Efficient human cytomegalovirus reactivation is maturation dependent in the Langerhans dendritic cell lineage and can be studied using a CD14+ experimental latency model

Studies from a number of laboratories have shown that the myeloid lineage is prominent in human cytomegalovirus (HCMV) latency, reactivation, dissemination, and pathogenesis. Existing as a latent infection in CD34(+) progenitors and circulating CD14(+) monocytes, reactivation is observed upon differentiation to mature macrophage or dendritic cell (DC) phenotypes. Langerhans' cells (LCs) are a subset of periphery resident DCs that represent a DC population likely to encounter HCMV early during primary infection. Furthermore, we have previously shown that CD34(+) derived LCs are a site of HCMV reactivation ex vivo. Accordingly, we have utilized healthy-donor CD34(+) cells to study latency and reactivation of HCMV in LCs. However, the increasing difficulty acquiring healthy-donor CD34(+) cells--particularly from seropositive donors due to the screening regimens used--led us to investigate the use of CD14(+) monocytes to generate LCs. We show here that CD14(+) monocytes cultured with transforming growth factor β generate Langerin-positive DCs (MoLCs). Consistent with observations using CD34(+) derived LCs, only mature MoLCs were permissive for HCMV infection. The lytic infection of mature MoLCs is productive and results in a marked inhibition in the capacity of these cells to promote T cell proliferation. Pertinently, differentiation of experimentally latent monocytes to the MoLC phenotype promotes reactivation in a maturation and interleukin-6 (IL-6)-dependent manner. Intriguingly, however, IL-6-mediated effects were restricted to mature LCs, in contrast to observations with classical CD14(+) derived DCs. Consequently, elucidation of the molecular basis behind the differential response of the two DC subsets should further our understanding of the fundamental mechanisms important for reactivation

The minimum CD34 threshold depends on prior chemotherapy in autologous peripheral blood stem cell recipients

We analysed 57 patients with non-myeloid malignancies who received a non-purged autologous PBSCT, All had similar mobilisation and conditioning regimens. A high prior chemotherapy score and the number of chemotherapy lines used (P = 0.015 and P = 0.01, respectively) were adverse predictors of CD34 cell yields. Lower CD34 values (P = 0.002) were seen in patients treated with potent stem cell toxins (BCNU, melphalan, CCNU and mustine), designated toxicity factor 4 agents (TF4), All patients infused with grafts containing CD34 cell doses between 1.0 and 2.0 x 10(6)/kg (range 1.25-1.90) engrafted by day 51. The only variable associated with slow platelet recovery was exposure to TF4 (P = 0.007), The majority of patients with CD34 >1.0 x 106/kg achieved rapid and sustained engraftment and the only predictive factor of delayed recovery is prior exposure to stem cell toxins, Potential PBSCT candidates should if possible avoid first line and salvage chemotherapy containing TF4 drugs. We therefore advocate a minimum CD34 threshold of >1.0 x 10(6)/kg in patients without extensive prior chemoradiotherapy, and greater than or equal to 2.0 x 10(6)/kg in all other patients

Forum: Pauline Stafford\u27s Queens, Concubines, and Dowagers Thirty-Five Years On

This forum grew from a realization that virtually all medievalists who work on medieval women, family, or gender, or on early medieval history, admire the scholarship of Pauline Stafford, particularly her seminal book Queens, Concubines, and Dowagers: The King’s Wife in the Early Middle Ages (QCD), published in 1983 by the University of Georgia Press and reprinted with a new preface in 1998 by Leicester University Press. Over the years, all three editors have talked excitedly with colleagues, sharing stories of how we first read the book or the influence it has had upon our own work. Pauline’s scholarship has spurred many to become medievalists, to study women, queens, and their families, and indeed to see women as a part of the fabric of the medieval world, not as a separate or lesser subject. To younger generations of medievalists, QCD was already a classic and often served as the benchmark against which to measure one’s own scholarly contributions. For these reasons, as the thirty-fifth anniversary of the publication of QCD approached, the editors of Medieval Prosopography uniformly agreed that the journal wished to commemorate the publication of such a distinctly prosopographical book and to honor its influential author. These remembrances of Pauline and her scholarship were first presented in 2018 at the Fifty-Third International Congress on Medieval Studies in Kalamazoo, Michigan and at the International Medieval Congress in Leeds, United Kingdom to large audiences. The excitement of those present, their accounts of their own memories of the book, and the questions that Pauline’s body of scholarship continues to raise further testified to the enduring legacy of QCD. The contributors below revised their presentations for this publication in honor of Pauline Stafford and her extraordinary contributions to medieval history. We dedicate this publication to her in gratitude. This forum includes the following contributions: Pauline Stafford—A Heroic Journey, by Janet L. Nelson, King\u27s College London The Influence and Importance of Pauline Stafford’s Queens, Concubines, and Dowagers, by Charlotte Cartwright, Christopher Newport University Reflections on Pauline Stafford’s Book, Queens, Concubines, and Dowagers, by Theresa Earenfight, Seattle University The Lessons of a Serious History, by Valerie L. Garver, Northern Illinois University Pauline Stafford and the (Other) Empresses: Inspirational Figures, Then and Now, by Phyllis G. Jestice, College of Charleston Pauline Stafford, Queens, Concubines, and Dowagers, by Simon MacLean, University of St. Andrews Here’s to the First Edition!, by Penelope Nash, University of Sydney Arguing With Pauline Stafford, by Lucy K. Pick, Independent Scholar An Expelled Princess, a Slandered Empress, and an Abandoned Wife, by Dana M. Polanichka, Wheaton College (MA) In Which a Research Student Meets One of her Heroes, by Katherine Weikert, University of Winchester Pauline Stafford’s Queens, Concubines, and Dowagers Thirty-five Years Later, by Megan Welton, University of Utrecht (Continuing) Inspiration from Stafford’s Innovative Approach to Queenship, by Elena Woodacre, University of Wincheste

Autologous infusion of expanded mobilized adult bone marrow-derived CD34+ cells into patients with alcoholic liver cirrhosis

OBJECTIVES: Recent advances in regenerative medicine, including hematopoietic stem cell (HSC) transplantation, have brought hope for patients with severe alcoholic liver cirrhosis (ALC). The aim of this study was to assess the safety and efficacy of administering autologous expanded mobilized adult progenitor CD34+ cells into the hepatic artery of ALC patients and the potential improvement in the liver function. METHODS: Nine patients with biopsy-proven ALC, who had abstained from alcohol for at least 6 months, were recruited into the study. Following granulocyte colony-stimulating factor (G-CSF) mobilization and leukapheresis, the autologous CD34+ cells were expanded in vitro and injected into the hepatic artery. All patients were monitored for side effects, toxicities, and changes in the clinical, hematological, and biochemical parameters. RESULTS: On average, a five-fold expansion in cell number was achieved in vitro, with a mean total nucleated cell count (TNCC) of 2.3 x 10(8) pre infusion. All patients tolerated the procedure well, and there were no treatment-related side effects or toxicities observed. There were significant decreases in serum bilirubin (P < 0.05) 4, 8, and 12 wk post infusion. The levels of alanine transaminase (ALT) and aspartate transaminase (AST) showed improvement through the study period and were significant (P < 0.05) 1 wk post infusion. The Child-Pugh score improved in 7 out of 9 patients, while 5 patients had improvement in ascites on imaging. CONCLUSION: It is safe to mobilize, expand, and reinfuse autologous CD34+ cells in patients with ALC. The clinical and biochemical improvement in the study group is encouraging and warrants further clinical trials