Among literary scholars, several analytical approaches have dominated this critical field: the careful mapping of the social and cultural significance of individual foodstuffs or ingredients; the ...unpacking of recipes and cooking as forms of intellectual labor and creativity, particularly as engaged in by women; and the reading of banquets as spectacles, both on- and offstage. In the process, increased production of beer contributed to social and economic shifts, driving urban growth, capital investment, and the professionalization and masculinization of brewing. ...Hal's predilection for small beer-the drink of the poorest Londoners-not only links him with lowness in ways that he cannot completely control, but also marks the networks of relationship in which he is implicated, and to which he is subject, as essentially English. Julia Reinhard Lupton's "Room for Dessert: Sugared Shakespeare and the Dramaturgy of Dwelling," by contrast, examines the dramatic resonances of the "banquet" of sweets that often ended lavish meals, which was marked as a forum for reflection and renewal by its spatial and temporal separation from the main meal.
The Maryland Primary Care Program is a statewide advanced primary care program that works directly with practices to transform healthcare delivery by managing chronic disease, preventing unnecessary ...hospital utilization, and integrating with the public health system. The Maryland Primary Care Program has demonstrated how linking the public health system to primary care practices, paired with strategic financial and resource investments in primary care, can enable the delivery of high-value care and reduce acute hospital utilization. Such a system is especially prudent when responding to crises. Throughout the COVID-19 pandemic, the Maryland Primary Care Program was able to capitalize on existing infrastructure to quickly engage primary care in a robust pandemic response. Successes of this relationship included early and consistent communication channels, as well as coordinated resource distribution. In particular, this partnership allowed primary care providers, the most trusted source of healthcare in patients' lives, to directly provide patients with health information and vaccines. Now comprising more than 500 practices, this vaccine program uses data-driven reports to facilitate intentional vaccine outreach. The program has enabled a more equitable vaccine distribution system, resulting in over 400,000 vaccines administered in Maryland counties. The effectiveness of Maryland's integrated response indicates that partnerships between public health and primary care will result in an effective response in future times of crisis.
Chimeric antigen receptor (CAR) T cell therapy has been highly successful in hematological malignancies leading to their US Food and Drug Administration (FDA) approval. However, the efficacy of CAR ...T cells in solid tumors is limited by tumor-induced immunosuppression, leading to the development of combination approaches, such as adjuvant programmed cell death 1 (PD-1) blockade. Current FDA-approved methods for generating CAR T cells utilize either anti-CD3 and interleukin (IL)-2 or anti-CD3/CD28 beads, which can generate a T cell product with an effector/exhausted phenotype. Whereas different cytokine preconditioning milieu, such as IL-7/IL-15, have been shown to promote T cell engraftment, the impact of this approach on CAR T cell responses to adjuvant immune-checkpoint blockade has not been assessed. In the current study, we reveal that the preconditioning of CAR T cells with IL-7/IL-15 increased CAR T cell responses to anti-PD-1 adjuvant therapy. This was associated with the emergence of an intratumoral CD8+CD62L+TCF7+IRF4– population that was highly responsive to anti-PD-1 therapy and mediated the vast majority of transcriptional and epigenetic changes in vivo following PD-1 blockade. Our data indicate that preservation of CAR T cells in a TCF7+ phenotype is crucial for their responsiveness to adjuvant immunotherapy approaches and should be a key consideration when designing clinical protocols.
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Internal tandem duplication of the FMS-like tyrosine kinase 3 gene (
) occurs in 30% of all acute myeloid leukemias (AML). Limited clinical efficacy of FLT3 inhibitors highlights the need for ...alternative therapeutic modalities in this subset of disease. Using human and murine models of FLT3-ITD-driven AML, we demonstrate that FLT3-ITD promotes serine synthesis and uptake via ATF4-dependent transcriptional regulation of genes in the
serine biosynthesis pathway and neutral amino acid transport. Genetic or pharmacologic inhibition of PHGDH, the rate-limiting enzyme of
serine biosynthesis, selectively inhibited proliferation of FLT3-ITD AMLs
and
. Moreover, pharmacologic inhibition of PHGDH sensitized FLT3-ITD AMLs to the standard-of-care chemotherapeutic cytarabine. Collectively, these data reveal novel insights into FLT3-ITD-induced metabolic reprogramming and reveal a targetable vulnerability in FLT3-ITD AML. SIGNIFICANCE: FLT3-ITD mutations are common in AML and are associated with poor prognosis. We show that FLT3-ITD stimulates serine biosynthesis, thereby rendering FLT3-ITD-driven leukemias dependent upon serine for proliferation and survival. This metabolic dependency can be exploited pharmacologically to sensitize FLT3-ITD-driven AMLs to chemotherapy.
