Division-of-focal plane (DoFP) imaging polarimeters are useful instruments for measuring polarization information for a variety of applications. Recent advances in nanofabrication have enabled the ...practical manufacture of DoFP sensors for the visible spectrum. These sensors are made by integrating nanowire polarization filters directly with an imaging array, and size variations of the nanowires due to fabrication can cause the optical properties of the filters to vary up to 20% across the imaging array. If left unchecked, these variations introduce significant errors when reconstructing the polarization image. Calibration methods offer a means to correct these errors. This work evaluates a scalar and matrix calibration derived from a mathematical model of the polarimeter behavior. The methods are evaluated quantitatively with an existing DoFP polarimeter under varying illumination intensity and angle of linear polarization.
Arachidonic acid can be oxygenated by a variety of different enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s, and can be converted to a complex mixture of oxygenated products ...as a result of lipid peroxidation. The initial products in these reactions are hydroperoxyeicosatetraenoic acids (HpETEs) and hydroxyeicosatetraenoic acids (HETEs). Oxoeicosatetraenoic acids (oxo-ETEs) can be formed by the actions of various dehydrogenases on HETEs or by dehydration of HpETEs. Although a large number of different HETEs and oxo-ETEs have been identified, this review will focus principally on 5-oxo-ETE, 5S-HETE, 12S-HETE, and 15S-HETE. Other related arachidonic acid metabolites will also be discussed in less detail. 5-Oxo-ETE is synthesized by oxidation of the 5-lipoxygenase product 5S-HETE by the selective enzyme, 5-hydroxyeicosanoid dehydrogenase. It actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, suggesting that it may be important in eosinophilic diseases such as asthma. 5-Oxo-ETE also appears to stimulate tumor cell proliferation and may also be involved in cancer. Highly selective and potent OXE receptor antagonists have recently become available and could help to clarify its pathophysiological role. The 12-lipoxygenase product 12S-HETE acts by the GPR31 receptor and promotes tumor cell proliferation and metastasis and could therefore be a promising target in cancer therapy. It may also be involved as a proinflammatory mediator in diabetes. In contrast, 15S-HETE may have a protective effect in cancer. In addition to GPCRs, higher concentration of HETEs and oxo-ETEs can activate peroxisome proliferator-activated receptors (PPARs) and could potentially regulate a variety of processes by this mechanism. This article is part of a Special Issue entitled “Oxygenated metabolism of PUFA: analysis and biological relevance”.
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•HETEs are AA metabolites formed by lipoxygenases, cyclooxygenases, and P450 enzymes.•Oxo-ETEs are formed from HETEs by specific dehydrogenases.•Receptors have been identified for 5-oxo-ETE (OXE receptor) and 12S-HETE.•5-Oxo-ETE is an eosinophil chemoattractant that may be involved in asthma and allergy.•12S-HETE promotes tumor cell proliferation and may be involved in cancer and diabetes.
Eicosanoids comprise a group of oxidation products of arachidonic and 5,8,11,14,17-eicosapentaenoic acids formed by oxygenases and downstream enzymes. The two major pathways for eicosanoid formation ...are initiated by the actions of 5-lipoxygenase (5-LO), leading to leukotrienes (LTs) and 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), and cyclooxygenase (COX), leading to prostaglandins (PGs) and thromboxane (TX). A third group (specialized pro-resolving mediators; SPMs), including lipoxin A4 (LXA4) and resolvins (Rvs), are formed by the combined actions of different oxygenases. The actions of the above eicosanoids are mediated by approximately 20 G protein-coupled receptors, resulting in a variety of both detrimental and beneficial effects on airway smooth muscle and inflammatory cells that are strongly implicated in asthma pathophysiology. Drugs targeting proinflammatory eicosanoid receptors, including CysLT1, the receptor for LTD4 (montelukast) and TP, the receptor for TXA2 (seratrodast) are currently in use, whereas antagonists of a number of other receptors, including DP2 (PGD2), BLT1 (LTB4), and OXE (5-oxo-ETE) are under investigation. Agonists targeting anti-inflammatory/pro-resolving eicosanoid receptors such as EP2/4 (PGE2), IP (PGI2), ALX/FPR2 (LXA4), and Chemerin1 (RvE1/2) are also being examined. This review summarizes the contributions of eicosanoid receptors to the pathophysiology of asthma and the potential therapeutic benefits of drugs that target these receptors. Because of the multifactorial nature of asthma and the diverse pathways affected by eicosanoid receptors, it will be important to identify subgroups of asthmatics that are likely to respond to any given therapy.
