases Tcon frequencies, which is enhanced by pomalidomide/lenalidomide. Isatuximab reduces Foxp3 and IL10 in Tregs and restores proliferation and function of Tcons. It augments multiple myeloma cell lysis by CD8
T and natural killer cells. Coculture of multiple myeloma cells with Tcons significantly induces Tregs (iTregs), which express even higher CD38, CD25, and FoxP3 than natural Tregs. This is associated with elevated circulating CD38
Tregs in multiple myeloma patients versus normal donors. Conversely, isatuximab decreases multiple myeloma cell- and bone marrow stromal cell-induced iTreg by inhibiting both cell-cell contact and TGFβ/IL10. Finally, CD38 levels correlate with differential inhibition by isatuximab of Tregs from multiple myeloma versus normal donors.
Targeting CD38 by isatuximab can preferentially block immunosuppressive Tregs and thereby restore immune effector function against multiple myeloma.
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Intelligent personal assistants (IPAs) are a valuable tool in language learning because they provide opportunities for authentic interaction. However, their effectiveness, compared with that of human ...interlocutors, in facilitating second and foreign language interaction has not been explored. Therefore, this study investigated the effect of IPAs (i.e. Google Assistant on smartphones) on English as a foreign language (EFL) learners' oral proficiency outside the classroom and the differences between IPA-human interaction and human-only interaction. A total of 89 college freshmen participated in an out-of-class program consisting of 10-minute sessions twice a week for one semester. The participants were randomly divided into three groups: (1) those who interacted with Google Assistant on smartphones; (2) those who interacted with L1 English speakers; and (3) those who interacted with L2 English speakers. Both quantitative (English oral proficiency tests) and qualitative data (focus group interviews) were collected and analyzed. The results revealed that the out-of-class use of Google Assistant significantly improved the EFL learners' oral proficiency, with a positive effect similar to that of interaction with L1 English speakers. A detailed analysis of the interviews revealed that the mobility and ubiquity of Google Assistant exposed learners to a large amount of high-quality oral input, provided opportunities to practice speaking with immediate, multimodal feedback, engaged learners through various modes of interaction, eliminated learners' fear of making mistakes, reduced learners' anxiety in speaking English, and encouraged self-directed learning outside the classroom, which are all conducive to improving EFL learners' oral proficiency.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Intelligent Personal Assistant (IPA) has emerged as a valuable tool for EFL learning by offering interactive authentic contexts. Although IPA is believed to be motivational and useful, empirical ...evidence is limited and contradictory, especially the efficacy of listening comprehension. Therefore, the study investigated the impact of IPA on adolescent EFL learners' listening comprehension, particularly regarding the presentation mode of IPA responses and its interaction styles. Ninety-two ninth-grade EFL learners were recruited from three intact classes and randomly divided into two experimental groups (i.e. GA-Hub group, using Google Nest Hub with multimodal responses; GA-Mini group, using Google Nest Mini with audio responses) and one control group (non-GA group, using a CD player as they did in the conventional class). Both quantitative (English listening tests) and qualitative data (questionnaires and interviews) were collected and analyzed in the 10-week study. The results showed that Google Assistant, especially via Google Nest Hub, positively promoted the participants' listening comprehension. Detailed analyses of interviews demonstrated that Google Assistant provided interactive listening, presented multimodal screen-based responses, encouraged peer collaboration, and offered edutainment (a combination of IPA- and game-based learning), which added authenticity, flexibility, and enjoyment for meaningful interaction and thus promoted EFL listening.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Here we show that overexpression or activation of B-cell maturation antigen (BCMA) by its ligand, a proliferation-inducing ligand (APRIL), promotes human multiple myeloma (MM) progression in vivo. ...BCMA downregulation strongly decreases viability and MM colony formation; conversely, BCMA overexpression augments MM cell growth and survival via induction of protein kinase B (AKT), MAPK, and nuclear factor (NF)-κB signaling cascades. Importantly, BCMA promotes in vivo growth of xenografted MM cells harboring p53 mutation in mice. BCMA-overexpressing tumors exhibit significantly increased CD31/microvessel density and vascular endothelial growth factor compared with paired control tumors. These tumors also express increased transcripts crucial for osteoclast activation, adhesion, and angiogenesis/metastasis, as well as genes mediating immune inhibition including programmed death ligand 1, transforming growth factor β, and interleukin 10. These target genes are consistently induced by paracrine APRIL binding to BCMA on MM cells, which is blocked by an antagonistic anti-APRIL monoclonal antibody hAPRIL01A (01A). 01A is cytotoxic against MM cells even in the presence of protective bone marrow (BM) myeloid cells including osteoclasts, macrophages, and plasmacytoid dendritic cells. 01A further decreases APRIL-induced adhesion and migration of MM cells via blockade of canonical and noncanonical NF-κB pathways. Moreover, 01A prevents in vivo MM cell growth within implanted human bone chips in SCID mice. Finally, the effect of 01A on MM cell viability is enhanced by lenalidomide and bortezomib. Taken together, these data delineate new molecular mechanisms of in vivo MM growth and immunosuppression critically dependent on BCMA and APRIL in the BM microenvironment, further supporting targeting this prominent pathway in MM.
•APRIL/BCMA activation promotes MM proliferation, survival, and immunosuppression in vitro and in vivo.•Targeting the APRIL/BCMA pathway represents a promising mechanism-based immunotherapy to target MM and overcome drug resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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