Defining the mechanisms by which lenalidomide can modulate the human T cell alloresponse to improve the outcome of allogeneic haematopoietic stem cell transplantation

PhDImmunomodulatory drugs (IMiDs) could enhance both direct anti-tumour and graft-versus-tumour effects after allogeneic haematopoietic stem cell transplantation (AHSCT). However, clinical experience with IMiDs after AHSCT using adult peripheral blood (APB) as a stem-cell source has been limited by graft-versus-host disease. Characterization of the mechanisms by which IMIDs modulate alloresponses of T cells and identification of differential effects on T cells from different cell sources could facilitate more effective use of these drugs in the setting of AHSCT. Using in vitro modelling, multi-parameter flow cytometry and gene expression analysis, I have determined the impact of the widely used IMiD lenalidomide on alloresponses of APB and umbilical cord blood (UCB)-derived T cells. Lenalidomide-treatment potentiates net alloproliferation of APB-derived T cells by selectively enhancing proliferation of CD8+ T cells. These CD8+ T cells have enhanced effector memory differentiation, are enriched for polyfunctional effectors, have enhanced direct-cytotoxicity against heamatopoietic target-cells and have a distinct gene expression profile with altered expression of key immunoregulatory-genes and depletion of cellular ikaros. Importantly, while effects on CD8+ T cells derived from UCB are similar, lenalidomide has contrasting effects on allospecific proliferation of APB and UCB-derived CD4+ T cells. While lenalidomide-treatment has no effect on alloproliferation of APB-derived CD4+ T cells, it reduces alloproliferation of UCB-derived CD4+ T cells. The reduction in UCB-derived CD4+ T cell alloproliferation is accompanied by selective expansion of CD4+CD25+FOXP3+ regulatory T cells (Treg), resulting in an overall reduction in UCB-derived T cell alloproliferation. These findings demonstrate that lenalidomide has a differential impact on alloresponses of T cells from different cell sources; alloresponses of APB-derived T cells are increased via selective expansion of polyfunctional CD8+ effectors, while alloresponses of UCB-derived T cells are limited by expansion of tolerogenic Treg. These findings have important implications for the future use of IMiDs in the setting of AHSCT.MRC (Clinical Research Fellowship MR/M001733/1) and Barts and The London Charity (Clinical Research Fellowship 512/1737)

Does continuity of care impact decision making in the next birth after a caesarean section (VBAC)? A randomised controlled trial

BACKGROUND: Caesarean section (CS) has short and long-term health effects for both the woman and her baby. One of the greatest contributors to the CS rate is elective repeat CS. Vaginal birth after caesarean (VBAC) is an option for many women; despite this the proportion of women attempting VBAC remains low. Potentially the relationship that women have with their healthcare professional may have a major influence on the uptake of VBAC. Models of service delivery, which enable an individual approach to care, may make a difference to the uptake of VBAC. Midwifery continuity of care could be an effective model to encourage and support women to choose VBAC. METHODS/DESIGN: A randomised, controlled trial will be undertaken. Eligible pregnant women, whose most recent previous birth was by lower-segment CS, will be randomly allocated 1:1 to an intervention group or control group. The intervention provides midwifery continuity of care to women through pregnancy, labour, birth and early postnatal care. The control group will receive standard hospital care from different midwives through pregnancy, labour, birth and early postnatal care. Both groups will receive an obstetric consultation during pregnancy and at any other time if required. Clinical care will follow the same guidelines in both groups. DISCUSSION: This study will determine whether midwifery continuity of care influences the decision to attempt a VBAC and impacts on mode of birth, maternal experiences with care and the health of the neonate. Outcomes from this study might influence the way maternity care is provided to this group of women and thus impact on the CS rate. This information will provide high level evidence to policy makers, health service managers and practitioners who are working towards addressing the increased rate of CS. TRIAL REGISTRATION: This trial is registered with the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN1261100121492

Agenda-Building Influences on the News Media\u27s Coverage of the U.S. Food and Drug Administration\u27s Push to Regulate Tobacco, 1993-2009

Citing agenda-building theory, this article examines the influence of three key factors on the news media\u27s coverage of the process of placing tobacco and tobacco products under regulation of the U.S. Food and Drug Administration between 1993 and 2009. We analyzed data from a content analysis of 570 news articles from The New York Times and Washington Post and found that the media published significantly more FDA regulation articles during the Clinton administration than during the Bush administration. Our analysis links that imbalance of media coverage to the influence of the president of the United States (Clinton and Bush, during the duration of this study), journalistic routines and real world events. We compared the Clinton and Bush era news coverage on article prominence, article topics, and reasons to support/oppose FDA regulation and found significant differences, which we suggest led to the imbalance of news articles in the two administrations

