Data derived from high-throughput sequencing technologies have allowed a deeper understanding of the molecular landscape of Acute Myeloid Leukemia (AML), paving the way for the development of novel ...therapeutic options, with a higher efficacy and a lower toxicity than conventional chemotherapy. In the antileukemia drug development scenario, ascorbic acid, a natural compound also known as Vitamin C, has emerged for its potential anti-proliferative and pro-apoptotic activities on leukemic cells. However, the role of ascorbic acid (vitamin C) in the treatment of AML has been debated for decades. Mechanistic insight into its role in many biological processes and, especially, in epigenetic regulation has provided the rationale for the use of this agent as a novel anti-leukemia therapy in AML. Acting as a co-factor for 2-oxoglutarate-dependent dioxygenases (2-OGDDs), ascorbic acid is involved in the epigenetic regulations through the control of TET (ten-eleven translocation) enzymes, epigenetic master regulators with a critical role in aberrant hematopoiesis and leukemogenesis. In line with this discovery, great interest has been emerging for the clinical testing of this drug targeting leukemia epigenome. Besides its role in epigenetics, ascorbic acid is also a pivotal regulator of many physiological processes in human, particularly in the antioxidant cellular response, being able to scavenge reactive oxygen species (ROS) to prevent DNA damage and other effects involved in cancer transformation. Thus, for this wide spectrum of biological activities, ascorbic acid possesses some pharmacologic properties attractive for anti-leukemia therapy. The present review outlines the evidence and mechanism of ascorbic acid in leukemogenesis and its therapeutic potential in AML. With the growing evidence derived from the literature on situations in which the use of ascorbate may be beneficial
in vitro
and
in vivo
, we will finally discuss how these insights could be included into the rational design of future clinical trials.
Abstract Purpose Procalcitonin (PCT) is a biomarker used to help sepsis diagnosing and monitoring and guide antibiotic therapy. Anastomotic leak (AL) after colorectal surgery is a severe complication ...associated with relevant short- and long-term sequelae. The aim of our study is to assess the predictive value of PCT levels to early diagnose AL after colorectal surgery. Methods Between September 2011 and September 2012, a series of 99 patients underwent colorectal surgery in our institution. In all cases, white blood cell (WBC) count, C-reactive protein (CRP), and PCT levels were measured in first, third, and fifth postoperative day (POD). Anastomotic leaks and all other postoperative complications were recorded. Results We registered 7 ALs (7.1%). Decreased PCT levels had a significant negative predictive value (NPV) for AL in third and fifth POD (96.7% and 96.7%, respectively), compared with CRP and WBC. The best diagnostic performance was obtained with the combination of PCT and CRP measurements in third and fifth POD (area under the curve, 0.87 and 0.94, respectively). In 5th POD, PCT improves diagnosis, but not in a statistically significant way (area under the curve, 0.86). Conclusions Compared with more established biochemical values such as CRP and WBC, PCT is an earlier, more sensitive, and reliable marker of AL. Increased PCT levels in early PODs after colorectal surgery may provide a more effective way to detect AL, before clinical symptoms appear. Moreover, normal PCT values might be also a useful marker to facilitate a safe and early discharge of selected patients after colorectal surgery.
Black-footed ferrets (Mustela nigripes (Audubon and Bachman, 1851)), a North American species of mustelid, faced near extinction after westward expansion during the 20th century destroyed a majority ...of the population of prairie dogs (genus Cynomys Rafinesque, 1817), their primary food source. Fearing extinction of the black-footed ferret, the U.S. Fish and Wildlife Service captured the entire population between 1985 and 1987 and began a captive breeding program. While in captivity, the fertility and genetic diversity of the species was closely monitored; however, there is little information about other health consequences of this breeding program. For instance, the black-footed ferrets have been fed a diet that is very different than what they consume in the wild. How did the composition of this diet affect the oral health of these animals? An analysis of dentition of wild and captive black-footed ferrets reveals that calculus accumulation and periodontal diseases occurred with greater severity in captive black-footed ferrets, suggesting that such oral pathologies arose from the unnaturally soft diet fed to them. These findings offer insight into how mechanical properties of diet can affect oral health and how these dietary properties should be considered, not only in regard to the health of black-footed ferrets but also to the health of all mammals including humans.