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Approximately 20% of acute myeloid leukaemia (AML) patients carry mutations in genes that encode the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and -2. Mutant IDH proteins possess a ...neomorphic enzymatic activity and produce the oncometabolite D-2-hydroxyglutarate (2-HG) that modulates numerous pathways implicated in cell fate decisions and cancer. We and others have shown that IDH mutations can contribute to leukaemia initiation and maintenance both in vitro and in vivo. Small molecule inhibitors that block production of 2-HG are starting to enter the clinic, however, the biomarkers of response and mechanisms of de novo and acquired resistance to mutant IDH inhibition remain poorly understood. We have engineered a series of murine AML models driven by inducible expression of mutant IDH proteins. To uncover the molecular mechanisms that underpin response and adaptation to mutant IDH inhibition we integrated bulk and single-cell RNA sequencing with chromatin immuno-precipitation sequencing. We demonstrate that genetic depletion and pharmacological inhibition of mutant IDH has striking effects, altering self-renewal and differentiation programs of leukaemic cells. Importantly, we identify a population of cells that persist during treatment and characterise genetic programs that circumvent effective IDH inhibition, ultimately leading to therapy resistance and disease relapse. Our studies provide detailed mechanistic insight into the oncogenic properties of mutant IDH proteins in maintaining the transformed state of AML cells.
Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with ...myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1-5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOA
mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.
Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signaling demonstrate potent but self-limited antilymphoma activity as single agents ...in the context of cellular Myelocytomatosis (
) oncogene-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anticancer activity with the potential for more sustained disease responses due to the mutual antagonism of compensatory epigenetic and signaling networks. Here, we describe the mechanistic and therapeutic validation of rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores. The lead candidate demonstrates high selectivity, nanomolar range cellular potency, and compelling in vivo efficacy, including curative responses in the aggressive Eµ-
lymphoma model. These studies further support the therapeutic strategy of combined PI3K and BET inhibition and provide a potential step-change in approach to orthogonal MYC antagonism using optimized chimeric small-molecule technology.
Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene occur in approximately 30% of all acute myeloid leukaemias (AMLs) and are associated with poor prognosis. The clinical utility of FLT3 ...inhibitor monotherapy has been limited by the rapid development of resistance, highlighting the need for identification of alternative therapeutic targets for the treatment of FLT3-mutant AML. Using a syngeneic murine model of AML harbouring FLT3 internal tandem duplication (FLT3-ITD), we demonstrate that FLT3-ITD promotes serine uptake and serine synthesis via transcriptional regulation of neutral amino acid transporters (SLC1A4 and SLC1A5) and genes in the de novo serine synthesis pathway (PHGDH and PSAT1). Mechanistically, dysregulation of serine metabolism was dependent on the mTORC1-ATF4 axis, which promoted RNA-Pol II occupancy at PHGDH, PSAT1, SLC1A4 and SLC1A5 in AML cells harbouring FLT3-ITD mutations. Genetic or pharmacological inhibition of the de novo serine synthesis pathway selectively inhibited the proliferation and viability of FLT3-ITD AML cells, and purine supplementation effectively rescued the apoptotic effects of inhibiting FLT3-ITD, consistent with the hypothesis that serine fuels purine nucleotide synthesis in FLT3-ITD AML cells. To exploit these findings in the context of standard-of-care therapy in AML, we show that pharmacological inhibition of the de novo serine synthesis pathway, using the PHGDH inhibitor WQ-2101, sensitises FLT3-ITD AML cells to the chemotherapy agent cytarabine by greatly exacerbating the DNA damage response in AML cell lines harbouring FLT3-ITD mutations, primary AML patient samples, and an aggressive PDX mouse model of FLT3-ITD-driven AML. Collectively, these data reveal new insights into FLT3-ITD-induced metabolic reprogramming in AML, and suggest a novel combinatorial therapeutic strategy for the treatment of FLT3-mutant AML.
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