Effective bridging therapy can improve CD19 CAR-T outcomes while maintaining safety in patients with large B-cell lymphoma

The impact of bridging therapy (BT) on CD19-directed chimeric antigen receptor T-cell (CD19CAR-T) outcomes in large B-cell lymphoma (LBCL) is poorly characterised. Current practice is guided by physician preference rather than established evidence. Identification of effective BT modalities and factors predictive of response could improve CAR-T intention to treat and clinical outcomes. We assessed BT modality and response in 375 adult LBCL patients in relation to outcomes following axicabtagene ciloleucel (Axi-cel) or tisagenlecleucel (Tisa-cel). The majority of patients received BT with chemotherapy (57%) or radiotherapy (17%). We observed that BT was safe for patients, with minimal morbidity/mortality. We showed that complete or partial response to BT conferred a 42% reduction in disease progression and death following CD19CAR-T therapy. Multivariate analysis identified several factors associated with likelihood of response to BT, including response to last line therapy, the absence of bulky disease, and the use of Polatuzumab-containing chemotherapy regimens. Our data suggested that complete/partial response to BT may be more important for Tisa-cel than Axi-cel, as all Tisa-cel patients with less than partial response to BT experienced frank relapse within 12 months of CD19CAR-T infusion. In summary, BT in LBCL should be carefully planned towards optimal response and disease debulking, to improve CD19CAR-T patient outcomes. Polatuzumab-containing regimens should be strongly considered for all suitable patients, and failure to achieve complete/partial response to BT pre-Tisa-cel may prompt consideration of further lines of BT where possible

Organ complications after CD19 CAR T-cell therapy for large B cell lymphoma: a retrospective study from the EBMT transplant complications and lymphoma working party.

We investigated ≥ grade 3 (CTC-AE) organ toxicities for commercial CD19 chimeric antigen receptor T cell (CAR-T cell) products in 492 patients (Axi-Cel; n = 315; Tisa-Cel; n = 177) with Large B-cell Lymphoma in the European Society for Blood and Marrow Transplantation (EBMT) CAR-T registry. The incidence of ≥ grade 3 organ toxicities during the first 100 days after CAR-T was low and the most frequent were: renal (3.0%), cardiac (2.3%), gastro-intestinal (2.3%) and hepatic (1.8%). The majority occurred within three weeks after CAR-T cell therapy. Overall survival was 83.1% [79.8-86.5; 95% CI] at 3 months and 53.5% [49-58.4; 95% CI] at one year after CAR-T. The most frequent cause of death was tumour progression (85.1%). Non-relapse mortality was 3.1% [2.3-4.1; 95% CI] at 3 months and 5.2% [4.1-6.5; 95% CI] at one year after CAR-T. The most frequent causes of non-relapse mortality were cell-therapy-related toxicities including organ toxicities (6.4% of total deaths) and infections (4.4% of total deaths). Our data demonstrates good safety in the European real-world setting

Advances in Molecular Quantum Chemistry Contained in the Q-Chem 4 Program Package

A summary of the technical advances that are incorporated in the fourth major release of the Q-Chem quantum chemistry program is provided, covering approximately the last seven years. These include developments in density functional theory methods and algorithms, nuclear magnetic resonance (NMR) property evaluation, coupled cluster and perturbation theories, methods for electronically excited and open-shell species, tools for treating extended environments, algorithms for walking on potential surfaces, analysis tools, energy and electron transfer modelling, parallel computing capabilities, and graphical user interfaces. In addition, a selection of example case studies that illustrate these capabilities is given. These include extensive benchmarks of the comparative accuracy of modern density functionals for bonded and non-bonded interactions, tests of attenuated second order Møller–Plesset (MP2) methods for intermolecular interactions, a variety of parallel performance benchmarks, and tests of the accuracy of implicit solvation models. Some specific chemical examples include calculations on the strongly correlated Cr2 dimer, exploring zeolite-catalysed ethane dehydrogenation, energy decomposition analysis of a charged ter-molecular complex arising from glycerol photoionisation, and natural transition orbitals for a Frenkel exciton state in a nine-unit model of a self-assembling nanotube