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Morecambe and Lonsdale was a constituency of the British House of Commons which existed until 1983.

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Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study
Oscar Fernández ,
Roles Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Visualization, Writing – original draft, Writing – review & editing
* E-mail: oscar.fernandez.sspa@gmail.com
Affiliation Unidad de Gestión Clínica de Neurociencias Clínicas, Servicio de Neurología y Servicio de Neurofisiología, Hospital Regional Universitario, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Malaga, Malaga, Spain
Guillermo Izquierdo,
Roles Investigation, Writing – review & editing
Affiliation Servicio de Neurología, Hospital Universitario Virgen Macarena, University of Seville, Seville, Spain
Victoria Fernández,
Roles Data curation, Investigation, Writing – original draft, Writing – review & editing
Laura Leyva,
Roles Investigation, Methodology, Writing – review & editing
Virginia Reyes,
Miguel Guerrero,
Antonio León,
Carlos Arnaiz,
Guillermo Navarro,
Maria Dolores Páramo,
Antonio De la Cuesta,
Bernat Soria,
Roles Conceptualization, Investigation, Writing – review & editing
Affiliation CABIMER (Andalusian Molecular Biology and Regenerative Medicine Centre), Seville, Spain
Abdelkrim Hmadcha,
David Pozo,
Roles Investigation
Rafael Fernandez-Montesinos,
Maria Leal,
Itziar Ochotorena,
Patricia Gálvez,
Maria Angeles Geniz,
Francisco Javier Barón,
Roles Formal analysis
Affiliations Unidad de Gestión Clínica de Neurociencias Clínicas, Servicio de Neurología y Servicio de Neurofisiología, Hospital Regional Universitario, Instituto de Investigación Biomédica de Málaga (IBIMA), University of Malaga, Malaga, Spain, Public Health Department, University of Malaga, Malaga, SPAIN
Rosario Mata,
Roles Methodology, Project administration, Resources, Supervision, Writing – review & editing
Affiliation Andalusian Initiative for Advanced Therapies, Junta de Andalucía, Seville, Spain
Cristina Medina,
Roles Formal analysis, Writing – review & editing
Carlos Caparrós-Escudero,
Affiliation Servicio de Radiodiagnóstico, Hospital Universitario Virgen Macarena, University of Seville, Seville, Spain
Ana Cardesa,
Roles Methodology, Resources, Supervision, Writing – review & editing
Natividad Cuende,
[ ... ],
on behalf of the Research Group Study EudraCT 2008-004015-35
¶Complete membership of the Research Group Study EudraCT 2008-004015-35 can be found in the Acknowledgments.
[ view less ]
Oscar Fernández,
Maria Dolores Páramo
Oscar Fernández Guillermo Izquierdo ... on behalf of the Research Group Study EudraCT 2008-004015-35
Currently available treatments for secondary progressive multiple sclerosis(SPMS) have limited efficacy and/or safety concerns. Adipose-mesenchymal derived stem cells(AdMSCs) represent a promising option and can be readily obtained using minimally invasive procedures.
In this triple-blind, placebo-controlled study, cell samples were obtained from consenting patients by lipectomy and subsequently expanded. Patients were randomized to a single infusion of placebo, low-dose(1x106cells/kg) or high-dose(4x106cells/kg) autologous AdMSC product and followed for 12 months. Safety was monitored recording adverse events, laboratory parameters, vital signs and spirometry. Expanded disability status score (EDSS), magnetic-resonance-imaging, and other measures of possible treatment effects were also recorded.
Thirty-four patients underwent lipectomy for AdMSCs collection, were randomized and thirty were infused (11 placebo, 10 low-dose and 9 high-dose); 4 randomized patients were not infused because of karyotype abnormalities in the cell product. Only one serious adverse event was observed in the treatment arms (urinary infection, considered not related to study treatment). No other safety parameters showed changes. Measures of treatment effect showed an inconclusive trend of efficacy.
Infusion of autologous AdMSCs is safe and feasible in patients with SPMS. Larger studies and probably treatment at earlier phases would be needed to investigate the potential therapeutic benefit of this technique.
