The functional significance of the Duffy negative polymorphism

I investigated the impact of DARC expression on haematopoiesis using DARC-deficient (DD) mice and developed humanised transgenic DARC models expressing the $FYB(ES)$ and $FYB$ human genes. I developed murine irradiation chimeras with differential DARC expression and showed that the absence of erythroid DARC but continued DARC endothelial expression was associated with reduced peripheral blood neutrophil counts. FYB(ES)TG mice showed reduced peripheral neutrophil counts and expansion of BM myelopoiesis, and reduced lymphopoiesis and erythropoiesis, compared to FYBTG mice. FYB(ES)TG and DD mice had reduced GMP cells and LSK cells, and proliferation and apoptosis of these cells were reduced. Microarray analysis of differentially expressed genes showed increased myeloid gene expression in GMP and LSK cells. Mixed irradiation chimeras showed that DD BM retained these changes, suggesting an intrinsic cell effect. Analysis of BM and serum showed a significant increase in G-CSF and eotaxin. Morphological analysis of myeloid cells in femur sections revealed increased myeloid cell clustering in DD and FYB(ES)TG mice. These data suggest that neutrophils are preferentially retained in the DD BM, possibly as a result of loss of optimal chemokine gradients created by erythroblast DARC which may favour neutrophil egress and thereby leading to peripheral neutropenia

Duffy antigen receptor for chemokines and its involvement in patterning and control of inflammatory chemokines

Leukocyte functions are linked to their migratory responses, which, in turn, are largely determined by the expression profile of classical chemokine receptors. Upon binding their cognate chemokines, these G-protein-coupled receptors (GPCRs) initiate signaling cascades and downstream molecular and cellular responses, including integrin activation and cell locomotion. Chemokines also bind to an alternative subset of chemokine receptors, which have serpentine structure characteristic for GPCRs but lack DRYLAIV consensus motive required for coupling to G-proteins. Duffy antigen receptor for chemokines (DARC) is a member of this atypical receptor subfamily. DARC binds a broad range of inflammatory CXC and CC chemokines and is expressed by erythrocytes, venular endothelial cells, and cerebellar neurons. Erythrocyte DARC serves as blood reservoir of cognate chemokines but also as a chemokine sink, buffering potential surges in plasma chemokine levels. Endothelial cell DARC internalizes chemokines on the basolateral cell surface resulting in subsequent transcytosis of chemokines and their immobilization on the tips of apical microvilli. These DARC-mediated endothelial cell interactions allow chemokines produced in the extravascular tissues to optimally function as arrest chemokines on the luminal endothelial cell surface

Diseño de una planta de procesamiento de productos lácteos y elaboración de un plan de contingencia contra deslaves en el Instituto Tecnológico Universitario Guatemala Sur-USAC. Palón, Escuintla.

La presente investigación se realizó en el Instituto Tecnológico Universitario Guatemala Sur, es una dependencia de la Universidad de San Carlos de Guatemala, descentralizada con patrimonio propio, encargado de desarrollar la formación teórica y práctica y la educación profesional en las áreas tecnológicas. Está ubicado en el municipio de Palín, departamento de Escuintla. En el Instituto Tecnológico Universitario Guatemala Sur (ITUGS), se imparten 5 carreras técnicas, dentro de las cuales está la carrera de Técnico en Producción Alimentaria donde se imparte el curso de procesamiento de productos lácteos. La carrera de Técnico necesita el aprendizaje práctico y técnico de la elaboración de alimentos y actualmente el ITUGS no cuenta con las instalaciones adecuadas para desarrollar las prácticas de dicha carrera, por lo que se propone el diseño de una planta de procesamiento de productos lácteos, en donde los alumnos puedan realizar las prácticas de los conocimientos aprendidos en la teoría

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues

This work was supported by the National Institutes of Health (NIH) grant AI112521 and the John and Virginia Kaneb Fellowship

Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease

Introduction Chronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects. Methods We performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006–2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment. Results cGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients. Conclusion cGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT

Population-based real-world registry study to evaluate clinical outcomes of chronic graft-versus-host disease.

