This article reviews retinopathy of prematurity, particularly regarding oxygen use, and describes current and potential therapies based on mechanistic studies in models relevant to current oxygen ...stresses in preterm infants.
Retinopathy of prematurity is a vision-threatening disease associated with abnormal retinal vascular development that occurs only in premature infants.
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Low birth weight and prematurity are strongly associated with an increased risk of the disease.
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In the Early Treatment for Retinopathy of Prematurity study, the disorder developed in 68% of premature infants born in the United States and weighing less than 1251 g; among infants with the disorder, severe retinopathy of prematurity developed in almost 37%.
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The incidence of premature births is increasing throughout the world, and with it, retinopathy of prematurity is now appearing in countries with the technology to . . .
Cell adhesion is an essential aspect of cellular behavior. Finding innovative methods to probe the adhesion of cells in their native state can greatly advance the understanding of control and ...regulation of cellular behavior and their impact on human health. The quartz crystal microbalance (QCM) is a label-free, biosensing system that has, in the past fifty years, evolved from a simple acoustic based mass sensor to a powerful bioanalytical tool. Its unique capability of monitoring the cell-substrate interaction non-invasively in real time has led to the emergence of its applications in areas that are relevant to fundamental cell biology and medical research. This review is intended to provide readers an overview of the use of the QCM for examination of cell-substrate adhesion. It also describes how this innovative approach can be extended to the study of other aspects of cellular behavior, such as cell morphology, cell mechanics, cell motility, cell signaling, all of which can potentially be applied to medical diagnosis and/or pharmaceutical development. In this review a major emphasis is placed on informing readers about some of the most important practical aspects of the QCM-based cell study including data acquisition and analysis, the substrate surface manipulation, and cell manipulation.
•Overview of the use of the QCM for examination of cell-substrate adhesion.•Discussion on how the QCM-based approach can be extended to the study of other aspects of cellular behavior.•Review of some of the most important practical aspects of the QCM-based cell study.
In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast ...cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD).
Patients were randomized to paclitaxel plus nonpegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study end points disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in formalin-fixed, paraffin-embedded tumor samples of 193/315 (61.3%) participants with TNBC. Homologous recombination (HR) deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA).
A significantly better DFS (hazard ratio 0.56, 95% CI 0.34–0.93; P = 0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors. HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) odds ratio (OR) 2.60, 95% CI 1.26–5.37, P = 0.008. Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P = 0.001), but only marginally in HR nondeficient tumors (from 20.0% to 29.6%, P = 0.540; test for interaction P = 0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46–9.37, P = 0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR nondeficient (hazard ratio 0.44, 0.17–1.17, P = 0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P = 0.059).
The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.
Retinal vascular basement membrane (BM) thickening is an early structural abnormality of diabetic retinopathy (DR). Recent studies suggest that BM thickening contributes to the DR pathological ...cascade; however, much remains to be elucidated about the exact mechanisms by which BM thickening develops and subsequently drives other pathogenic events in DR. Therefore, we undertook a systematic analysis to understand how human retinal microvascular endothelial cells (hRMEC) and human retinal pericytes (hRP) change their expression of key extracellular matrix (ECM) constituents when treated with diabetes-relevant stimuli designed to model the three major insults of the diabetic environment: hyperglycemia, dyslipidemia, and inflammation. TNFα and IL-1β caused the most potent and consistent changes in ECM expression in both hRMEC and hRP. We also demonstrate that conditioned media from IL-1β-treated human Müller cells caused dose-dependent, significant increases in collagen IV and agrin expression in hRMEC. After narrowing our focus to inflammation-induced changes, we sought to understand how ECM deposited by hRMEC and hRP under inflammatory conditions affects the behavior of naïve hRMEC. Our data demonstrated that diabetes-relevant alterations in ECM composition alone cause both increased adhesion molecule expression by and increased peripheral blood mononuclear cell (PBMC) adhesion to naïve hRMEC. Taken together, these data demonstrate novel roles for inflammation and pericytes in driving BM pathology and suggest that inflammation-induced ECM alterations may advance other pathogenic behaviors in DR, including leukostasis.
Overexpression of stromal cell-derived factor-1 in injured tissue leads to improved end-organ function. In this study, we quantify the local trophic effects of mesenchymal stem cell (MSC) stromal ...cell-derived factor-1 release on the effects of MSC engraftment in the myocardium after acute myocardial infarction.
Conditional cardiac myocyte CXCR4 (CM-CXCR4) null mice were generated by use of tamoxifen-inducible cardiac-specific cre by crossing CXCR4 floxed with MCM-cre mouse. Studies were performed in littermates with (CM-CXCR4 null) or without (control) tamoxifen injection 3 weeks before acute myocardial infarction. One day after acute myocardial infarction, mice received 100,000 MSC or saline via tail vein. We show α-myosin heavy chain MerCreMer and the MLC-2v promoters are active in cardiac progenitor cells. MSC engraftment in wild-type mice decreased terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling positive CM (-44%, P<0.01), increased cardiac progenitor cell recruitment (100.9%, P<0.01), and increased cardiac myosin-positive area (39%, P<0.05) at 4, 7, and 21 days after acute myocardial infarction, respectively. MSC in wild-type mice resulted in 107.4% (P<0.05) increase in ejection fraction in comparison with 25.9% (P=NS) increase in CM-CXCR4 null mice. These differences occurred despite equivalent increases (16%) in vascular density in response to MSC infusion in wild-type and CM-CXCR4 null mice.