Citation: Fernández O, Izquierdo G, Fernández V, Leyva L, Reyes V, Guerrero M, et al. (2018) Adipose-derived mesenchymal stem cells (AdMSC) for the treatment of secondary-progressive multiple sclerosis: A triple blinded, placebo controlled, randomized phase I/II safety and feasibility study. PLoS ONE 13(5): e0195891. https://doi.org/10.1371/journal.pone.0195891
Editor: Tim Friede, University Medical Center Gottingen, GERMANY
Received: June 28, 2017; Accepted: March 26, 2018; Published: May 16, 2018
Copyright: © 2018 Fernández et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: This work was supported by Instituto de Salud Carlos III, Ministry of Health – Spain – Grant number: EC08/00224-ISCIII; Grants from ISCIII cofunded by Fondos FEDER, FIS PI14/01015; RD/oo19/0028 and RD16/0011/0034 to B Soria and PI16/00259 to A Hmadcha. The sponsor was the Andalusian Initiative for Advanced Therapies, supported by the Andalusian Health and Progress Foundation.
There are two main forms of multiple sclerosis (MS): relapsing remitting MS (RRMS), whose underlying pathophysiology is considered inflammatory, and secondary progressive MS (SPMS), which develops from RRMS [1] A primary progressive form (PPMS) also exists but is rarer 10–15% of cases of MS). In recent years, great progress has been made in the treatment of RRMS, with the availability of a range of new drugs that target the inflammatory component of the disease[2]. In the case of SPMS, whose pathological processes are thought to involve neurodegeneration,[3] little progress has been made and few treatments are authorized. Although interferon β is indicated for SPMS with disease activity (exacerbations or magnetic resonance imaging new, enlarging or enhancing lesions), the evidence for efficacy of this treatment is tenuous.[4] Mitoxantrone, in contrast, appears to have some impact on the disease [5] but has problems with long-term toxicity (cardiotoxicity and leukemia).[6] Ocrelizumab have recently been approved by the FDA for the treatment of PPMS [7]. PPMS is part of a spectrum of overlapping MS phenotypes with different pathogenesis. Thus, despite the highly debilitating nature of SPMS and the clear medical need, there is currently no truly effective treatment available.Recently, stem cells have demonstrated safety and a variable degree of efficacy in a diverse range of indications [8–17], but they are approved just for transplantation of blood stem cells to treat diseases and conditions of the blood and immune system, or to restore the blood system after treatments for specific cancers; skin stem cells to grow skin grafts for patients with severe burns on very large areas of the body and limbal stem-cell-based treatment to repair damage to the cornea. As of now, no treatments using mesenchymal stem cells have been licensed. There are, however, some clinical trials investigating the safety and effectiveness of MSC treatments for repairing bone or cartilage. Other trials are investigating whether mesenchymal stem cells might help repair blood vessel damage linked to heart attacks or diseases such as critical limb, help treat transplant rejection or autoimmune diseases are still under thorough investigation. In the case of MS, paracrine effects on central nervous system and the potential for increased endogenous axonal and myelin repair processes may be of benefit.[18,19] Encouraged by endogenous CNS repair demonstrated by stem cells in animal models of MS,[20] investigators aimed to test the effects of stem cells in humans [21] and a number of studies with intrathecal and/or intravenous administration of bone-marrow derived mesenchymal stem cells (BM-MSCs) in patients with MS have been reported.[22–25] Of particular note was an exploratory not blinded study of patients with SPMS involving visual pathways, in which the treatment was found to be safe and evidence was reported of structural, functional, and physiological improvement in visual endpoints. Particularly, the use of visual evoked potentials as an outcome measure proved to be of a great usefulness detecting subtle improvements, as the treatment demonstrated a decreased visual evoked response latency (-1·33 ms, 95%CI-2·44 to -0·21; p = 0·020).[26] Other studies have investigated both intravenous and intrathecal administration of BM-MSCs in patients with either MS or amyotrophic lateral sclerosis (ALS) [27], and RRMS patients,[28] showing that the procedures are safe and some evidence of immunomodulatory effects.
Adipose-derived stem cells (AdMSCs) are another source of MSC, [29] with the advantage that the samples for stem cell production can be taken with a minimally invasive lipectomy procedure. With the exception of a report of 3 patients treated with stromal vascular fraction (cells from unexpanded adipose samples) [30], and another two small studies [31,32] the potential of adipose tissue as a source of stem cells has not been explored. The aim of the present study was to assess the safety and feasibility of two different doses of AdMSCs administered by intravenous infusion in patients with SPMS.
Design and patients
In this two-center (Hospital Regional Universitario de Málaga and Hospital Virgen Macarena in Seville), phase I/II, placebo-controlled study, we randomized patients 1:1:1 to an intravenous infusion of placebo or one of two dose-groups (1x106 cells/kg or 4x106 cells/kg). The study was triple blinded; treating physician, patient and statisticians were unaware of treatment assignment. The laboratory staff producing the AdMSC drug product or placebo had no direct contact with the clinical staff. Randomization was performed at CABIMER with a random allocation sequence using sequentially numbered containers stratified by treatment center.
