Publications by authors named "David M Foureau"

Phosphosidesterases (PDEs) are key regulators of cyclic nucleotide signaling, controlling many hallmarks of cancer and playing a role in resistance to chemotherapy in non-small-cell lung cancer (NSCLC). We evaluated the anti-tumor activity of the anti-folate agent pemetrexed (PMX), alone or combined with biochemical inhibitors of PDE5, 8, 9, or 10, against squamous and non-squamous NCSLC cells. Genomic alterations to PDE genes (PDE) or PDE biochemical inhibition (PDEi) can sensitize NSCLC to PMX in vitro (observed in 50% NSCLC evaluated).

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High-dose (HD) IL-2 was the first immuno-oncology agent approved for treating advanced renal cell carcinoma and metastatic melanoma, but its use was limited because of substantial toxicities. Multiple next-generation IL-2 agents are being developed to improve tolerability. However, a knowledge gap still exists for the genomic markers that define the target pharmacology for HD IL-2 itself.

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The revised International Prognostic Index (R-IPI) is an important prognostic tool in diffuse large B cell lymphoma (DLBCL); however, outcomes can vary markedly within R-IPI groups, and additional prognostic markers are needed. We conducted a prospective observational study to evaluate the circulating immature myeloid (IM) cell subsets and cytokine profiles of 31 patients with newly diagnosed DLBCL before and after chemoimmunotherapy. Among circulating IM cells, myeloid-derived suppressor cells (MDSCs) were the predominant cell type (73.

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Background: Most high-risk neuroblastoma patients who relapse succumb to disease despite the existing therapy. We recently reported increased event-free and overall survival in neuroblastoma patients receiving difluoromethylornithine (DFMO) during maintenance therapy. The effect of DFMO on cellular processes associated with neuroblastoma tumorigenesis needs further elucidation.

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Introduction: Treatment of patients with multiple myeloma (MM) in first relapse remains a challenge. This phase II study combined elotuzumab (Elo) with carfilzomib, lenalidomide, and dexamethasone (KRd) for treatment of MM in first relapse with the aim of improving efficacy.

Methods: Enrolled patients received Elo-KRd induction for 4 cycles, and Elo-lenalidomide maintenance until progression.

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Background: Metabolomics studies to date have described widespread metabolic reprogramming events during the development of non-squamous non-small cell lung cancer (NSCLC). Extending far beyond the Warburg effect, not only is carbohydrate metabolism affected, but also metabolism of amino acids, cofactors, lipids, and nucleotides.

Methods: We evaluated the clinical impact of metabolic reprogramming.

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Introduction: Minimal residual disease (MRD) status is an established prognostic biomarker for patients with multiple myeloma. Commonly used MRD testing techniques such as next generation sequencing or next generation flow cytometry can detect as little as one or two multiple myeloma plasma cells in 10 normal bone marrow cells. Early pull of bone marrow aspirates (BMA), necessary to achieve such level of sensitivity, can be difficult to secure in routine clinical practice due to the competing need for early pull samples for clinical response assessment, therefore introducing the risk of analytical interference during MRD testing.

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Purpose: Doxorubicin is standard therapy for advanced soft-tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings of advanced STS.

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Background: Intravesical bacillus Calmette-Guérin (BCG) therapy is standard treatment for high-risk non-muscle invasive bladder cancer (NMIBC) but overall efficacy is low, and no reliable predictive biomarkers currently exist to refine patient selection. We performed genomic analysis on high-grade (HG) T1 NMIBCs to determine if response to therapy is predicted by certain mutational and/or expressional changes.

Methods: Patients with HG T1 NMIBC treated with induction BCG were stratified by response into durable and non-durable responders.

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TNB-383B is a fully human BCMA-targeting T-cell engaging bispecific monoclonal antibody (T-BsAb). We assessed ex vivo efficacy of this drug to mediate killing of bone marrow mononuclear cells (BMMCs) freshly isolated from 10 patients with relapsed multiple myeloma (MM). BMMC were treated ex vivo with TNB-383B at doses ranging from 0.

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Extramedullary multiple myeloma (EMM) is an aggressive subentity of multiple myeloma, characterized by the ability of a subclone to thrive and grow independent of the bone marrow microenvironment, resulting in a high-risk state associated with increased proliferation, evasion of apoptosis and treatment resistance. Despite improvement in survival for most patients with multiple myeloma over recent decades, outcomes are generally poor when EMM develops. Understanding the molecular underpinnings leading to homing of plasma cells in ecosystems outside the bone marrow will be crucial for therapeutically manipulating the microenvironment and targeting key signaling pathways.

