Summary Background It has been 13 years since the discovery of human embryonic stem cells (hESCs). Our report provides the first description of hESC-derived cells transplanted into human patients. ...Methods We started two prospective clinical studies to establish the safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium (RPE) in patients with Stargardt's macular dystrophy and dry age-related macular degeneration—the leading cause of blindness in the developed world. Preoperative and postoperative ophthalmic examinations included visual acuity, fluorescein angiography, optical coherence tomography, and visual field testing. These studies are registered with ClinicalTrials.gov , numbers NCT01345006 and NCT01344993. Findings Controlled hESC differentiation resulted in greater than 99% pure RPE. The cells displayed typical RPE behaviour and integrated into the host RPE layer forming mature quiescent monolayers after transplantation in animals. The stage of differentiation substantially affected attachment and survival of the cells in vitro after clinical formulation. Lightly pigmented cells attached and spread in a substantially greater proportion (>90%) than more darkly pigmented cells after culture. After surgery, structural evidence confirmed cells had attached and continued to persist during our study. We did not identify signs of hyperproliferation, abnormal growth, or immune mediated transplant rejection in either patient during the first 4 months. Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study ETDRS visual acuity chart) in the study eye of the patient with Stargardt's macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28). Interpretation The hESC-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. The future therapeutic goal will be to treat patients earlier in the disease processes, potentially increasing the likelihood of photoreceptor and central visual rescue. Funding Advanced Cell Technology.
Summary Background Since they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity ...and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients. Methods In the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardt's macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50 000, 100 000, and 150 000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov , numbers NCT01345006 (Stargardt's macular dystrophy) and NCT01344993 (age-related macular degeneration). Findings There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16–25 points 3–12 months after transplantation in patients with atrophic age-related macular degeneration and 8–20 points in patients with Stargardt's macular dystrophy. Interpretation The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement. Funding Advanced Cell Technology.
Measurements of the Collins and Sivers asymmetries for charged pions and charged and neutral kaons produced in semi-inclusive deep-inelastic scattering of high energy muons off transversely polarised ...protons are presented. The results were obtained using all the available COMPASS proton data, which were taken in the years 2007 and 2010. The Collins asymmetries exhibit in the valence region a non-zero signal for pions and there are hints of non-zero signal also for kaons. The Sivers asymmetries are found to be positive for positive pions and kaons and compatible with zero otherwise.
Eight proton transverse-spin-dependent azimuthal asymmetries are extracted in four regions of the photon virtuality Q2 from the COMPASS 2010 semi-inclusive hadron measurements in deep inelastic ...muon–nucleon scattering. These Q2 regions correspond to the four regions of the di-muon mass Q2 used in the ongoing analyses of the COMPASS Drell–Yan measurements, which allows for a future direct comparison of the nucleon transverse-momentum-dependent parton distribution functions extracted from these two alternative measurements. In addition, for the azimuthal asymmetries induced by the Sivers transverse-momentum-dependent parton distribution function various two-dimensional kinematic dependences are presented. The integrated Sivers asymmetries are found to be positive with an accuracy that appears to be sufficient to test the sign change of the Sivers function predicted by Quantum Chromodynamics.
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The isobar model EtaMAID has been updated with new and high precision data for
η
and
η
photoproduction on protons and neutrons from MAMI, ELSA, GRAAL and CLAS. The background is described in a ...recently developed Regge cut model, and for the resonance part the whole list of nucleon resonances has been investigated with 21
N
*
states contributing to
η
photoproduction and 12
N
*
states contributing to
η
photoproduction. A new approach is discussed to avoid double counting in the overlap region of Regge and resonances. A comparison is done among four newly updated partial waves analyses for observables and partial waves. Finally, the possibility of a narrow resonance near
W
=
1900
MeV is discussed, that would be able to explain unexpected energy and angular dependence of observables in
p
(
γ
,
η
)
p
near
η
threshold.