To be eligible for the study, adult patients of either sex had to have a diagnosis of SPMS, with an Expanded Disability Status Score (EDSS) between 5.5 and 9 and have failed previous therapies and have activity or progression of the disease (relapse in the previous year or progression of at least 0.5 points on the EDSS despite therapy). Patients were excluded if they had experienced a relapse or had received steroid treatment in the month prior to inclusion. Patients positive for HIV, hepatitis B, or hepatitis C, history of malignant neoplasms, participation in an interventional trial in the previous 3 months, contraindications for magnetic resonance imaging (MRI), history of liver, kidney, cardiac, or psychiatric disease that may have impacted the study procedures were also excluded. Finally, it had to be possible to collect 30 g of adipose tissue for the AdMSC preparation.
After infusion at the baseline visit, patients entered 1 year follow-up (with visits scheduled at 30 days, 6 months and 12 months after the baseline visit). Prior to any study procedures, full informed consent was obtained in writing from all participants. The study was approved by the corresponding ethics committee (Comité Coordinador de Ética de la Investigación Biomédica de Andalucía) and registered with the clinicaltrials.gov clinical registry (ID, NCT01056471) prior to initiation. The sponsor was the Andalusian Initiative for Advanced Therapies, supported by the Andalusian Health and Progress Foundation.
AdMSC preparation.
Abdominal subcutaneous adipose tissue from MS patients was obtained by lipectomy at the participating centers. The fresh adipose tissue was transported to the Good Manufacturing Practice (GMP) facility (Centro Andaluz de Biología Molecular y Medicina Regenerativa [CABIMER], Seville, Spain) at 2–20°C within 12 hours of collection.
Adipose tissue was washed at least three times with phosphate buffered saline (PBS) supplemented with a Penicillin-streptomycin mixture (Sigma-Aldrich, St Louis,MO,USA). The adipose tissue was minced and was enzymatically digested with an equal volume of 0.2% collagenase type I (Sigma-Aldrich) solution for 1 hour at 37°C with shaking. Cells were then separated by centrifugation at 600×g for 10 min after addition of 10% fetal bovine serum (FBS,SAFCBiosciences,Lenexa,Kansas,USA). The semisolid phase and the pellets were passed through a 100 μm cell-strainer to remove debris and cell clumps. Subsequently, the stromal vascular fraction (SVF) cells underwent a second centrifugation, and the isolated cells were re-suspended in a culture medium (Dulbecco's modified Eagle's medium[DMEM,Sigma-Aldrich]) supplemented with 10%FBS and 2%L-alanyl-L-glutamine (Sigma-Aldrich) for cell count and assessment of viability.
After adjusting the cell seeding concentration, cells were plated into polystyrene cell culture flasks and incubated at 37°C in humidified 5%CO2 atmosphere. After 24–72 hours of incubation, the medium was changed and non-adherent cells were removed. For AdMSC cultures, a complete change of medium every 2–3 days until reaching ≥ 80% confluence was applied. The AdMSCs were then washed with PBS and treated with 0.05% trypsin-ethylenediaminetetraacetic acid(EDTA)(Invitrogen) for 15 minutes to detach them from the surface of the culture flask and harvested with culture medium. The resulting suspension was re-plated in new cell culture flasks. AdMSC expansion proceeded this way until reaching the dose level to which the patient had been assigned (1x106cells/kg or 4x106cells/kg).
The cells were then harvested with basal medium after the treatment with trypsin-EDTA, centrifuged and counted in a Neubauer chamber. After counting, the AdMSCs were washed and resuspended in Ringer's lactate supplemented with human serum albumin and glucose at the appropriate concentration, and then packaged in 50 mL-syringes with female luer-lock caps.
The finished product was released after meeting the following quality controls: immunophenotype (>90% positivity for CD90,CD73,CD105,CD13 and CD29, and <10%positivity for CD14/CD20/CD34/CD45/CD31 and HLA class II), negativity for mycoplasms, negativity for endotoxins, and no numeric or structural karyotype abnormalities. Results from the sterility test were obtained prior to infusion and 14 days after the release of the finished product. The placebo product consisted of Ringer's lactate packaged in identical opaque 50 mL-syringes.
Administration.
The AdMSCs were administered intravenously through a peripheral venous catheter over 2 hours, using an infusion pump, mounted on a laboratory shaker to avoid aggregation of the cells in the syringe. The speed of the infusion, number of cells infused per minute, was calculated to be similar to the habitual rate of transfusion of red cells. During all the procedures the blinding was assured by the appropriate measures (dark, opaque syringes and tubes were used). After infusion, patients remained in the clinic for 24 hours to monitor for possible adverse events (AEs).