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5-Oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) is an arachidonic acid metabolite formed by oxidation of the 5-lipoxygenase (5-LO) product 5S-hydroxy-6,8,11,14-eicosatetraenoic acid ...(5S-HETE) by the NADP+-dependent enzyme 5-hydroxyeicosanoid dehydrogenase. It is the only 5-LO product with appreciable chemoattractant activity for human eosinophils. Its actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, basophils, neutrophils and monocytes. Orthologs of the OXER1 gene, which encodes this receptor, are found in many species except for rodents. Intradermal injection of 5-oxo-ETE into humans and monkeys elicits eosinophil infiltration into the skin, raising the possibility that it may play a pathophysiological role in eosinophilic diseases. To investigate this and possibly identify a novel therapy we sought to prepare synthetic antagonists that could selectively block the OXE receptor. We synthesized a series of indole-based compounds bearing substituents that mimic the regions of 5-oxo-ETE that are required for biological activity, which we modified to reduce metabolism. The most potent of these OXE receptor antagonists is S-Y048, which is a potent inhibitor of 5-oxo-ETE-induced calcium mobilization (IC50, 20 pM) and has a long half-life following oral administration. S-Y048 inhibited allergen-induced eosinophil infiltration into the skin of rhesus monkeys that had been experimentally sensitized to house dust mite and inhibited pulmonary inflammation resulting from challenge with aerosolized allergen. These data provide the first evidence for a pathophysiological role for 5-oxo-ETE in mammals and suggest that potent and selective OXE receptor antagonists such as S-Y048 may be useful therapeutic agents in asthma and other eosinophilic diseases.
Caste evolution is a central process in the adaptive diversification of insect superorganisms. Nevertheless, how ecology shapes adaptive caste evolution remains poorly understood. Recent work with ...the ant genus Cephalotes has provided new comparative evidence that ecological specialization may drive adaptive caste specialization. Here, three key predictions of this adaptive hypothesis are supported, using a representative of the highest level of ecological specialization and the most specialized soldier phenotype. First, soldier defensive performance was maximal for the specific nesting resource used most often in nature. Second, colonies only used a specialized subset of available nesting resources and preferred the specific resource that maximizes soldier performance. Third, soldier performance and its limitations on resource use were found to have both direct and indirect consequences for colony reproduction. These findings suggest that the most specialized soldier phenotype in Cephalotes is indeed an adaptation to ecological specialization on a narrowly defined subset of available nesting resources.
Aspirin gained tremendous popularity during the 1918 Spanish Influenza virus pandemic, 50 years prior to the demonstration of their inhibitory action on prostaglandins. Here, we show that during ...influenza A virus (IAV) infection, prostaglandin E2 (PGE2) was upregulated, which led to the inhibition of type I interferon (IFN) production and apoptosis in macrophages, thereby causing an increase in virus replication. This inhibitory role of PGE2 was not limited to innate immunity, because both antigen presentation and T cell mediated immunity were also suppressed. Targeted PGE2 suppression via genetic ablation of microsomal prostaglandin E-synthase 1 (mPGES-1) or by the pharmacological inhibition of PGE2 receptors EP2 and EP4 substantially improved survival against lethal IAV infection whereas PGE2 administration reversed this phenotype. These data demonstrate that the mPGES-1-PGE2 pathway is targeted by IAV to evade host type I IFN-dependent antiviral immunity. We propose that specific inhibition of PGE2 signaling might serve as a treatment for IAV.
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•PGE2 inhibits macrophage recruitment to the lungs during IAV infection•PGE2 inhibits type I IFN production and apoptosis in IAV-infected macrophages•PGE2 impairs macrophage antigen presentation and adaptive immunity against IAV•Pharmacological suppression of PGE2 protects against IAV infection
The addition of pembrolizumab to chemotherapy for metastatic lung cancer without
EGFR
or
ALK
mutations resulted in better progression-free and overall survival than chemotherapy alone. Immune-related ...adverse effects were more common with the combination.
