Bacterial patterning controlled by light exposure Velema, Willem A; van der Berg, Jan Pieter; Szymanski, Wiktor ...
Organic & biomolecular chemistry,
02/2015, Letnik:
13, Številka:
6
Journal Article
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Patterning of multiple bacterial strains in one system is achieved by employing a single photo-activated antibiotic. Varying the light-exposure time results in zones with mixed and single populations.
Photocaged compounds are important tools for studying and regulating multiple processes, including biological functions. Reported herein is the use of the Passerini multicomponent reaction for ...modular preparation of photocaged carboxylic acids. The reaction is compatible with several functionalities and proceeds smoothly both in water and dichloromethane. The choice of aldehyde determines the wavelength used for deprotection and enables formation of orthogonally protected products. The isocyanide component can be used for introduction of reactive tags and photosensitizers, as well as for immobilization on a solid support.
Die Passerini‐Mehrkomponentenreaktion wurde zur Synthese von photospaltbaren Carbonsäuren genutzt. Durch die sorgfältige Wahl des Aldehyds lassen sich die Entschützungswellenlänge exakt einstellen sowie orthogonal geschützte Produkte erzeugen. Die Isocyanid‐Komponente kann zur Immobilisierung auf einem festen Träger oder zur Einführung einer reaktiven Markierung oder eines Photosensibilisators genutzt werden.
Cancer treatment suffers from limitations that have a major impact on the patient’s quality of life and survival. In case of chemotherapy, the systemic distribution of cytotoxic drugs reduces their ...efficacy and causes severe side effects due to non-selective toxicity. Photopharmacology allows a novel approach to address these problems, as it employs external, local activation of chemotherapeutic agents using light. We report here the development of photoswitchable Histone Deacetylase inhibitors as potential antitumor agents. Analogs of the clinically used chemotherapeutic agents Vorinostat, Panobinostat and Belinostat were designed with a photoswitchable azobenzene moiety incorporated into their structure. The most promising compound exhibits high inhibitory potency in the thermodynamically less stable
cis
form and a significantly lower activity for the
trans
form, both on HDACs activity and proliferation of HeLa cells. This approach offers a clear prospect towards local photo-activation of HDAC inhibition, to avoid severe side effects in chemotherapy.
Willem Velema
Angewandte Chemie International Edition,
May 15, 2023, Letnik:
62, Številka:
21
Journal Article
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“My favorite piece of research is the development of the microfluidic chip by Professor Robert Austin dubbed the ‘death galaxy’ … My favorite quote is ‘In the end the universe tends to unfold as it ...should.’ “ Find out more about Willem Velema in his Introducing … Profile.
Identification of patients at risk for primary and secondary manifestations of atherosclerotic disease progression is based mainly on established risk factors. The atherosclerotic plaque composition ...is thought to be an important determinant of acute cardiovascular events, but no prospective studies have been performed. The objective of the present study was to investigate whether atherosclerotic plaque composition is associated with the occurrence of future vascular events.
Atherosclerotic carotid lesions were collected from patients who underwent carotid endarterectomy and were subjected to histological examination. Patients underwent clinical follow-up yearly, up to 3 years after carotid endarterectomy. The primary outcome was defined as the composite of a vascular event (vascular death, nonfatal stroke, nonfatal myocardial infarction) and vascular intervention. The cumulative event rate at 1-, 2-, and 3-year follow-up was expressed by Kaplan-Meier estimates, and Cox proportional hazards regression analyses were performed to assess the independence of histological characteristics from general cardiovascular risk factors. During a mean follow-up of 2.3 years, 196 of 818 patients (24%) reached the primary outcome. Patients whose excised carotid plaque revealed plaque hemorrhage or marked intraplaque vessel formation demonstrated an increased risk of primary outcome (risk difference=30.6% versus 17.2%; hazard ratio HR with 95% confidence interval=1.7 1.2 to 2.5; and risk difference=30.0% versus 23.8%; HR=1.4 1.1 to 1.9, respectively). Macrophage infiltration (HR=1.1 0.8 to 1.5), large lipid core (HR=1.1 0.7 to 1.6), calcifications (HR=1.1 0.8 to 1.5), collagen (HR=0.9 0.7 to 1.3), and smooth muscle cell infiltration (HR=1.3 0.9 to 1.8) were not associated with clinical outcome. Local plaque hemorrhage and increased intraplaque vessel formation were independently related to clinical outcome and were independent of clinical risk factors and medication use.