Exhaustive data about the adequate dosing of AdMSCs intravenously administered in human treatment is lacking, so taking into account the existing literature [8–32], we estimated that the ideal number of cells to administer intravenously to our MS patients would be between 107–1010.
Neurological assessments were performed by experienced neurologists at the participating centers. Safety was assessed primarily by monitoring for AEs and standard laboratory measures. Vital signs and spirometric parameters were also monitored. Possible treatment effects were assessed by changes in baseline, 6 and 12 months after infusion: clinical variables (number of exacerbations, EDSS), immunologic assessments, analysis of cerebrospinal fluid (CSF), MRI (T2-weighted lesions, T1 lesions, T1 gadolinium-enhanced lesions, volume, and magnetization transfer ratio-MTR), evoked potentials (EP) (visual-VEP, acoustic-BAEP, somatosensory-SEP and motor-MEP), optical coherence tomography (OCT) of the retina (retinal nerve fiber layer- RNFL), cognition measured with Paced Auditory Serial Addition Test (PASAT) and quality-of-life by questionnaire SF-36, EuroqoL-5D and MusiQoL.
Given that this was an exploratory study and that previous efficacy and safety studies with AdMSCs were lacking, no formal sample size calculations were performed. In order to provide an indication of safety and dose-effect and to support future larger efficacy studies, 30 evaluable patients were considered sufficient.
For the purposes of this study, the safety analysis population was defined as all patients who underwent a lipectomy procedure. The intention-to-treat population comprised all patients who were randomized and received an infusion and the per protocol population comprised patients which accomplished the inclusion criteria with at least 1 post baseline visit.
Descriptive statistics were calculated for all outcome measures (means and standard deviations, standard errors, medians and interquartile ranges, or numbers and percentages, as appropriate). Baseline clinical and paraclinical data were compared to 12 months after treatment data using Student´s t test. The treatment effect of the two doses of treatment vs placebo was analyzed by non-parametric tests (Kruskal-Wallis test) and ANOVA of repeated measures for the clinical and paraclinical test performed at baseline, and 12 months.
Study patients
The patient disposition is shown in Fig 1. 34 patients were randomized following lipectomy. Four randomized patients (3 assigned to the high dose group and 1 to the low dose group) were not infused because of karyotype anomalies in the cell product. There were no clinical differences of this group of 4 patients (age, EDSS or disease duration) when compared with the final infused group (data not shown). Thus 30 patients were infused and constitute the intention-to-treat population (ITT, Table 1). Of these 30 patients, 29 had at least 1 post-baseline assessment and were considered the per-protocol population. One patient had choking and bronchial aspiration while being fed 2 days after the infusion and died subsequently. All 29 patients in the per-protocol population completed 12 months follow-up. Analysis reported in this paper have been performed on all patients having had a procedure of lipectomy for tolerability and safety, according to predefined statistical analysis (Table 2) and on the ITT population for the efficacy variables.
Fig 1. Patient disposition.
Low dose = 1x106 AdMSCs/Kg; High dose = 4 x 106 AdMSCs/Kg.
Table 1. Baseline disease characteristics.
Table 2. Adverse events during the trial.
The patients baseline characteristics are summarized in Table 1. 70% were women and ages ranged from 31 to 61 years. The disease duration ranged from 8 to 38 years. Most patients (25/30 [83%]) had monofocal symptoms at presentation and the baseline EDSS ranged from 6.0 to 9.0. Only 2 patients (7%) had experienced more than 1 relapse in the 2 years prior to enrolment. The mean number of Gd-enhanced T1 lesions was higher in the high-dose group (2.0±2.88 SD3.56±5.39) compared to the other groups, although this difference was driven by an outlier patient with 16 lesions (compared to maxima of 5 and 3 in the placebo and low-dose groups). Otherwise, the number of T2 lesions was not statistically different between groups.
Two patients in the placebo group, died during the study: one patient had choking and bronchial aspiration while being fed 2 days after the infusion and one patient had a respiratory infection nine months after infusion. They were women of 31 and 43 years old, with an EDSS at the beginning of the clinical trial of 9 and 8,5 and with 13 years of evolution of the disease in both cases.
A total of 70 AEs were reported during the trial period in 22 patients (67%). The most frequently reported individual AEs were urinary infection, respiratory infection and anemia (Table 2). Four serious AEs were reported (2 of these resulted in death, as described above). None of these serious AEs were considered related to treatment by the investigators and only 1 (urinary infection in a patient who already had a urinary infection on inclusion) occurred in an active treatment group (high-dose group).
