1. Malaria in pregnancy alters l-arginine bioavailability and placental vascular development.
Reducing adverse birth outcomes due to malaria in pregnancy (MIP) is a global health priority. However, there are few safe and effective interventions. L-Arginine is an essential amino acid in pregnancy and an immediate precursor in the biosynthesis of nitric oxide (NO), but there are limited data on the impact of MIP on NO biogenesis. Chloe R. McDonald at University of Toronto in Toronto, Canada and his colleagues hypothesized that hypoarginemia contributes to the pathophysiology of MIP and that L-arginine supplementation would improve birth outcomes. In a prospective study of pregnant Malawian women, they show that MIP was associated with lower concentrations of L-arginine and higher concentrations of endogenous inhibitors of NO biosynthesis, asymmetric and symmetric dimethylarginine, which were associated with adverse birth outcomes. In a model of experimental MIP, L-arginine supplementation in dams improved birth outcomes (decreased stillbirth and increased birth weight) compared with controls. The mechanism of action was via normalized angiogenic pathways and enhanced placental vascular development, as visualized by placental microcomputerized tomography imaging. These data define a role for dysregulation of NO biosynthetic pathways in the pathogenesis of MIP and support the evaluation of interventions to enhance L-arginine bioavailability as strategies to improve birth outcomes.
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2. A PET imaging approach for determining EGFR mutation status for improved lung cancer patient management.
Tumor heterogeneity and changes in epidermal growth factor receptor (EGFR) mutation status over time challenge the design of effective EGFR tyrosine kinase inhibitor (TKI) treatment strategies for non–small cell lung cancer (NSCLC). Therefore, there is an urgent need to develop techniques for comprehensive tumor EGFR profiling in real time, particularly in lung cancer precision medicine trials. Xilin Sun at Harbin Medical University in Harbin, Heilongjiang, China and his colleagues report a positron emission tomography (PET) tracer, N-(3-chloro-4-fluorophenyl)-7-(2-(2-(2-(2-18F-fluoroethoxy) ethoxy) ethoxy) ethoxy)-6-methoxyquinazolin-4-amine (18F-MPG), with high specificity to activating EGFR mutant kinase. They evaluate the feasibility of using 18F-MPG PET for noninvasive imaging and quantification of EGFR-activating mutation status in preclinical models of NSCLC and in patients with primary and metastatic NSCLC tumors. 18F-MPG PET in NSCLC animal models showed a significant correlation (R2 = 0.9050) between 18F-MPG uptake and activating EGFR mutation status. In clinical studies with NSCLC patients (n = 75), the concordance between the detection of EGFR activation by 18F-MPG PET/computed tomography (CT) and tissue biopsy reached 84.29%. There was a greater response to EGFR-TKIs (81.58% versus 6.06%) and longer median progression-free survival (348 days versus 183 days) in NSCLC patients when 18F-MPG PET/CT SUVmax (maximum standard uptake value) was ≥2.23 versus <2.23. Their study demonstrates that 18F-MPG PET/CT is a powerful method for precise quantification of EGFR-activating mutation status in NSCLC patients, and it is a promising strategy for noninvasively identifying patients sensitive to EGFR-TKIs and for monitoring the efficacy of EGFR-TKI therapy.
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3. Smartphone-based blood pressure monitoring via the oscillometric finger-pressing method.
