GVT

Allogeneic hematopoietic stem cell transplantation (aHSCT) can cure patients with otherwise fatal leukemias and lymphomas. However, the benefits of aHSCT are limited by graft-versus-host disease (GVHD). Minnelide, a water-soluble analog of triptolide, has demonstrated potent anti-inflammatory and anti-tumor activity in several pre-clinical models and has proven both safe and efficacious in clinical trials for advanced gastro-intestinal malignancies. Here, we tested the effectiveness of Minnelide in preventing acute GVHD as compared to cyclophosphamide post-aHSCT (PTCy)...

IIdentifying the interactome for a protein of interest is challenging due to the large number of possible binders. High-throughput experimental approaches narrow down possible binding partners but often include false positives. Furthermore, they provide no information about what the binding region is (e.g., the binding epitope). We introduce a novel computational pipeline based on an AlphaFold2 (AF) Competition Binding Assay (AF-CBA) to identify proteins that bind a target of interest from a pull-down experiment and the binding epitope...

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is not a standard therapy for solid cancer because of its high toxicity and insufficient evidence levels. However, the potential graft-versus-solid-tumor (GVT) effect of this therapy has been discussed. Many case reports have also described treatment effects of allo-HSCT in patients with hematologic malignancies and active solid tumors. A 38-year-old woman treated with fulvestrant and abemaciclib for recurrent breast cancer with multiple lung metastases was diagnosed with myelodysplastic syndrome (MDS) with increased blasts 2...

G-protein coupled receptor 15 (GPR15) is expressed on T-cells. We previously reported knockout of GPR15 increased acute graft-versus-host disease (GvHD) in mice. In this study, we identified thrombin receptor activating peptide-6 (TRAP-6, peptide sequence: SFLLRN) as an activator of GPR15. GRP15 and β-arrestin2 were needed for TRAP-6-mediated inhibition of mixed lymphocyte reactions. TRAP-6 decreased acute GvHD in allotransplant models in mice, an effect dependent on GPR15-expression in donor T-cells...

Influenza A and B viruses overcome the host antiviral response to cause a contagious and often severe human respiratory disease. Here, integrative structural biology and biochemistry studies on non- structural protein 1 of influenza B virus (NS1B) reveal a previously unrecognized viral mechanism for innate immune evasion. Conserved basic groups of its C-terminal domain (NS1B-CTD) bind 5'- triphosphorylated double-stranded RNA (5'ppp-dsRNA), the primary pathogen-associated feature that activates the host retinoic acid-inducible gene I protein (RIG-I) to initiate interferon synthesis and the cellular antiviral response...

Identifying the interactome for a protein of interest is challenging due to the large number of possible binders. High-throughput experimental approaches narrow down possible binding partners, but often include false positives. Furthermore, they provide no information about what the binding region is (e.g. the binding epitope). We introduce a novel computational pipeline based on an AlphaFold2 (AF) Competition Assay (AF-CBA) to identify proteins that bind a target of interest from a pull-down experiment, along with the binding epitope...

Allogenic hematopoietic stem-cell transplantation (allo-HSCT) is a widely employed treatment for a broad range of hematological malignancies because of its graft-versus-tumor (GvT) effect. Unfortunately, allo-HSCT is still associated with morbidity and mortality related to relapse and transplant complications, namely graft-versus-host-disease (GvHD). In an era of therapies specifically targeting molecular pathways, transcription factors and cytokines, a better understanding of GvHD physiopathology is essential for the development of new therapeutic approaches...

While a plethora of articles discuss management of deep venous thromboses in extremities, there is a relative scarcity of literature comprehensively describing intra-abdominal venous thromboses, and their management. Intra-abdominal venous thromboses include iliocaval venous obstruction (ICVO), hepatic venous thrombosis (HVT), portal venous thrombosis (PVT), renal vein thrombosis (RVT), splenic vein thrombosis (SVT), and gonadal vein thrombosis (GVT); each of which provides unique microenvironmental challenges to management...

Immune checkpoint blockade (ICB) therapies developed over the past decade have been among the most promising approaches for the treatment of patients with advanced cancers. However, the overall objective response rate of ICB therapy for various cancers remains insufficient. Hence, novel strategies are required to improve the efficacy of immunotherapy for advanced cancers. The graft-versus-tumor (GVT) effect, which reflects strong antitumor immunity, is known to occur after allogeneic hematopoietic stem cell transplantation (HSCT)...

Donor lymphocyte infusion (DLI) cures relapsed hematologic malignancies after allogeneic hematopoietic stem cell transplantation through the graft-versus-tumor (GVT) effect. Although the important role of magnesium in enhancing immunity has been mentioned in studies, limited clinical data have explored how magnesium affects the efficacy of DLI. Besides, although laboratory data demonstrate that magnesium can enhance CD8+ T cells effector function, whether magnesium regulates the tumor killing effect of peripheral blood mononuclear cells (PBMCs) remains to be explored...