Purpose
Diabetic Retinopathy (DR) is one of the hallmark microvascular diseases secondary to diabetes. Endothelial cells and perivascular cells are key players in the pathogenesis. It has been shown ...that VEGF coordinates interactions between endothelial and perivascular cells. In rodent studies, VEGF injected into the eyes results in vascular retinal permeability with pericyte loss. Immunochemistry used for quantification of perivascular cells is well described for murine species but not for rabbit. The aim of the present study was to evaluate perivascular cell pattern in rabbit induced retinal permeability model.
Methods
Ten pigmented rabbits were induced by intravitreal injection of 500 ng rhVEGF165 into the right eye. At day 2, quantification of vascular leakage was evaluated by fluorometry in both eyes. At day 3, both eye were sampled and fixed. Anti‐ SMA and Isolectin B4 staining was performed on flat‐mounted retina. The evaluation of SMA+cells was performed along the microvasculature.
Results
Area of SMA+cells decreased with distal progression along the arterioles and venules: from 78% to 47% of coverage for arteriolar tree and 69% to 47% for venular tree, less coverage for capillary (30%). Flat‐mounted retina immunostaining analysis revealed that VEGF‐induced treated eyes displayed a remodeling and a loss of the SMA+cells coverage in comparison with left non‐induced eyes: Radial arteriole coverage decreased by 27% (A2) and 23% (A3) in VEGF‐induced eye. Radial venular coverage decreased by 22% (V2) in VEGF‐induced eye. No difference was observed on capillary vessel type with SMA immunolabelling.
Conclusions
This study showed the SMA+cells coverage pattern of retinal microvasculature in rabbit eyes and indicates that VEGF decreased SMA+cells coverage of both arteriolar and venular tree in an induced blood‐retinal barrier breakdown rabbit model.
Purpose Glaucoma is a progressive optic neuropathy and elevated intraocular pressure (IOP) is one of the most important risk factors. Here we present two experimental models of high IOP in rats and ...rabbits. One is related to the side effects of corticosteroids and the other one on the hypersaline stress.
Methods In the rat model, elevation of IOP was induced by instillations of 0.1% dexamethasone twice daily. One group received only saline instillations. The three dexamethasone induced groups received either 0.9% NaCl or brimonidine/timolol (0.2%/0.25%) or latanoprost (0.002%). The IOP was measured using a TonoLab® tonometer. In the rabbit model, elevation of IOP was induced by intravitreal (IVT) injection of 5% saline solution. The first received isotonic saline solution (0.9%) by IVT injection, the other two groups received hypertonic saline solution (5%) by IVT injection, one treated with an instillation of 0.9% NaCl and the other with an instillation of brimonidine‐timolol (0.2%/0.25%). IOP were recorded with a pneumatonometer.
Results In the rat model, 0.1% dexamethasone instillations induced a significant and chronic increase of the IOP over 35 days. The high IOP significantly decreased after treatment with the IOP‐lowering agents. In the rabbit model, the treatment showed a significant and acute increase of the IOP over 30 min to 120 min, after treatment the IOP significantly decreased.
Conclusion These two models of high intraocular pressure with simple experimental handling and low cost, can be used as a tool for discovering therapeutic drugs in glaucoma targeting the outflow
Purpose
Dry eye syndrome is a common disease with multifactorial causes. Symptoms typically include irritation, dryness, burning and decreased or fluctuating vision. Anti‐inflammatory drugs are ...widely used for the treatment of the inflammation produced by the disease with corticoid or cyclosporine A (CsA). Restasis® (Allergan), a CsA emulsion, was approved by the FDA but is not available in Europe. Here we propose to show the action of Optimmune® (MSD Animal Health) a marketed veterinary ophthalmic ointment that contains CsA in an experimental mouse model of dry eye induced by scopolamine, a tropane alkaloid drug with muscarinic antagonist effects.
