Priming Leukemia with 5-Azacytidine Enhances CAR T Cell Therapy

Purpose: Despite the success of chimeric antigen receptor (CAR) T cells in clinical studies, a significant proportion of responding patients eventually relapsed, with the latter correlating with low CAR T cell expansion and persistence. Methods and Results: Using patient-derived xenograft (PDX) mouse models of CD19+ B cell acute lymphoblastic leukemia (B-ALL), we show that priming leukemia-bearing mice with 5-azacytidine (AZA) enhances CAR T cell therapy. AZA given 1 day prior to CAR T cell infusion delayed leukemia growth and promoted CAR T cell expansion and effector function. Priming leukemia cells with AZA increased CAR T cell/target cell conjugation and target cell killing, promoted CAR T cell divisions and expanded IFNγ+ effector T cells in co-cultures with CD19+ leukemia Nalm-6 and Raji cells. Transcriptome analysis revealed activation of diverse immune pathways in leukemia cells isolated from mice treated with AZA. We propose that epigenetic priming with AZA induces transcriptional changes that sensitize tumor cells to subsequent CAR T cell treatment. Among the candidate genes up-regulated by AZA is TNFSF4 which encodes OX40L, one of the strongest T cell co-stimulatory ligands. OX40L binds OX40, the TNF receptor superfamily member highly specific for activated T cells. TNFSF4 is heterogeneously expressed in a panel of pediatric PDXs, and high TNFSF4 expression correlated with increased CAR T cell numbers identified in co-cultures with individual PDXs. High OX40L expression in Nalm-6 cells increased their susceptibility to CAR T cell killing while OX40L blockade reduced leukemia cell killing. Conclusion: We propose that treatment with AZA activates OX40L/OX40 co-stimulatory signaling in CAR T cells. Our data suggest that the clinical use of AZA before CAR T cells could be considered

An ambipolar BODIPY derivative for a white exciplex OLED and cholesteric liquid crystal laser toward multifunctional devices

A new interface engineering method is demonstrated for the preparation of an efficient white organic light-emitting diode (WOLED) by embedding an ultrathin layer of the novel ambipolar red emissive compound 4,4-difluoro-2,6-di(4-hexylthiopen-2-yl)-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (bThBODIPY) in the exciplex formation region. The compound shows a hole and electron mobility of 3.3 × 10–4 and 2 × 10–4 cm2 V–1 s–1, respectively, at electric fields higher than 5.3 × 105 V cm–1. The resulting WOLED exhibited a maximum luminance of 6579 cd m–2 with CIE 1931 color coordinates (0.39; 0.35). The bThBODIPY dye is also demonstrated to be an effective laser dye for a cholesteric liquid crystal (ChLC) laser. New construction of the ChLC laser, by which a flat capillary with an optically isotropic dye solution is sandwiched between two dye-free ChLC cells, provides photonic lasing at a wavelength well matched with that of a dye-doped planar ChLC cell

Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer

The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of MPC1 in around 78% of cases and reduced MPC1 mRNA expression. To explore the metabolic effect of reduced expression, we demonstrate that depleting MPC1 in HGSOC cell lines drives expression of key proline biosynthetic genes; PYCR1, PYCR2 and PYCR3, and biosynthesis of proline. We show that altered proline metabolism underpins cancer cell proliferation, reactive oxygen species (ROS) production, and type I and type VI collagen formation in ovarian cancer cells. Furthermore, exploring The Cancer Genome Atlas, we discovered the PYCR3 isozyme to be highly expressed in a third of HGSOC patients, which was associated with more aggressive disease and diagnosis at a younger age. Taken together, our study highlights that targeting proline metabolism is a potential therapeutic avenue for the treatment of HGSOC

Current challenges and proposed solutions to the effective implementation of the RTS, S/AS01 Malaria Vaccine Program in sub-Saharan Africa: A systematic review.

