409 research outputs found
Self-renewal of the long-term reconstituting subset of hematopoietic stem cells is regulated by Ikaros
Hematopoietic stem cells (HSCs) are rare, ancestral cells that underlie the development, homeostasis, aging, and regeneration of the blood. Here we show that the chromatin-associated protein Ikaros is a crucial self-renewal regulator of the long-term (LT) reconstituting subset of HSCs. Ikaros, and associated family member proteins, are highly expressed in self-renewing populations of stem cells. Ikaros point mutant mice initially develop LT-HSCs with the surface phenotype cKit+Thy1.1(lo)Lin(-/lo)Sca1+Flk2-CD150+ during fetal ontogeny but are unable to maintain this pool, rapidly losing it within two days of embryonic development. A synchronous loss of megakaryocyte/erythrocyte progenitors results, along with a fatal, fetal anemia. At this time, mutation of Ikaros exerts a differentiation defect upon common lymphoid progenitors that cannot be rescued with an ectopic Notch signal in vitro, with hematopoietic cells preferentially committing to the NK lineage. Althoughdispensable for the initial embryonic development of blood, Ikaros is clearly needed for maintenance of this tissue. Achieving successful clinical tissue regeneration necessitates understanding degeneration, and these data provide a striking example by a discrete genetic lesion in the cells underpinning tissue integrity during a pivotal timeframe of organogenesis
Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease A feasibility study
AbstractObjectivesWe conducted a pilot study to evaluate the feasibility of transendocardial delivery of autologous bone marrow (ABM) strategy in patients with severe symptomatic chronic myocardial ischemia not amenable to conventional revascularization.BackgroundTransendocardial injection of ABM cells appears to enhance perfusion of ischemic porcine myocardium.MethodsTen patients underwent transendocardial injection of freshly aspirated and filtered unfractionated ABM using left ventricular electromechanical guidance. Twelve injections of 0.2 ml each were successfully delivered into ischemic noninfarcted myocardium pre-identified by single-photon emission computed tomography perfusion imaging.ResultsAutologous bone marrow injection was successful in all patients and was associated with no serious adverse effects; in particular, there was no arrhythmia, evidence of infection, myocardial inflammation, or increased scar formation. Two patients were readmitted for recurrent chest pain. At three months, Canadian Cardiovascular Society angina score significantly improved (3.1 ± 0.3 vs. 2.0 ± 0.94, p = 0.001), as well as stress-induced ischemia occurring within the injected territories (2.1 ± 0.8 vs. 1.6 ± 0.8, p < 0.001). Treadmill exercise duration, available in nine patients, increased, but the change was not significant (391 ± 155 vs. 485 ± 198, p = 0.11).ConclusionsThis study provides preliminary clinical data indicating feasibility of catheter-based transendocardial delivery of ABM to ischemic myocardium
Physical model of near-Earth asteroid (1917) Cuyo from ground-based optical and thermal-IR observations
Context: The near-Earth asteroid (1917) Cuyo was subject to radar and lightcurve observations during a close approach in 1989, and observed up until 2008. It was selected as one of our ESO Large Programme targets, aimed at observational detections of the YORP effect through long-term lightcurve monitoring and physical modelling of near-Earth asteroids.
Aims: We aimed to constrain physical properties of Cuyo: shape, spin-state, and spectroscopic & thermophysical properties of the surface.
Methods: We acquired photometric lightcurves of Cuyo spanning the period between 2010 and 2013, which we combined with published lightcurves from 1989-2008. Our thermal-infrared observations were obtained in 2011. Rotationally-resolved optical spectroscopy data were acquired in 2011 and combined with all available published spectra to investigate any surface material variegation.
Results: We developed a convex lightcurve-inversion shape of Cuyo that suggests the presence of an equatorial ridge, typical for an evolved system close to shedding mass due to fast rotation. We determine limits of YORP strength through lightcurve-based spin-state modelling, including both negative and positive acceleration values, between -0.7x10-8 rad day-2 and 1.7x10-8 rad day-2. Thermo-physical modelling with the ATPM provides constraints on the geometric albedo, PV = 0.24 ± 0.07, the effective diameter Deff = 3.15 ± 0.08 km, the thermal inertia, 44 ±- 9 J m-2s-1/2K-1, and a roughness fraction of 0.52 ± 0.26. This enabled a YORP strength prediction of (-6.39 ± 0.96)x10-10 rad day-2. We also see evidence of surface compositional variation.
Conclusions: The low value of YORP predicted by means of thermophysical analysis, consistent with the results of the lightcurve study, might be due to the self-limiting properties of rotational YORP, possibly involving movement of sub-surface and surface material. This may also be consistent with the surface compositional variation that we see. The physical model of Cuyo can be used to investigate cohesive forces as a way to explain why some targets survive rotation rates faster than the fission limit
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Reprogramming human T cell function and specificity with non-viral genome targeting.