Summary
Reasons for performing study: The metacarpo/metatarsophalangeal (MCP/MTP) joint is a common site of lameness in the Thoroughbred racehorse. Radiographs may fail to show pathology consistent ...with the degree of lameness. With a high incidence of stress fractures occurring in the distal third metacarpal/metatarsal (MC3/MT3) condyles and proximal phalanx, a definitive diagnosis as to the nature of the pathology is essential.
Objective: To describe the low‐field magnetic resonance imaging (MRI) findings in Thoroughbred racehorses with MCP/MTP joint pain scanned under standing sedation.
Methods: The MR images and clinical records of all Thoroughbred racehorses undergoing MRI of the MCP/MTP joint between October 2006 and August 2010 were reviewed. A total of 168 joints from 131 horses were selected for inclusion. The MRI finding considered most significant in the lame (or lamest) limb was noted.
Results: Diagnostic quality images were obtainable in 97.8% of horses. The most common finding was palmar/plantar osteochondral disease in MC3/MT3 (54.9% of horses). Incomplete condylar fracture was diagnosed in 19.8% of horses, with the lateral condyle predominating. An incomplete sagittal fracure of P1 was diagnosed in 14.5% of horses and 11.4% were diagnosed with ‘dorsal joint disease’. Other findings included transverse MC3 stress fractures (1.5%), soft tissue injuries (12.2%) and proximal phalangeal ‘contusions’ (3.8%). No significant bone/soft tissue injury was detected in 5.4% of cases.
Conclusions: Standing MRI can detect a spectrum of disease within the MCP/MTP joints of racehorses. The procedure is well tolerated and may lead to a definitive diagnosis where radiographic imaging is inconclusive.
Potential relevance: A total of 35.8% of cases had MRI findings consistent with fracture pathology, which could not be confirmed radiographically at the time of the MRI examination. This has important therapeutic and prognostic implications and may help to prevent catastrophic injury.
In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed–platinum) significantly improved overall survival (OS) and progression-free ...survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed–platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed–platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab.
Eligible patients were randomized 2 : 1 to receive pembrolizumab 200 mg (n = 410) or placebo (n = 206) every 3 weeks (for up to 35 cycles, ∼2 years) plus four cycles of pemetrexed (500 mg/m2) and investigators’ choice of cisplatin (75 mg/m2) or carboplatin (area under the curve 5 mg·min/ml) every 3 weeks, followed by pemetrexed until progression. Patients assigned to placebo plus pemetrexed–platinum could cross over to pembrolizumab upon progression if eligibility criteria were met. The primary endpoints were OS and PFS.
After a median follow-up of 31.0 months, pembrolizumab plus pemetrexed–platinum continued to improve OS hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.46-0.69 and PFS (HR, 0.49; 95% CI, 0.41-0.59) over placebo plus pemetrexed–platinum regardless of programmed death-ligand 1 expression. Objective response rate (ORR) (48.3% versus 19.9%) and time to second/subsequent tumor progression on next-line treatment (PFS2; HR, 0.50; 95% CI, 0.41-0.61) were improved in patients who received pembrolizumab plus pemetrexed–platinum. Eighty-four patients (40.8%) from the placebo plus pemetrexed–platinum group crossed over to pembrolizumab on-study. Grade 3-5 adverse events occurred in 72.1% of patients receiving pembrolizumab plus pemetrexed–platinum and 66.8% of patients receiving placebo plus pemetrexed–platinum. Fifty-six patients completed 35 cycles (∼2 years) of pembrolizumab; ORR was 85.7% and 53 (94.6%) were alive at data cut-off.
Pembrolizumab plus pemetrexed–platinum continued to show improved efficacy outcomes compared with placebo plus pemetrexed–platinum, with manageable toxicity. These findings support first-line pembrolizumab plus pemetrexed–platinum in patients with previously untreated metastatic nonsquamous NSCLC.
•KEYNOTE-189 evaluated the efficacy and safety of pembrolizumab + pemetrexed–platinum versus placebo + pemetrexed–platinum in NSCLC.•Pembrolizumab + pemetrexed–platinum improved OS (HR, 0.56; 95% CI, 0.46-0.69) versus placebo + pemetrexed–platinum.•Pembrolizumab + pemetrexed–platinum improved PFS (HR, 0.49; 95% CI, 0.41-0.59) versus placebo + pemetrexed–platinum.•ORR was 85.7% in patients who completed 35 cycles (2 years) of pembrolizumab therapy.•Pembrolizumab + pemetrexed–platinum had manageable toxicity.
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