BACKGROUND: The Malaria Vaccine Implementation Program, coordinated by the World Health Organization, intended to initiate the roll-out of the RTS, S/AS01 malaria vaccine in 3 sub-Saharan African countries in 2018. With sub-optimal implementation, the effectiveness of this vaccine in routine clinical use could be significantly lower than its measured efficacy in randomized trials. This study had as objectives to systematically review and summarize published studies addressing the challenges faced during the implementation phase of malaria vaccination programs and randomized trials conducted in sub-Saharan Africa. The review also sought to report proposed solutions to the challenges identified. METHOD: This was a systematic review of studies published between 1947 and 2017. Medline, Embase and the Cochrane library databases were searched. Of the 365 studies retrieved, 8 eligible studies reported on challenges of implementing a malaria vaccine in sub-Saharan Africa and possible solutions to these challenges. Data were abstracted from the eligible studies and a qualitative synthesis was done. RESULTS: The 8 studies included in the review had a total of 6189 participants and used a variety of methodologies (3 qualitative, 1 quantitative, 3 mixed method studies and 1 clinical trial review). There was an overall positive acceptance towards the new malaria vaccine (n = 6/8 studies), with a mean acceptance rate of 86.1% (95% CI: 62.0-110.2, n = 2). The main challenges to vaccine receptivity were: inadequate community engagement due to lack of information about the vaccine (n = 6), fear of the vaccine's side effects (n = 5), inefficient delivery of vaccination services to children (n = 4), and sub-optimal quality of the health services (n = 3). Main themes identified from the proposed solutions consisted of the following: using dynamic communication models and trusted sources for delivering vaccine-related health information to the communities (n = 6), community engagement at both national and district level (n = 6), implementing the new vaccine services alongside the existing health services already delivered (n = 6). CONCLUSION/RECOMMENDATIONS: Effective implementation of the malaria vaccine program requires careful consideration of the socio-cultural context of each community. The RTS, S/AS01 malaria vaccine acceptance and uptake may be significantly enhanced if caregivers' perceptions about vaccines and their importance are adequately fine-tuned. In order to achieve these, community participation and the provision of adequate information in an acceptable form via reliable communication channels seem to be imperative

Self-controlled case series studies: just how rare does a rare non-recurrent outcome need to be?

The self-controlled case series method assumes that adverse outcomes arise according to a non-homogeneous Poisson process. This implies that it is applicable to independent recurrent outcomes. However, the self-controlled case series method may also be applied to unique, non-recurrent outcomes or first outcomes only, in the limit where these become rare. We investigate this rare outcome assumption when the self-controlled case series method is applied to non-recurrent outcomes. We study this requirement analytically and by simulation, and quantify what is meant by ‘rare’ in this context. In simulations we also apply the self-controlled risk interval design, a special case of the self-controlled case series design. To illustrate, we extract data on the incidence rate of some recurrent and non-recurrent outcomes within a defined study population to check whether outcomes are sufficiently rare for the rare outcome assumption to hold when applying the self-controlled case series method to first or unique outcomes. The main findings are that the relative bias should be no more than 5% when the cumulative incidence over total time observed is less than 0.1 per individual. Inclusion of age (or calendar time) effects will further reduce bias. Designs that begin observation with exposure maximise bias, whereas little or no bias will be apparent when there is no time trend in the distribution of exposures, or when exposure is central within time observed

Backbone and side-chain 1H, 13C and 15N assignments of the ubiquitin-associated domain of human X-linked inhibitor of apoptosis protein

X-linked inhibitor of apoptosis protein (XIAP), a leading member of the family of inhibitor of apoptosis (IAP) proteins, is considered as the most potent and versatile inhibitor of caspases and apoptosis. It has been reported that XIAP is frequently overexpressed in cancer and its expression level is implicated in contributing to tumorigenesis, disease progression, chemoresistance and poor patient-survival. Therefore, XIAP is one of the leading targets in drug development for cancer therapy. Recently, based on bioinformatics study, a previously unrecognized but evolutionarily conserved ubiquitin-associated (UBA) domain in IAPs was identified. The UBA domain is found to be essential for the oncogenic potential of IAP, to maintain endothelial cell survival and to protect cells from TNF-α-induced apoptosis. Moreover, the UBA domain is required for XIAP to activate NF-κB. In the present study, we report the near complete resonance assignments of the UBA domain-containing region of human XIAP protein. Secondary structure prediction based on chemical shift index (CSI) analysis reveals that the protein is predominately α-helical, which is consistent with the structures of known UBA proteins

Ultrafiltration versus diuretics on prognostic cardiac and renal biomarkers in acute decompensated heart failure : a systematic review and meta-analysis

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