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells
Survival of Trojan-Type Companions of Neptune During Primordial Planet Migration
We investigate the survivability of Trojan-type companions of Neptune during
primordial radial migration of the giant planets Jupiter, Saturn, Uranus, and
Neptune. Loss of Neptune Trojans during planetary migration is not a random
diffusion process. Rather, losses occur almost exclusively during discrete
episodes when Trojan particles are swept by secondary resonances associated
with mean-motion commensurabilities of Uranus with Neptune. The single greatest
episode of loss ejects nearly 75% of existing Neptune Trojans and occurs just
prior to Neptune reaching its final orbit.Comment: LaTeX file, 26 total pages with 1 table and 11 eps figures. Submitted
to Icaru
Polymer-based paclitaxel-eluting stents reduce in-stent neointimal tissue proliferation A serial volumetric intravascular ultrasound analysis from the TAXUS-IV trial
ObjectivesThe aim of this study was to use serial volumetric intravascular ultrasound (IVUS) to evaluate the effects of polymer-based, paclitaxel-eluting stents on in-stent neointima formation and late incomplete stent apposition.BackgroundThe TAXUS-IV trial demonstrated that the slow-release, polymer-based, paclitaxel-eluting stent reduces angiographic restenosis and the need for repeat revascularization procedures. Serial IVUS studies reveal details of the pattern of vascular responses provoked by stent implantation that provide insight into device safety and efficacy.MethodsIn the TAXUS-IV trial, patients were randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). As part of a formal substudy, complete volumetric IVUS data were available in 170 patients, including 88 TAXUS patients and 82 controls, at implantation and at nine-month follow-up.ResultsNo baseline differences were present in the clinical characteristics or IVUS parameters between the control and TAXUS groups. At nine-month follow-up, IVUS lumen volumes were larger in the TAXUS group (123 ± 43 mm3vs. 104 ± 44 mm3, p = 0.005), due to a reduction in neointimal volume (18 ± 18 mm3vs. 41 ± 23 mm3, p < 0.001). Millimeter-by-millimeter analysis within the stent demonstrated uniform suppression of neointimal growth along the entire stent length. Late lumen loss was similar at the proximal edge of the stent between the two groups, and reduced with the TAXUS stent at the distal edge (p = 0.004). Incomplete stent apposition at nine months was observed in only 3.0% of control and 4.0% of TAXUS stents (p = 0.12).ConclusionsPolymer-based, paclitaxel-eluting TAXUS stents are effective in inhibiting neointimal tissue proliferation, and do not result in late incomplete stent apposition
The epithelial origin of a stromal cell population in adenocarcinoma of the rat prostate.
Dunning R3327-H rat prostate adenocarcinoma cells,
when grown in syngeneic (Copenhagen) rats or nude
mice, produce tumors with prominent hypercellular
stroma. The authors have previously demonstrated the
presence of anomalous steroid-sensitive cells in both
the epithelium and stromal compartments of this
model system. In order to better understand the histogenesis of these cells, the authors studied samples of the
tumor which were radiolabeled overnight with tritiated dihydrotestosterone (3H-DHT). Frozen sections
of the tissues were thaw-mounted onto autoradiographic emulsion-coated slides to permit silver grain identification in association with nuclei of androgensensitive cells. Surprisingly, numerous silver grains
were found to be associated with nuclei of large cells
within the stroma. Therefore, these cells were termed
"epithelioid" pending confirmation of their origin. To
further define these cells and their relationship to the
surrounding matrix, autoradiograms have now been
examined immunohistochemically with antibodies directed against the basement membrane glycoprotein, laminin, as well as antibodies specific for intermediate
cytoskeletal filaments. Following identification of
acinar basement membranes, epithelioid cells were
identifiable both in the stroma and in the acinar epithelial cell layer. Histochemical staining with acid phosphatase, a marker for prostatic epithelium, was performed and shown to be present in acinar epithelial
cells as well as in epithelioid cells. Additionally, fluorescence-activated cell sorting was employed to characterize the DNA content of cell types within the H
tumor. Epithelioid cells were found to be in highest
concentration in an aneuploid peak with a ploidy of
approximately 6N. The autoradiographic, immunohistochemical, cytometric, and ultramicroscopic studies suggest that 1) epithelioid cells are epithelial derived stromal cells; 2) these epithelioid cells arise by
pathologic division of aneuploid neoplastic precursor
cells of approximately 3N ploidy, which are found
within the prostatic epithelium; and 3) the resulting
6N cells degrade the basement membrane locally, invade the stroma, and populate it. Here, they can be
distinguished from fibroblasts by their size, acid phosphatase activity, and hormone receptor content. Thus,
the term "epithelioid" is inappropriate; and these cells
should be regarded simply as large neoplastic epithelial (LNE) cells. The presence of this cell type suggests that
this tumor subline represents a useful naturally occurring model for the study of the initial stages of neoplastic transformation
A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity
BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up
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