Full-thickness skin wounds are common and could be a heavy physical and economic burden. With the development of three dimensional (3D) printing technology, skin-like constructs have been fabricated for skin wound healing and regeneration. Although the 3D printed skin has great potential and enormous advantages before vascular networks can be well-constructed, living cells are not recommended for 3D skin printing for in vivo applications. Herein, we designed and printed a bilayer membrane (BLM) scaffold consisting of an outer poly (lactic-co-glycolic acid) (PLGA) membrane and a lower alginate hydrogel layer, which respectively mimicked the skin epidermis and dermis. The multi-porous alginate hydrogel of the BLM scaffolds promoted cell adhesion and proliferation in vitro, while the PLGA membrane prevented bacterial invasion and maintained the moisture content of the hydrogel. Skin regeneration using the bilayer scaffold was compared with that of PLGA, alginate hydrogel and the untreated defect in vivo. Tissue samples were analyzed using histopathological and immunohistochemical staining of CD31. In addition, mRNA expression levels of collagen markers [collagen type 1 alpha 1 (COL1a1) and collagen type 3 alpha 1 (COL3a1)] and inflammatory markers [interleukin-1β (IL-1β), as well as tumor necrosis factor (TNF-α)] were measured. Conclusively, the application of BLM scaffold resulted in highest levels of best skin regeneration by increasing neovascularization and boosting collagen I/III deposition. Taken together, the 3D-printed BLM scaffolds can promote wound healing, and are highly suitable for a wide range of applications as wound dressings or skin substitutes.

Background CD19-specific chimeric antigen receptor (CAR) T cell therapy has achieved high efficacy in acute lymphoblastic leukemia patients. However, the treatment of acute myeloid leukemia (AML) has remained a particular challenge due to the heterogeneity of AML bearing cells, which renders single antigen targeting CAR T cell therapy ineffective. CLL1 and CD33 are often used as targets for AML CAR T cell therapy. CLL1 is associated with leukemia stem cells and disease relapse, and CD33 is expressed on the bulk AML disease. Previously, we demonstrated the profound anti-tumor activity of CLL1-CD33 compound CAR (cCAR) T cells. Here we present the efficacy of cCAR in preclinical study and update the success in level 1 dose escalation clinical trial on relapsed/refractory AML patients. Methods We engineered a cCAR comprising of an anti-CLL1 CAR linked to an anti- CD33 CAR via a self-cleaving P2A peptide and expressing both functional CAR molecules on the surface of a T-cell cell. We tested the anti-leukemic activities of CLL1-CD33 cCAR using multiple AML cell lines, primary human AML samples, human leukemia cell line (REH cells) expressing either CLL1 or CD33, and multiple mouse models. An alemtuzumab safety switch has also been established to ensure the elimination of CAR T cells following tumor eradication. Children and adults with relapsed/refractory AML were enrolled in our phase 1 dose escalation trial with primary objective to evaluate the safety of cCAR and secondary objective to assess the efficacy of cCAR anti-tumor activity. Results Co-culture assays results showed that cCAR displayed profound tumor killing effects in AML cell lines, primary patient samples and multiple mouse model systems. Our preclinical findings suggest that cCAR, targeting two discrete AML antigens: CLL1 and CD33, is an effective two-pronged approach in treating bulk AML disease and eradicating leukemia stem cells. Patients enrolled in the phase 1 dose escalation trial have shown remarkable response to cCAR treatment. Noticeably, a 6-yr-old female patient diagnosed with a complex karyotype AML including FLT3-ITD mutation had achieved complete remission. The patient was diagnosed with Fanconi anemia, which had progressed to juvenile myelomonocytic leukemia and eventually transformed into AML. The patient had been resistant to multiple lines of treatments, including 5 cycles of chemotherapy with FLT3 inhibitor prior to receiving cCAR. Before the treatment, patient's leukemia blasts comprised 73% of the peripheral blood mononuclear cells and 81% of the bone marrow. Patient underwent lymphodepletion therapy (Fludarabine and Cyclophosphamide) prior to cCAR infusion. Two split doses, each consisting of 1x106/kg CAR T cells, were infused on day 1 and day 2 respectively. On day 12, while leukemia blast still counting up to 98% of the bone marrow (Fig. 1A), robust CAR T cell expansion was detected in both peripheral blood and bone marrow. On day 19, patient achieved MRD- complete remission with bone marrow aspirates revealing complete ablation of myeloid cells (Fig. 1B). Flow cytometry confirmed the absence of leukemia blasts and showed that CAR T cells comprised 36% of the PBMC and 60% of the bone marrow. The patient later underwent non-myeloablative hematopoietic cell transplantation with less toxicities compared to conventional total body radiation and high dose chemotherapies. Updated results on other patients enrolled in this clinical trial including adverse events will be presented. Conclusion Our first-in-human clinical trial demonstrates promising efficacy of cCAR therapy in treating patients with relapsed/ refractory AML. cCAR is able to eradicate leukemia blasts and leukemia stem cells, exerting a profound tumor killing effect that is superior to single target CAR T cell therapies. cCAR is also shown to induce total myeloid ablation in bone marrow, suggesting that it may act as a safer alternative to avoid the severe toxicities caused by standard bone marrow ablation regimens without sacrificing the anti-tumor efficacy. This strategy will likely benefit patients who are unable to tolerate total body radiation or high dose chemotherapies. In addition to AML, cCAR also has the potential to treat blast crisis developed from myelodysplastic syndrome, chronic myeloid leukemia, and chronic myeloproliferative neoplasm. Disclosures Pinz: iCell Gene Therapeutics LLC: Employment. Ma:iCAR Bio Therapeutics Ltd: Employment. Wada:iCell Gene Therapeutics LLC: Employment. Chen:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC: Employment. Ma:iCell Gene Therapeutics LLC, iCAR Bio Therapeutics Ltd: Consultancy, Equity Ownership, Research Funding.