The local atherosclerotic plaque composition in patients undergoing carotid endarterectomy is an independent predictor of future cardiovascular events.
Introduction Studies using histologic examination and protein analysis of atherosclerotic plaques are increasingly being performed, but reproducibility of plaque histology and variation of plaque ...composition among different parts of the plaque, which are key to reliability of these studies, are relatively unexplored. Therefore, this study investigated the intraobserver and interobserver variability of plaque histology and spatial variability in plaque composition. Methods Atherosclerotic plaques (n = 100) obtained during carotid endarterectomy were divided into 0.5-cm segments. Paraffin sections were stained and semiquantitatively analyzed (four categories: no, minor, moderate, and heavy) for fat, macrophages, smooth muscle cells, collagen, calcification, thrombus, and overall phenotype. First, to determine the intraobserver and interobserver reproducibility, two independent observers independently analyzed the plaques. Second, to investigate spatial variability in plaque composition, histologic appearances of the culprit lesions (0-segment) were compared with the histologic appearances of adjacent (+5 mm) and more distant (+10 mm) plaque segments of 30 specimens. Results The κ values for intraobserver variability of fat, macrophages, smooth muscle cells, collagen, calcifications, thrombus, and overall phenotype were 0.83, 0.85, 0.71, 0.63, 0.81, 0.80, and 0.86, respectively, and κ values for interobserver variability were 0.68, 0.74, 0.54, 0.59, 0.82, 0.75, and 0.71, respectively. Comparison of the histologic scorings of adjacent segments revealed a mean κ of 0.40 (range, 0.33 to 0.60). When the culprit segment was compared with the more distant segment, the mean κ was 0.24; however, in 91% of cases, the difference between the culprit segment and the distal segment was one category or less. Conclusion Semiquantitative analysis of carotid atherosclerotic plaque histology was well reproducible, both intraobserver and interobserver. Although variation between different plaque segments in histologic appearance was observed, differences were small in almost all cases. Variability in histologic examination needs to be taken into account in studies comparing plaque imaging with histopathology and plaque research studies.
Chronic obstructive pulmonary disease (COPD) is a widespread disease with high morbidity rates. Advanced stages can be complicated by unintentional weight loss and muscle wasting, which may ...contribute to increased morbidity and mortality. Reversal of weight loss increases muscle strength and exercise capacity and improves survival. This can partly be achieved by nutritional support, preferably combined with increase in exercise. Androgenic anabolic steroids (AASs), of which testosterone is the parent hormone, increase muscle size and strength. Due to these anabolic effects, AASs may emerge as a treatment option in COPD patients suffering from muscle wasting.
Seven trials investigated the effects of AAS in patients with COPD. Some studies also included nutritional therapy and/or a pulmonary rehabilitation program. Compared with placebo, AASs increase lean body mass (LBM) and muscle size. However, no consistent effects on muscle strength, exercise capacity, or pulmonary function are seen.
AASs increase LBM in patients with advanced stages of COPD. No consistent beneficial effect on other endpoints was demonstrated in the reviewed trials. However, probably higher doses of AASs are needed to exert a clinically meaningful effect on muscle strength or exercise capacity. Currently, no evidence is available to recommend AASs to all patients with COPD. In individual cases, treatment with AASs can be considered, particularly in men with advanced COPD, moderate-to-severe functional impairment, muscle wasting and on chronic corticosteroid therapy. Treatment with AASs should preferably be combined with a rehabilitation program and nutritional support. AASs should not be used in women or in men with symptomatic heart disease. When treatment with AASs is considered, intramuscular nandrolone-decanoate is preferred in a dose of 50-200 mg per week for a period of 12 weeks. However, the efficacy of AAS treatment in COPD patients needs further clarification in well designed, adequately powered clinical studies.
Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic ...plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery 0% vs. 4% and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice. This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value.
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