IntroductionChronic graft-versus-host disease (cGVHD) is a serious immune-mediated complication after allogeneic haematopoietic stem cell transplantation (HSCT), but in patients with malignancy, cGVHD development is associated with superior survival. Lack of reliable biomarkers and clinical underreporting means there is insufficient understanding of cGVHD clinical outcomes and balance between cGVHD treatment and maintaining beneficial graft-versus-tumour effects.MethodsWe performed a Swedish population-wide registry study following patients who underwent allogeneic HSCT 2006-2015. cGVHD status was retrospectively classified using a real-world method based on the timing and extent of systemic immunosuppressive treatment.ResultscGVHD incidence among patients surviving ≥6 months post-HSCT (n = 1246) was 71.9%, significantly higher than previously reported. 5-year overall survival in patients surviving ≥6 months post-HSCT was 67.7%, 63.3%, and 65.3%, in non-, mild, and moderate-severe cGVHD, respectively. Non-cGVHD patients had a mortality risk almost five-fold higher compared to moderate-severe cGVHD patients 12-months post-HSCT. Moderate-severe cGVHD patients had greater healthcare utilization compared with mild and non cGVHD patients.ConclusioncGVHD incidence was high among HSCT survivors. Non-cGVHD patients had higher mortality during the first 6 months of follow-up; however, moderate-severe cGVHD patients had more comorbidities and healthcare utilization. This study highlights the urgent need for new treatments and real-time methods to monitor effective immunosuppression after HSCT

Anti‐thymocyte globulin and post‐transplant cyclophosphamide predisposes to inferior outcome when using cryopreserved stem cell grafts

During 2020, the concurrent novel COVID-19 pandemic lead to widespread cryopreservation of allogeneic hematopoietic cell transplant grafts based on National Marrow Donor Program and European Society of Blood and Marrow Transplantation recommendations, in order to secure grafts before the start of conditioning chemotherapy. We sought to examine the impact of this change in practice on patient outcomes. We analyzed the outcomes of 483 patients who received hematopoietic stem cell transplantation (HSCT) between August 2017 and August 2020, at Princess Margaret Cancer Centre, Canada, in the retrospective study, comparing the outcomes between those who received cryopreserved or fresh peripheral blood stem cell grafts. Overall compared with those who received fresh grafts (n = 348), patients who received cryopreserved grafts (n = 135) had reduced survival and GRFS, reduced incidence of chronic graft-versus-host disease (GvHD), delay in neutrophil engraftment, and higher graft failure (GF), with no significant difference in relapse incidence or acute GvHD. However, recipients of cryopreserved matched-related donor HSCT showed significantly worse OS, NRM, GRFS compared with fresh grafts. Multivariable analysis of the entire cohort showed significant impact of cryopreservation on OS, relapse, cGvHD, GF, and GRFS. We conclude that cryopreservation was associated with inferior outcomes post-HSCT, possibly due to the combination of ATG and post-transplant cyclophosphamide impacting differential tolerance to cryopreservation on components of the stem cell graft; further studies are warranted to elucidate mechanisms for this observation

Cell Therapy Transplant Canada (CTTC) Consensus-Based Guideline 2024 for Management and Treatment of Chronic Graft-Versus-Host Disease and Future Directions for Development

This is a consensus-based Canadian guideline whose primary purpose is to standardize and facilitate the management of chronic graft-versus-host disease (cGvHD) across the country. Creating uniform healthcare guidance in Canada is a challenge for a number of reasons including the differences in healthcare authority structure, funding and access to healthcare resources between provinces and territories, as well as the geographic size. These differences can lead to variable and unequal access to effective therapies for GvHD. This document will provide comprehensive and practical guidance that can be applied across Canada by healthcare professionals caring for patients with cGvHD. Hopefully, this guideline, based on input from GvHD treaters across the country, will aid in standardizing cGvHD care and facilitate access to much-needed novel therapies. This consensus paper aims to discuss the optimal approach to the initial assessment of cGvHD, review the severity scoring and global grading system, discuss systemic and topical treatments, as well as supportive therapies, and propose a therapeutic algorithm for frontline and subsequent lines of cGvHD treatment in adults and pediatric patients. Finally, we will make suggestions about the future direction of cGvHD treatment development such as (1) a mode-of-action-based cGvHD drug selection, according to the pathogenesis of cGvHD, (2) a combination strategy with the introduction of newer targeted drugs, (3) a steroid-free regimen, particularly for front line therapy for cGvHD treatment, and (4) a pre-emptive approach which can prevent the progression of cGvHD in high-risk patients destined to develop severe and highly morbid forms of cGvHD.Other UBCNon UBCReviewedFacultyResearche