No significant changes from baseline were observed for mean vital signs, spirometry or laboratory values, except for a significant decrease in cholesterol and creatinine in the low-dose group and a decrease in lymphocytes counts in the high-dose group, although the mean values remained within normal reference ranges.
Treatment effects
Outcomes in treatment effects variables after 12 months of treatment are shown in Table 3. No variable showed statistically significant differences in repetitive measures neither by ANOVA (pFisher—p.F) nor by Kruskal-Wallis (p.KW) tests.
Table 3. Changes in treatment effects variables after 12 months of treatment.
The mean EDSS score did not show statistically significant variations over the course of the study (baseline EDSS for placebo, low-dose and high-dose groups were 7.64±0.314, 7.50±0.24, and 7.78±0.16 SE at baseline, compared to 7.55±0.35, 7.75±0.24, and 8.06±0.41 SE at 12 months p.F = 0,57; p.kW = 0,20). Individual EDSS changes were not significant as well. (See Supplementary Files S2 File—EDSS individual changes and S9 File—Changes in treatment effects variables after 12 months of treatment-complete data)
Baseline MRI data of the three groups were similar, with no significant differences. Non statistically significant post-baseline changes were observed in low and high dose group for number of active lesions in the Gd-enhanced T1 scans (although, as mentioned above, at baseline, an outlier patient in the high dose group had 16 active lesions). A decrease in MRI non normalized cerebral volume in low dose group and in MTR was observed, being significant in paired t-test between baseline and the 12 months outcome, although there were no differences between the three groups when compared between them (MRI non normalized cerebral volume: p.F = 0,23; p.kW = 0,28; MTR: p.F = 0,60; p.kW = 0,50).
Evoked potentials showed no significant baseline difference between groups. We found some non-statistically significant differences between the placebo and treatment groups for the evoked potentials parameters after 12 months of treatment. Tibial SEP central conduction time (N22-P39) and the MEP central conduction time for the legs, demonstrated statistically significant diminishing latencies over time in placebo and the two treatment groups, but these differences were not statistically significant comparing placebo and both treatment groups. Visual evoked potential-VEP and median nerve SEP (N13-N20) also showed a trend of stabilization or amelioration of latencies over time in treatment groups, although these differences didn´t reach statistically significance over the time, as well as between groups;(p.F = 0,59; p.kW = 0,89).
No significant changes from baseline were observed for the analysis of cerebral spinal fluid, OCT measurements, cognition or quality of life questionnaires.
The immunological parameters of this study will be published separately.
In this phase I/II proof-of-concept trial, intravenous infusion of AdMSCs was safe over the 12-month follow-up period. The pattern of AEs reported was one that would be expected from the underlying disease. No related serious AEs occurred and laboratory tests, vital signs, and spirometry did not identify any safety issues.
The safety findings from this study are in line with previous reports of stem cells in patients with SPMS, although these studies were performed with BM-MSC.[22–28] In the study reported by Connick et al,[26] 10 patients were intravenously infused with BM-MSCs, with the only AEs of note being 2 cases of infections and 2 skin reactions over up to 10.2 months of follow-up. In another study, Karussis et al [27] treated 15 patients with MS and 19 with ALS either intrathecally (34 patients) or intravenously (14 patients), the overall safety profile was good, with no major events reported during up to 25 months of follow-up, except for a case of meningeal irritation and aseptic meningitis in 1 patient. In the randomized, double-blind, placebo-controlled, crossover phase II clinical trial by Llufriu [28]28, 9 RRMS patients were treated and no serious adverse events were identified after 12 months of follow-up.
The most frequently reported individual AEs in this clinical trial were urinary infections, respiratory infections and anemia. None of these serious AEs were considered related to treatment by the investigators and only 1 (urinary infection in a patient who already had a urinary infection on inclusion) occurred in an active treatment group (high-dose group). Two patients in the placebo group, died during the study: one patient had choking and bronchial aspiration while being fed 2 days after the infusion and one patient had a respiratory infection nine months after infusion. Transplantation of stem cells can increase the risk of neoplasms. [33] No neoplasms were reported during our study after one year postinfusion. Animal studies with AdMSCs and MSC in humans have not detected any oncogenic potential.[34–36]
Evidence for a treatment effect was detected in the aforementioned studies with BM-MSCs. Connick et al,[26] reported evidence of structural, functional and physiological improvement after treatment in some visual endpoints. Karussis et al,[27]reported almost immediate immunomodulatory effects and a significant reduction in EDSS score in MS patients (from mean±SD 6.7± 1.0 before the intervention to 5.9±1.6 after the intervention). Llufriu [28], showed a trend but not significant treatment differences in the secondary efficacy endpoints.