Methods
Animals were divided in three groups of ten pigmented mice: Two groups were exposed to desiccating conditions (relative humidity <25%, air‐flow 15 L/min, temperature 20‐22°C) with transdermal scopolamine administration (0.5 mg/72 h) for 14 days. Animals were treated topically three times a day with 0.2% CsA ointment or vehicle. Controls were saline‐treated animals placed in a normal environment. Tear production was measured with the phenol red thread test, corneal defects were examined by slit‐lamp observation using blue light after 0.5% fluorescein eye drop. These examinations were performed in both eyes before exposure and on days 3, 7 and 14. A histological study was performed at the end of the study.
Results
Cyclosporine A eye ointment appeared to show efficacy in this model.
Conclusions
Cyclosporine A eye ointment significantly reduced clinical signs of dry eye by decreasing corneal defect more than cyclosporine A ophthalmic emulsion (internal studies).
Production of exclusive dijets in diffractive deep inelastic Formula omitted scattering has been measured with the ZEUS detector at HERA using an integrated luminosity of 372 pb Formula omitted. The ...measurement was performed for Formula omitted-p centre-of-mass energies in the range Formula omitted and for photon virtualities Formula omitted. Energy flows around the jet axis are presented. The cross section is presented as a function of Formula omitted and Formula omitted, where Formula omitted, x is the Bjorken variable and Formula omitted is the proton fractional longitudinal momentum loss. The angle Formula omitted is defined by the Formula omitted-dijet plane and the Formula omitted- Formula omitted plane in the rest frame of the diffractive final state. The Formula omitted cross section is measured in bins of Formula omitted. The results are compared to predictions from models based on different assumptions about the nature of the diffractive exchange.
•Butterfly fractures initiated in tension regardless of wedge orientation.•Incomplete cracks branched from the tensile initiation site.•Small, irregularly shaped fragments contained useful ...fractography features.•High-speed videos confirmed interpretations made using fractography.•Fractography can be used to interpret complex fracture propagation sequences.
Butterfly fractures are expected to form with the transverse portion on the tension side and the wedge portion on the compression side of a bent bone, however wedges have also been observed in the reverse orientation and are reported to be frequent in concentrated 4-point bending. To investigate how these fractures form, concentrated 4-point bending experiments were performed on nine human femora and documented using high-speed video. Videos showed the wedge portion formed as fracture initiated in tension, branched obliquely, then curved to terminate on the tension face. The transverse portion formed as a crack traveled between the curved fracture branch and the compression face. Fractography was also applied to evaluate fracture surfaces. At least one fractography feature was present in all femora and 32/35 bone fragments examined. Fracture propagation sequences interpreted using fractography matched those observed on video, demonstrating the utility of this method for evaluating complex fracture patterns.
This paper describes the design and the current state of implementation of an infrastructure made available to software developers within the Italian National Institute for Nuclear Physics (INFN) to ...support and facilitate their daily activity. The infrastructure integrates several tools, each providing a well-identified function: project management, version control system, continuous integration, dynamic provisioning of virtual machines, efficiency improvement, knowledge base. When applicable, access to the services is based on the INFN-wide Authentication and Authorization Infrastructure. The system is being installed and progressively made available to INFN users belonging to tens of sites and laboratories and will represent a solid foundation for the software development efforts of the many experiments and projects that see the involvement of the Institute. The infrastructure will be beneficial especially for small- and medium-size collaborations, which often cannot afford the resources, in particular in terms of know-how, needed to set up such services.
PDF