A set of measurements of azimuthal asymmetries in the production of pairs of identified hadrons in deep-inelastic scattering of muons on transversely polarised 6LiD (deuteron) and NH3 (proton) ...targets is presented. All available data collected in the years 2003–2004 and 2007/2010 with the COMPASS spectrometer using a muon beam of 160GeV/c at the CERN SPS were analysed. The asymmetries provide access to the transversity distribution functions via a fragmentation function that in principle may be independently obtained from e+e− annihilation data. Results are presented, discussed and compared to existing measurements as well as to model predictions. Asymmetries of π+π− pairs measured with the proton target as a function of the Bjorken scaling variable are sizeable in the range x>0.032, indicating non-vanishing transversity distribution and di-hadron interference fragmentation functions. As already pointed out by several authors, the small asymmetries of π+π− measured on the 6LiD target can be interpreted as indication for a cancellation of u and d-quark transversity distributions.
Precise measurements of charged-kaon multiplicities in deep inelastic scattering were performed. The results are presented in three-dimensional bins of the Bjorken scaling variable x, the relative ...virtual-photon energy y, and the fraction z of the virtual-photon energy carried by the produced hadron. The data were obtained by the COMPASS Collaboration by scattering 160 GeV muons off an isoscalar 6LiD target. They cover the kinematic domain 1(GeV/c)2<Q2<60(GeV/c)2 in the photon virtuality, 0.004<x<0.4, 0.1<y<0.7, 0.20<z<0.85, and W>5 GeV/c2 in the invariant mass of the hadronic system. The results from the sum of the z-integrated K+ and K− multiplicities at high x point to a value of the non-strange quark fragmentation function larger than obtained by the earlier DSS fit.
The Sivers function describes the correlation between the transverse spin of a nucleon and the transverse motion of its partons. For quarks, it was studied in previous measurements of the azimuthal ...asymmetry of hadrons produced in semi-inclusive deep inelastic scattering of leptons off transversely polarised nucleon targets, and it was found to be non-zero. In this letter the evaluation of the Sivers asymmetry for gluons is presented. The contribution of the photon–gluon fusion subprocess is enhanced by requiring two high transverse-momentum hadrons. The analysis method is based on a Monte Carlo simulation that includes three hard processes: photon–gluon fusion, QCD Compton scattering and the leading-order virtual-photon absorption process. The Sivers asymmetries of the three processes are simultaneously extracted using the LEPTO event generator and a neural network approach. The method is applied to samples of events containing at least two hadrons with large transverse momentum from the COMPASS data taken with a 160 GeV/c muon beam scattered off transversely polarised deuterons and protons. With a significance of about two standard deviations, a negative value is obtained for the gluon Sivers asymmetry. The result of a similar analysis for a Collins-like asymmetry for gluons is consistent with zero.
Multiplicities of charged pions and charged hadrons produced in deep-inelastic scattering were measured in three-dimensional bins of the Bjorken scaling variable x, the relative virtual-photon energy ...y and the relative hadron energy z. Data were obtained by the COMPASS Collaboration using a 160GeV muon beam and an isoscalar target (6LiD). They cover the kinematic domain in the photon virtuality Q2>1(GeV/c)2, 0.004<x<0.4, 0.2<z<0.85 and 0.1<y<0.7. In addition, a leading-order pQCD analysis was performed using the pion multiplicity results to extract quark fragmentation functions.
Spin-averaged asymmetries in the azimuthal distributions of positive and negative hadrons produced in deep inelastic scattering were measured using the CERN SPS longitudinally polarised muon beam at ...160 GeV/c and a 6LiD target. The amplitudes of the three azimuthal modulations cosϕh, cos2ϕh and sinϕh were obtained binning the data separately in each of the relevant kinematic variables x, z or pTh and binning in a three-dimensional grid of these three variables. The amplitudes of the cosϕh and cos2ϕh modulations show strong kinematic dependencies both for positive and negative hadrons.
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