Although data on possible markers of treatment effects were collected, our study with AdMSCs was not powered to demonstrate such effects and, unsurprisingly, no clear effects were detected. In the MRI studies, non statistically significant post-baseline changes were observed in the low and high dose group for number of active lesions in the Gd-enhanced T1. EP measures showed a statistically significant trend of efficacy by the reduction of latencies of somatosensory central conduction time for the arms, and some of the measured EP parameters: VEP latency, the tibial SEP central conduction time for the legs (N22-P39) and the MEP central conduction time for the arms and legs, demonstrated diminishing latencies over time, but these differences were not statistically significant with placebo. In clinical trials involving patients in advanced phases of MS, when the neurodegenerative phase of the disease is more prominent, dramatic effects are not to be expected, and there are no gold standard measures of neurodegeneration, we should look for measures that are able to detect even minimal but objective positive changes like evoked potentials have shown in other clinical trials [25] and in this clinical trial.
We have to note that the baseline mean EDSS score of our patients was greater than 7.5 whereas the patients included in the study by Connick et al [26,37] had a mean baseline EDSS of 6.1, implying that the patients in our study had more severe disease and that the baseline MRI, evoked potentials and OCT measures showed very much affected baseline parameters (very high number of baseline lesions in MRI, not recordable or very slow EP and very thin RNFL measured with OCT). This "ceiling effect" due to a severe disease is a well know bias in comparing this type of measures. when variance in an independent variable is not well measured or estimated above a certain level, and it impairs the ability of investigators to determine the central tendency of the data and differences between groups. We are afraid that this is the case of our possible markers of treatment.
Although several reports have used BM-MSCs,[22–26] very few studies have used expanded AdMSCs in patients with MS [31,32]. In view of the lack of robust data on treatment effects, we are unable to make affirmations about the relative merits of AdMSCs versus BM-MSCs. In principle, both are pluripotent stem cells that are able to undergo neural differentiation,[38] but their immunologic phenotypes do differ,[39] so their immunomodulatory properties may also vary.
Possible mechanisms of action of MSCs in SPMS include neuroprotection through paracrine modifications of the CNS microenvironment and increased endogenous axonal and myelin repair.[19,40]
From a procedural point of view, AdMSCs offer the potential advantage that the lipectomy or liposuction procedures, which we know now can be used alternatively, to obtain the cell sample are less invasive than bone marrow aspiration [29], and offer an alternative for the obtainment of the MSCs.
In conclusion, the present study demonstrates that infusion of AdMSCs is a safe and feasible procedure in patients with SPMS. Although the study was not powered to determine theefficacy, some hint of efficacy was observed by the use of MRI and evoked potentials. Larger studies would be needed to investigate the potential therapeutic benefit of the technique.
S1 File. Individual data file.
(RAR)
S2 File. Individual EDSS changes.
S3 File. Complete clinical trial protocol.
S4 File. Complete clinical trial protocol translation.
S5 File. Clinicaltrial gov full description.
S6 File. Clinical trial gov summary.
S7 File. Eudra protocol summary.
S8 File. CONSORT checklist.
S9 File. Changes in treatment effects variables after 12 months of treatment-complete data.
To Greg Morley, MD (Docuservicio) for technical assistance in the writing of this article.
Research Group Study EudraCT 2008-004015-35:
Hospital Regional Universitario de Málaga–University of Málaga
O. Fernández, MD, PhD, M. Bravo, MD, J.A. Tamayo, MD, F. Romero, MD, PhD, T. Ojea, MD, A. León, MD, R. Bustamante, MD, A. Alonso, MD, J.C. López, MD, M. Guerrero, MD, M. Papais Alvarenga MD, PhD, V. Reyes MD, P. Urbaneja MD; T. Muñoz MD; MD, B. Asenjo, MD; V. Fernández, MD, PhD; A.L. Muñoz, BSc, Mª M. González, BSc, J.C. Arrabal, BSc; L. Leyva, MD, PhD, G. Estivil, BS, PhD, M. Suardíaz, BS PhD, B. Oliver, BSc, MªJ. Pinto-Medel, BSc. T. Orpez, BSc, C. López, BSc, J.A. García, BSc, C. Marin, BSc, B. García, BSc, I. Nevado BSc., A. Gosis BSc; J. Valenzuela MD.; J. de la Cruz MD; J. J. Bonilla MD; M.L. Vergara, RN, J. Cordero, RN, L, Rubio, RN; J. Barón MD, PhD, E. de Ramón, MD, PhD, C Medina MD; F. Díez de Baldeón, MD, PhD, G. Luque, MD, C. Arnaiz, MD.