High blood pressure (BP) is a major cardiovascular risk factor that is treatable, yet hypertension awareness and control rates are low. Ubiquitous BP monitoring technology could improve hypertension management, but existing devices require an inflatable cuff and are not compatible with such anytime, anywhere measurement of BP. Anand Chandrasekhar at Michigan State University in East Lansing, USA and his colleagues extended the oscillometric principle, which is used by most automatic cuff devices, to develop a cuff-less BP monitoring device using a smartphone. As the user presses her/his finger against the smartphone, the external pressure of the underlying artery is steadily increased while the phone measures the applied pressure and resulting variable-amplitude blood volume oscillations. A smartphone application provides visual feedback to guide the amount of pressure applied over time via the finger pressing and computes systolic and diastolic BP from the measurements. They prospectively tested the smartphone-based device for real-time BP monitoring in human subjects to evaluate usability (n = 30) and accuracy against a standard automatic cuff-based device (n = 32). They likewise tested a finger cuff device, which uses the volume-clamp method of BP detection. About 90% of the users learned the finger actuation required by the smartphone-based device after one or two practice trials. The device yielded bias and precision errors of 3.3 and 8.8 mmHg for systolic BP and −5.6 and 7.7 mmHg for diastolic BP over a 40 to 50 mmHg range of BP. These errors were comparable to the finger cuff device. Cuff-less and calibration-free monitoring of systolic and diastolic BP may be feasible via a smartphone.
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4. T follicular helper–like cells contribute to skin fibrosis.
Systemic sclerosis (SSc) is a debilitating inflammatory and fibrotic disease that affects the skin and internal organs. Although the pathophysiology of SSc remains poorly characterized, mononuclear cells, mainly macrophages and T cells, have been implicated in inflammation and fibrosis. Inducible costimulator (ICOS), which is expressed on a subset of memory T helper (TH) and T follicular helper (TFH) cells, has been shown to be increased in SSc and associated with disease pathology. However, the identity of the relevant ICOS+ T cells and their contribution to inflammation and fibrosis in SSc are still unknown. Devon K. Taylor at MedImmune LLC in Gaithersburg, USA and his colleagues show that CD4+ ICOS-expressing T cells with a TFH-like phenotype infiltrate the skin of patients with SSc and are correlated with dermal fibrosis and clinical disease status. ICOS+ TFH-like cells were found to be increased in the skin of graft-versus-host disease (GVHD)–SSc mice and contributed to dermal fibrosis via an interleukin-21– and matrix metalloproteinase 12–dependent mechanism. Administration of an anti-ICOS antibody to GVHD-SSc mice prevented the expansion of ICOS+ TFH-like cells and inhibited inflammation and dermal fibrosis. Interleukin-21 neutralization in GVHD-SSc mice blocked disease pathogenesis by reducing skin fibrosis. These results identify ICOS+ TFH-like profibrotic cells as key drivers of fibrosis in a GVHD-SSc model and suggest that inhibition of these cells could offer therapeutic benefit for SSc.
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5. Exploiting an Asp-Glu “switch” in glycogen synthase kinase 3 to design paralog-selective inhibitors for use in acute myeloid leukemia.
Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, are a concern in the translation of this target class because mutations and overexpression of β-catenin are associated with many cancers. Knockdown of GSK3α or GSK3β individually does not increase β-catenin and offers a conceptual resolution to targeting GSK3: paralog-selective inhibition. However, inadequate chemical tools exist. The design of selective adenosine triphosphate (ATP)–competitive inhibitors poses a drug discovery challenge due to the high homology (95% identity and 100% similarity) in this binding domain. Taking advantage of an Asp133→Glu196 “switch” in their kinase hinge, Florence F. Wagner at Broad Institute of Massachusetts Institute of Technology and Harvard University in Cambridge, USA and his colleagues present a rational design strategy toward the discovery of paralog-selective GSK3 inhibitors. These GSK3α- and GSK3β-selective inhibitors provide insights into GSK3 targeting in acute myeloid leukemia (AML), where GSK3α was identified as a therapeutic target using genetic approaches. The GSK3α-selective compound BRD0705 inhibits kinase function and does not stabilize β-catenin, mitigating potential neoplastic concerns. BRD0705 induces myeloid differentiation and impairs colony formation in AML cells, with no apparent effect on normal hematopoietic cells. Moreover, BRD0705 impairs leukemia initiation and prolongs survival in AML mouse models. These studies demonstrate feasibility of paralog-selective GSK3α inhibition, offering a promising therapeutic approach in AML.
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