Transcription factors play a major role in regulation and orchestration of immune responses. The immunological context of the response can alter the regulatory networks required for proper functioning. While these networks have been well-studied in canonical immune contexts like infection, the transcription factor landscape during alloactivation remains unclear. This review addresses how transcription factors contribute to the functioning of mature alloactivated T cells. This review will also examine how these factors form a regulatory network to control alloresponses, with a focus specifically on those factors expressed by and controlling activity of T cells of the various subsets involved in graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) responses...

BACKGROUND: Osteosarcoma (OS) patients that present with metastatic disease have a poor prognosis and no curative options. Allogeneic bone marrow transplant (alloBMT) is curative for hematologic malignancies through the graft-versus-tumor (GVT) effect, but to date has been ineffective for solid tumors like OS. CD155 is expressed on OS and interacts strongly with the inhibitory receptors TIGIT and CD96 but also binds to the activating receptor DNAM-1 on natural killer (NK) cells but has never been targeted after alloBMT...

BACKGROUND: Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematological malignancies. CBT tolerates HLA mismatches between donors and recipients, but which HLA mismatches generate graft-versus-tumor (GVT) effects is unknown. OBJECTIVE: Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT...

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative option for high-risk myeloid malignancies. Post-transplant cyclophosphamide (PT-Cy) has proven to be effective for graft versus host disease (GVHD) prophylaxis. Given that graft-versus-tumor (GVT) effect plays a major role in reducing the risk of disease relapse, the application of PT-Cy must balance the risk of relapse. Mixed chimerism (MC) refers to a state of concurrent presence of recipient and donor cells post allo-HSCT which may precede relapse disease...

BACKGROUND: Surgical resident operative autonomy is critical for trainee maturation to independence. Acute care surgery (ACS) cases commonly occur off-hours and tension between OR availability and on-call staff can affect resident operative autonomy. We examined operative resident autonomy for general, vascular, and thoracic (GVT) surgery during nights and weekends. We hypothesized that residents would be afforded less operative autonomy during off hours than weekdays. METHODS: This retrospective cohort study utilizes the VASQIP database, we examined all GVT cases at VA teaching hospitals from 2004-2019...

Motivated by the need to perform large-scale kinetic Monte Carlo (KMC) simulations, in the context of unravelling complex phenomena such as catalyst reconstruction and pattern formation, we extend the work of Ravipati et al. [S. Ravipati, G. D. Savva, I.-A. Christidi, R. Guichard, J. Nielsen, R. Réocreux and M. Stamatakis, Comput. Phys. Commun. , 2022, 270 , 108148] in benchmarking the performance of a distributed-computing, on-lattice KMC approach. The latter, implemented in our software package Zacros , combines the graph-theoretical KMC framework with the Time-Warp algorithm for parallel discrete event simulations, and entails dividing the lattice into subdomains, each assigned to a processor...

OBJECTIVES: Gains in pitch from gender affirming voice training (GVT) alone in trans women have historically been shown to decline after 1 year. Currently no standard exists for length and type of GVT that yields meaningful behavioral change and patient satisfaction with voice outcomes in trans women. This study aims to determine whether GVT alone leads to sustained pitch elevation and patient satisfaction in trans women. METHODS: Retrospective review from 2016 to 2020 of trans women patients who underwent GVT alone for voice change...

CD4+FOXP3+ regulatory T cells have demonstrated efficacy in graft-versus-host disease (GvHD) prevention and treatment. Preclinical and clinical studies indicate that Treg are able to protect from GvHD without interfering with the graft-versus-tumor (GvT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GvHD, we performed paired T cell receptor (TCRa, TCRb genes) repertoire sequencing and RNA sequencing analysis on conventional T cells (Tcon) and Treg before and after transplantation in an MHC major-mismatch mouse model of HCT...

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option for patients with hematological disorders and bone marrow failure syndromes. Graft-versus-Host Disease (GVHD) remains a leading cause of morbidity post-transplant. Regulatory T cell (Treg) therapies are efficacious in ameliorating GVHD but limited by variable suppressive capacities and the need for a high therapeutic dose. Here, we sought to expand Treg in vivo by expressing an orthogonal IL-2Rβ receptor (oIL2Rβ) that would selectively interact with orthogonal IL-2 (oIL2) cytokine and not wildtype IL2...

Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare myeloid malignancy with a generally poor prognosis. Although preliminary evidence suggests that hematopoietic cell transplantation (HCT) could improve outcome in patients with BPDCN, the individual contributions of conditioning and graft-versus-tumor (GVT) effects to HCT success are undefined. We present a retrospective study of 162 adult patients who underwent a first HCT (allogeneic 146, autologous 16) between 2009 and 2017, and were registered with the EBMT...