Hospital Universitario Virgen Macarena–University of Seville
G. Izquierdo MD, PhD; G. Navarro MD; M.D. Páramo MD; A de la Cuesta MD; J.L Ruiz MD; J.M García MD; M.A Gamero MD; L. Dinca, MD; S. Eichau MD; T. Montemayor MD; I Montero MD; M García MPsch; C Caparrós-Escudero MD; M.J. Rodríguez; M.D. Alfonso; S. Perez MD; D. Morales MD; N. Becerril RN; J.A. García RN; E Arellano RN; M Rus RN; A. Varas; Y Montserrat; M.A Geniz; M.A Quesada; C. Páramo.
CABIMER (Andalusian Molecular Biology and Regenerative Medicine Centre)
B. Soria MD, PhD; A. Hamdcha D. Pozo, MSc, PhD; R. Fernández-Montesinos MSc, PhD; M. Leal, MSc, I. Ochotorena MSc, MBA; P. Gálvez.
Andalusian Initiative for Advanced Therapies, Junta de Andalucía, Seville, Spain
N Cuende MD, PhD;; R Mata R MD, PhD; C Medina, MPharm; A Cardesa BChem, MBA.
1. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8:647–656. pmid:23007702
2. Sorensen PS. New management algorithms in multiple sclerosis. Curr Opin Neurol. 2014;27:246–259. pmid:24759080
3. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372:1502–1517. pmid:18970977
4. Mantia LL, Vacchi L, Rovaris M, Di Pietrantonj C, Ebers G, Fredrickson S et al. Interferon β for secondary progressive multiple sclerosis: a systematic review. J Neurol Neurosurg Psychiatry. 2013;84:420–426. pmid:22952326
5. Hartung H-P, Gonsette R, König N, Kwiecinski H, Guseo A, Morrissey SP, et al. Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002;360:2018–2025. pmid:12504397
6. Cohen BA, Mikol DD. Mitoxantrone treatment of multiple sclerosis: safety considerations. Neurology. 2004;63(12 Suppl 6):S28–S32.
7. Montalban X, Hauser SL, Kappos L, Arnold D,Bar-Or A, Comi G, et al. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017;376:209–220. pmid:28002688
8. Segers VFM, Lee RT. Stem-cell therapy for cardiac disease. Nature. 2008;451:937–942. pmid:18288183
9. Politis M, Lindvall O. Clinical application of stem cell therapy in Parkinson's disease. BMC Med. 2012;10:1. pmid:22216957
10. Glat MJ, Offen D. Cell and gene therapy in Alzheimer's disease. Stem Cells Dev. 2013;22:1490–1496. pmid:23320452
11. de la Portilla F, Alba F, García-Olmo D, Herrerías JM, González FX, Galindo A. Expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of complex perianal fistula in Crohn's disease: results from a multicenter phase I/IIa clinical trial. Int J Colorectal Dis. 2013;28:313–323. pmid:23053677
12. Panés J, García-Olmo D, Van Assche G, Colombel JF, Reinisch W, Baumgart DC et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn's disease: a phase 3 randomised, double blind controlled trial. Lancet. 2016;388:1281–90 pmid:27477896
13. Fisher SA, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2016;12:CD007888 pmid:28012165
14. Chen X, Wang C, Yin J, Xu J, Wei J, Zhang Y. Efficacy of Mesenchymal Stem Cell Therapy for Steroid-Refractory Acute Graft-Versus-Host Disease following Allogeneic Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis. PLoS One. 2015;10:e0136991 pmid:26323092
15. Jiang X, Zhang H, Teng M. Effectiveness of Autologous Stem Cell Therapy for the Treatment of Lower Extremity Ulcers: A Systematic Review and Meta-Analysis. Medicine (Baltimore). 2016;95:e2716.
16. Xu S, Liu H, Xie Y, Sang L, Liu J, Chen B. Effect of mesenchymal stromal cells for articular cartilage degeneration treatment: a meta-analysis. Cytotherapy. 2015;17:1342–52. pmid:26122717
17. El-Badawy A, El-Badri N. Clinical Efficacy of Stem Cell Therapy for Diabetes Mellitus: A Meta-Analysis. PLoS One. 2016;11:e0151938 pmid:27073927
18. Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008;8:726–736. pmid:19172693
19. Payne N, Siatskas C, Barnard A, Bernard CCA. The prospect of stem cells as multi-faceted purveyors of immune modulation, repair and regeneration in multiple sclerosis. Curr Stem Cell Res Ther. 2011;6:50–62. pmid:20955155
20. Bai L, Lennon DP, Eaton V, Maier K, Caplan AI, Miller SD et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia. 2009;57:1192–1203. pmid:19191336
21. Slavin S, Kurkalli BGS, Karussis D. The potential use of adult stem cells for the treatment of multiple sclerosis and other neurodegenerative disorders. Clin Neurol Neurosurg. 2008;110:943–946. pmid:18325660
22. Mohyeddin Bonab M, Yazdanbakhsh S, Lotfi J, Alimoghaddom K, Talebian F, Hooshmand F et al. Does mesenchymal stem cell therapy help multiple sclerosis patients? Report of a pilot study. Iran J Immunol IJI. 2007;4:50–57.