These data demonstrate that the local trophic effects of MSC require cardiac progenitor cell and CM-CXCR4 expression and are mediated by MSC stromal cell-derived factor-1 secretion. Our results further demonstrate and quantify for the first time a specific paracrine mechanism of MSC engraftment. In the absence of CM-CXCR4 expression, there is a significant loss of functional benefit in MSC-mediated repair despite equal increases in vascular density.
Optical coherence tomography (OCT) has become a standard-of-care in retinal imaging. OCT allows non-invasive imaging of the tissue structure but lacks specificity to contrast agents that could be ...used for in vivo molecular imaging. Photothermal OCT (PT-OCT) is a functional OCT-based technique that has been developed to detect absorbers in a sample. We demonstrate in vivo PT-OCT in the eye for the first time on both endogenous (melanin) and exogenous (gold nanorods) absorbers. Pigmented mice and albino mice (n = 6 eyes) were used to isolate the photothermal signal from the melanin in the retina. Pigmented mice with laser-induced choroidal neovascularization lesions (n = 7 eyes) were also imaged after a systemic injection of gold nanorods to observe their passive accumulation in the retina. This experiment demonstrates the feasibility of PT-OCT to image the distribution of both endogenous and exogenous absorbers in the mouse retina.
Nanoparticles for bioanalysis Penn, Sharron G; He, Lin; Natan, Michael J
Current opinion in chemical biology,
10/2003, Letnik:
7, Številka:
5
Journal Article
Recenzirano
This review covers the emerging field of nanobiotechnology, in which nanoparticles are applied to the analysis of biomolecules. Nanoparticles can be used in a variety of bioanalytical formats, and ...this review discusses four classes of use. First, nanoparticles as quantitation tags, such as the optical detection of quantum dots and the electrochemical detection of metallic nanoparticles. Second, encoded nanoparticles as substrates for multiplexed bioassays, such as striped metallic nanoparticles. Third, nanoparticles that leverage signal transduction, for example in colloidal gold-based aggregation assays. Fourth, functional nanoparticles that exploit specific physical or chemical properties of nanoparticles to carry out novel functions, such as the catalysis of a biological reaction. In addition, the review discusses the next generation of nanoparticles that will be utilized in the life sciences, such as nanodots and carbon nanotubes.
Cell-based therapies for the prevention and treatment of cardiac dysfunction offer the potential to significantly modulate cardiac function and improve outcomes in patients with cardiovascular ...disease. To date several clinical studies have suggested the potential efficacy of several different stem cell types; however, the benefits seen in clinical trials have been inconsistent and modest. In parallel, preclinical studies have identified key events in the process of cell-based myocardial repair, including stem cell homing, engraftment, survival, paracrine factor release, and differentiation that need to be optimized to maximize cardiac repair and function. The inconsistent and modest benefits seen in clinical trials combined with the preclinical identification of mediators responsible for key events in cell-based cardiac repair offers the potential for cell-based therapy to advance to cell-based gene therapy in an attempt to optimize these key events in the hope of maximizing clinical benefit. Below we discuss potential key events in cardiac repair and the mediators of these events that could be of potential interest for genetic enhancement of stem cell–based cardiac repair.
RATIONALE:Preclinical studies indicate that adult stem cells induce tissue repair by activating endogenous stem cells through the stromal cell-derived factor-1:chemokine receptor type 4 axis. JVS-100 ...is a DNA plasmid encoding human stromal cell-derived factor-1.
OBJECTIVE:We tested in a phase 1, open-label, dose-escalation study with 12 months of follow-up in subjects with ischemic cardiomyopathy to see if JVS-100 improves clinical parameters.
METHODS AND RESULTS:Seventeen subjects with ischemic cardiomyopathy, New York Heart Association class III heart failure, with an ejection fraction ≤40% on stable medical therapy, were enrolled to receive 5, 15, or 30 mg of JVS-100 via endomyocardial injection. The primary end points for safety and efficacy were at 1 and 4 months, respectively. The primary safety end point was a major adverse cardiac event. Efficacy end points were change in quality of life, New York Heart Association class, 6-minute walk distance, single photon emission computed tomography, N-terminal pro-brain natruretic peptide, and echocardiography at 4 and 12 months. The primary safety end point was met. At 4 months, all of the cohorts demonstrated improvements in 6-minute walk distance, quality of life, and New York Heart Association class. Subjects in the 15- and 30-mg dose groups exhibited improvements in 6-minute walk distance (15 mgmedian range41 minutes 3–61 minutes; 30 mg31 minutes 22–74 minutes) and quality of life (15 mg–16 points +1 to –32 points; 30 mg–24 points +17 to –38 points) over baseline. At 12 months, improvements in symptoms were maintained.
CONCLUSIONS:These data highlight the importance of defining the molecular mechanisms of stem cell-based tissue repair and suggest that overexpression of stromal cell-derived factor-1 via gene therapy is a strategy for improving heart failure symptoms in patients with ischemic cardiomyopathy.
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