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Objective: To compare baseline and 72-hour hormone levels in women with traumatic brain injury (TBI) and controls.

Setting: Hospital emergency department.

Participants: 21 women ages 18-35 with TBI and 21 controls.

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Changes in levels of cytokines and chemokines have been proposed as possible biomarkers of tissue injury, including liver injury due to drugs. Recently, in acute drug-induced liver injury (DILI), we showed that 19 of 27 immune analytes were differentially expressed and that disparate patterns of immune responses were evident. Lower values of serum albumin (< 2.

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Background & Aims: Analysis in silico suggests that occludin (OCLN), a key receptor for HCV, is a candidate target of miR-122; the most abundant hepatic micro RNA. We aimed to determine if miR-122 can decrease HCV entry through binding to the 3' UTR of OCLN mRNA.

Design: Huh7.

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Interleukin-2 (IL-2) therapy leads to clinically relevant responses in 10-16 % of patients with metastatic melanoma (MMEL) or 10-30 % of patients with metastatic renal cell carcinoma (MRCC). To date, no biomarkers have been validated to identify patients who are likely to respond. We hypothesized that changes in T cell subset distribution in patients undergoing IL-2 therapy may correlate with treatment outcomes.

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Drug-induced liver injury (DILI) with features of autoimmunity (AI) represents an important category of hepatotoxicity due to medication exposure. Drugs repeatedly associated with AI-DILI include diclofenac, α-methyl DOPA, hydralazine, nitrofurantoin, minocycline, and more recently statins and anti-TNF-α agents. Usually, symptoms of acute liver injury occur within a few months after initiation of a culprit medication, but a longer latency period is possible.

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Unlabelled: Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls.

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Choline dihydrogen phosphate (CDHP) is an ionic liquid reported to increase thermal stability of model proteins. The current work investigated CDHP effect on structural integrity and biological activity of recombinant human interleukin-2 (rhIL-2), a therapeutic protein used for treating advanced melanoma. CDHP biocompatibility was also evaluated using primary cell cultures, or B16-F10 cell line, chronically exposed to the ionic liquid.

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Hepatocellular carcinoma (HCC) is a global health burden with limited treatment options and poor prognosis. Silibinin, an antioxidant derived from the Milk Thistle plant (Silybum marianum), is reported to exert hepatoprotective and antitumorigenic effects in vitro and in vivo by suppressing oxidative stress and proliferation. Using a DEN-initiated mouse model of HCC, this study examined the effects of dietary silibinin supplementation alone, or in combination with chronic ethanol consumption on HCC progression.

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Ionic liquids are being intensely studied as promising media for the stabilization of proteins and other biomolecules. Choline dihydrogen phosphate (CDHP) has been identified as one of the most promising candidates for this application. In this work we have probed in more detail the effects that CDHP may have on the thermodynamics, structure, and stability of proteins, including one of therapeutic interest.

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Recombinant human interleukin-2 (rhIL-2) therapy is approved for treating patients with advanced melanoma yet significant responses are observed in only 10-15% of patients. Interleukin-2 induces Foxp3 expression in activated human CD8 T cells in vitro and expands circulating CD8 Foxp3+ T cells in melanoma patients. Employing IL-2 responsive (B16-F1, B16-BL6, JB/MS, MCA-205) and nonresponsive (JB/RH, B16-F10) subcutaneous tumor mouse models, we evaluated CD8 Foxp3+ T cell distribution and changes in response to rhIL-2 (50,000 U, i.

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Alpha-defensins (or Cryptdins [Crps]) are a group of antimicrobial peptides produced as a component of Paneth cell (PC) secretory granules in the small intestine. In vivo ligation of TLR9 by synthetic agonists leads to PC degranulation, although the mechanism by which this occurs remains uncertain. In this report, we investigated TLR9-dependent mechanisms, triggered by the parasite Toxoplasma gondii, inducing Crp release in the lumen.

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Mucosal tolerance has been considered a potentially important pathway for the treatment of autoimmune disease, including human multiple sclerosis and experimental conditions such as experimental autoimmune encephalomyelitis (EAE). There is limited information on the capacity of commensal gut bacteria to induce and maintain peripheral immune tolerance. Inbred SJL and C57BL/6 mice were treated orally with a broad spectrum of antibiotics to reduce gut microflora.

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T helper 17 (Th17) cells are pivotal in the immune pathogenesis of EAE. Glatiramer acetate (GA) can enhance Treg FOXp3 expression. We demonstrate that GA downregulates the expression of both IL-17 and IL-6 in two different EAE models.

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