Fully covered self-expanding metal stents placed temporarily in the bile duct: safety profile and histologic classification in a porcine model

<p>Abstract</p> <p>Background</p> <p>Fully covered Self-Expanding metal stents (FCSEMS) have been shown efficacious in palliating malignant biliary obstructions. There is little data analyzing mucosal response to their temporary placement in the bile duct.</p> <p>Methods</p> <p>Ten mini pigs underwent endoscopic placement of a FCSEMS (Wallflex, Boston Scientific). FCSEMS were kept in place for three months. At the end of the 3 months, FCSEMS were removed endoscopically. Five pigs were euthanized and their bile ducts harvested. The other five were kept alive for another month post removal. A single pathologist, created a scoring system (to determine degree of inflammation, fibrosis, and epithelial injury), examined all specimens in a blinded fashion.</p> <p>Results</p> <p>Four FCSEMS spontaneously migrated in the duodenum. On post mortem examination, mild mucosal thickness was noted in three bile duct specimens while superficial inflammation of the bile duct was noted in five animals. Histologic examination of the bile duct revealed focal acute inflammation in both groups. For the 5 animals euthanized immediately after stent removal, there was a tendency to have superficial mucosal erosion and fibrosis. In contrast, increased chronic inflammation was more commonly seen in the animals 1 month post stent removal, with all animals in this group showing moderate degrees of mononuclear inflammatory cell mucosal infiltrates. No severe inflammatory or fibrotic duct injury was observed in any of the study animals, with degree of injury graded as mild to moderate.</p> <p>Conclusion</p> <p>FCSEMS appear to induce minimal tissue overgrowth or fibrosis post placement. Ease of removability and no significant histologic injury are advantages noted with FCSEMS., however, further studies are needed to evaluate treating benign biliary strictures with FCSEMS in humans.</p

How and When Retailers’ Sustainability Efforts Translate into Positive Consumer Responses: The Interplay Between Personal and Social Factors

Contains fulltext : 179202pub.pdf (publisher's version ) (Open Access)27 juni 201

Photo-regulated control of cytokine signaling via bioinspired, polymer-induced latency

Abstract Cytokine signaling is challenging to study or therapeutically modulate as the effects of these protein are often pleotropic and context-dependent. One mechanism by which cytokines with diverse effects can, however, transmit cell type-specific information is via expression in an inactive, or latent, form in which the protein is sterically shielded by a binding partner that is later displaced or degraded (e.g. TGF-β1 association with GARP or LAP). Inspired by this precision, we hypothesized that photo-reversible chemical modification could impart orthogonal specificity to cytokines not expressed in a latent state, such as IL-2, IL-15, or IL-12. Here, we describe a strategy whereby cytokines are modified with photo-labile polymers that mimic the induction of latency while appended, then de-shield to recover protein activity in response to monochromatic light exposure, thus controlling the magnitude, duration, and location of cytokine signals. Using this strategy, we show that latent IL-2 and IL-15 activity can be photo-modulated as much as 103-fold and that polymer-induced IL-2 latency, alone, can bias affinity away from immunosuppressive CD25 binding. We further show that protein de-repression can be achieved with spatial resolution approaching that of a single immune cell and demonstrate the feasibility of transcutaneous IL-2 photoactivation using engineered tissue phantoms. We find that such modifications also prolong the circulation of IL-12 in vivo, thus obviating the need for frequent, high dosing in therapeutic settings. Future extensions of this approach could enable multicolor, optical reprogramming of cytokine signaling networks and lead to immunotherapies that are more tissue-specific and patient-personalized.</jats:p

Promoting anti-tumor immunity via bispecific T cell engaging cytokine (biteokine) therapy

Abstract Bispecific T cell engager (BiTE) therapy bypasses the need for natural recognition of tumor cells by cytotoxic T cells, inducing potent anti-tumor immunity. Currently, the FDA approved BiTE, Blinatumomab (Blin), provides an alternative to standard chemotherapy in patients with relapsed/refractory or MRD+ Acute Lymphoblastic Leukemia (ALL) and is in clinical trials for other B cell malignancies. Blin targets malignant B cells using the antigen binding domain of an αCD19 antibody linked to the antigen binding domain of a T cell-activating αCD3 antibody. Despite progress with Blin clinically, complete response is 39–69%, and a significant proportion of patients are refractory or relapse. To improve this outcome, we have engineered a nanoparticle-based assembly and screening approach to capitalize on cytokine-enhancement of BiTE activity. We found that IL-12 significantly improves Blin-induced B-ALL cell lysis in vitro and, using nanoparticles capable of displaying ~142 antibodies/particle, we generated 28 unique formulations with varying densities and ratios of antibodies to target CD19, activate CD3, and localize IL-12 in a non-neutralizing fashion. We screened these particles in parallel using a co-culture assay for target cell lysis and T cell expansion by flow cytometry. Through regression modeling of these data, we can select-for and optimize architectures that maximize target cell lysis and T cell proliferation. Our preliminary results indicate that optimally lytic architectures favor high αCD3 to αCD19 ratios and are improved linearly with increasing IL-12. This work seeks to innovate and enhance bispecific T cell engager therapy with a modular platform that can be used broadly in the treatment of cancer and autoimmunity.</jats:p

Rapid Assembly and Screening of Multivalent Immune Cell-Redirecting Therapies for Leukemia

ABSTRACTTherapies that bind with immune cells and redirect their cytotoxic activity towards diseased cells represent a promising and versatile approach to immunotherapy with applications in cancer, lupus, and other diseases; traditional methods for discovering these therapies, however, are often time-intensive and lack the throughput of related target-based discovery approaches. Inspired by the observation that the cytokine, IL-12, can enhance antileukemic activity of the clinically approved T cell redirecting therapy, blinatumomab, here we describe the structure and assembly of a chimeric immune cell-redirecting agent which redirects the lytic activity of primary human T cells towards leukemic B cells and simultaneously co-targets the delivery of T cell-stimulating IL-12. We further describe a novel method for the parallel assembly of compositionally diverse libraries of these bi-specific T cell engaging cytokines (BiTEokines) and their high-throughput phenotypic screening, requiring just days for hit identification and the analysis of structure-function relationships. Using this approach, we identified CD19 × CD3 × IL12 compounds that exhibit ex vivo lytic activity comparable to current FDA-approved therapies for leukemia and correlated drug treatment with specific cell-cell contact, cytokine delivery, and leukemia cell lysis. Given the modular nature of these multivalent compounds and their rapid assembly/screening, we anticipate facile extension of this therapeutic approach to a wide range of immune cells, diseased cells, and soluble protein combinations in the future.</jats:p