Role of Nitric Oxide in the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis.

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/)

Bile Acids Do Not Contribute to the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis.

© 2017. This manuscript version is made available under the [CC-BY 4.0] license http://creativecommons.org/licenses/by/4.0/ This document is the Accepted Manuscript version of a Published Work that appeared in final form in [Frontiers in Physiology]. To access the final edited and published work see [10.3389/fphys.2017.00384

Platelet function and microvesicle generation in patients with hemophilia A

Our results do not support any effect of FVIII on platelet function in patients with severe HA treated under the regime of prophylaxi

Platelet function and microvesicle generation in patients with hemophilia A

Our results do not support any effect of FVIII on platelet function in patients with severe HA treated under the regime of prophylaxi

A novel and efficient tandem CD19- and CD22-directed CAR for B-cell ALL.

CD19-directed chimeric antigen receptor (CAR) T-cells have yielded impressive response rates in refractory/relapse B-cell acute lymphoblastic leukemia (B-ALL);however, most patients ultimately relapse due to poor CAR T-cell persistence or resistance of either CD19+ or CD19- B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19+ and CD19- relapses. Indeed, CD22-CAR T-cells have been clinically used in B-ALL patients, although relapse also occurs. Tcells engineered with a tandem CAR (Tan-CAR) containing in a single contruct both CD19 and CD22 scFvs, might be advantageus in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T-cells showed similar in vitro expansion than CD19-CAR T-cells with no increased of tonic signaling. CRISPR/Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitro and in vivo using B-ALL cell lines, patient samples and patient-derived xenografts (PDXs). Strikingly, the robust anti-leukemic activity of the Tan-CAR was slightly more effective in controling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss

ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma

Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS. The target recognition element of the second-generation CAR construct is based on two antibodies, previously shown to react against OS. T cells transduced with these CAR constructs mediate efficient and effective cytotoxicity against ALPL-positive cells in in vitro settings and in state-of-the-art in vivo orthotopic models of primary and metastatic OS, without unexpected toxicities against hematopoietic stem cells or healthy tissues. In summary, CAR-T cells targeting ALPL-1 show efficiency and specificity in treating OS in preclinical models, paving the path for clinical translation