A facile method was found to incorporate a mussel-inspired adhesive moiety into synthetic polymers, and mussel mimetic polyurethanes were developed as adhesive hydrogels. In these polymers, a urethane backbone was substituted for the polyamide chain of mussel adhesive proteins, and dopamine was appended to mimic the adhesive moiety of adhesive proteins. A series of mussel mimetic polyurethanes were created through a step-growth polymerization based on hexamethylene diisocyanate as a hard segment, PEG having different molecular weights as a soft segment, and lysine-dopamine as a chain extender. Upon a treatment with Fe(3+), the aqueous mussel mimetic polyurethane solutions can be triggered by pH adjustment to form adhesive hydrogels instantaneously; these materials can be used as injectable adhesive hydrogels. Upon a treatment with NaIO4, the mussel mimetic polyurethane solutions can be cured in a controllable period of time. The successful combination of the unique mussel-inspired adhesive moiety with a tunable polyurethane structure can result in a new kind of mussel-inspired adhesive polymers.

Face detection has received intensive attention in recent years. Many works present lots of special methods for face detection from different perspectives like model architecture, data augmentation, label assignment and etc., which make the overall algorithm and system become more and more complex. In this paper, we point out that there is no gap between face detection and generic object detection. Then we provide a strong but simple baseline method to deal with face detection named TinaFace. We use as backbone, and all modules and techniques in TinaFace are constructed on existing modules, easily implemented and based on generic object detection. On the hard test set of the most popular and challenging face detection benchmark WIDER FACE [48], with single-model and single-scale, our TinaFace achieves 92.1% average precision (AP), which exceeds most of the recent face detectors with larger backbone. And after using test time augmentation (TTA), our TinaFace outperforms the current state-of-the-art method and achieves 92.4% AP. The code is available at https: // github. com/ Media-Smart/ vedadet/ tree/ main/ configs/ trainval/ tinaface .

Pseudomonas aeruginosa is one of the leading causes of opportunistic and hospital-acquired infections worldwide. The infection with P. aeruginosa is frequently linked with clinical treatment difficulties given drug resistance and abuse of antibiotics. Ibuprofen, a widely used non-steroidal anti-inflammatory drug, has been previously reported to exert antimicrobial activity, although the specific mechanism of its action requires additional investigation. Given the regulation effects on quorum sensing (QS), we hypothesized that inhibition of P. aeruginosa with ibuprofen is linked with the QS systems. First, we assessed the action of ibuprofen in P.aeruginosa by measuring CFU. The antimicrobial activity of ibuprofen was evaluated

Elevated Siglec-1 expression in PBMCs and monocytes can potentially serve as a biomarker for monitoring disease activity in RA. Siglec-1 may also play a proinflammatory role in stimulating lymphocyte proliferation and activation in RA.

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