23. Odinak MM, Bisaga GN, Novitskiĭ AV, Tyrenko VV, Fominykh MS, Bilibina AA et al. [Transplantation of mesenchymal stem cells in multiple sclerosis]. Zh Nevrol Psikhiatr Im S S Korsakova. 2011;111:72–6.
24. Yamout B, Hourani R, Salti H, Barada W, El-Hajj T, Al-Kutoubi A, et al. Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol. 2010;227:185–189. pmid:20728948
25. Bonab MM, Sahraian MA, Aghsaie A, Karvigh SA, Hosseinian SM, Nikbin B et al. Autologous mesenchymal stem cell therapy in progressive multiple sclerosis: an open label study. Curr Stem Cell Res Ther. 2012;7:407–414. pmid:23061813
26. Connick P, Kolappan M, Crawley C, Webber DJ, Patani R, Michell AW et al. Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol. 2012;11:150–156. pmid:22236384
27. Karussis D, Karageorgiou C, Vaknin-Dembinsky A, Gowda-Kurkalli B, Gomori JM, Kassis I, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67:1187–1194 pmid:20937945
28. Llufriu S, Sepúlveda M, Blanco Y, Marín P, Moreno B, Berenguer J, et al. A randomized placebo-controlled phase II trial of autologous mesenchymal stem cells in multiple sclerosis.PLoS One. 2014; 9:e113936 pmid:25436769
29. Gimble JM, Katz AJ, Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res. 2007;100:1249–1260. pmid:17495232
30. Riordan NH, Ichim TE, Min W-P, Wang H, Solano F, Lara F et al. Non-expanded adipose stromal vascular fraction cell therapy for multiple sclerosis. J Transl Med. 2009;7:29.24. pmid:19393041
31. Ra JC, Kang SK, Shin IS, Park HG, Joo SA, Kim JG et al. Stem cell treatment for patients with autoimmune disease by systemic infusion of culture-expanded autologous adipose tissue derived mesenchymal stem cells. J Transl Med. 2011 Oct 21;9:181 Ra 2011
32. Stepien A, Dabrowska NL, Maciagowska M, Macoch RP, Zolocinska A, Mazur S et al. Clinical Application of Autologous Adipose Stem Cells in Patients with Multiple Sclerosis: Preliminary Results. Mediators Inflamm. 2016;2016:5302120 pmid:27761060
33. Knoepfler PS. Deconstructing stem cell tumorigenicity: a roadmap to safe regenerative medicine. Stem Cells Dayt Ohio. 2009;27:1050–1056.
34. Vilalta M, Dégano IR, Bagó J, Gould D, Santos M, García-Arranz M et al. Biodistribution, long-term survival, and safety of human adipose tissue-derived mesenchymal stem cells transplanted in nude mice by high sensitivity non-invasive bioluminescence imaging. Stem Cells Dev. 2008;17:993–1003. pmid:18537463
35. Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY et al. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011;20(8):1297–1308. pmid:21303266
36. Lee JS, Hong JM, Moon GJ, Lee PH, Ahn YH, Bang OY et al. A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells Dayt Ohio. 2010;28:1099–1106.
37. Freedman MS, Uccelli A. Neurorepair with mesenchymal stem cells: hope or hype? Lancet Neurol. 2012;11:123–125. pmid:22236383
38. Erba P, Terenghi G, Kingham PJ. Neural differentiation and therapeutic potential of adipose tissue derived stem cells. Curr Stem Cell Res Ther. 2010;5:153–160. pmid:19941451
39. Al-Nbaheen M, Vishnubalaji R, Ali D, Bouslimi A, Al-Jassir F, Megges M et al. Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. Stem Cell Rev. 2013;9:32–43. pmid:22529014
40. Uccelli A, Laroni A, Freedman MS. Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol. 2011;10:649–656. pmid:21683930
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redpajama_set_name: RedPajamaCommonCrawl


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Event Tickets » Flushing, NY
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Al Kadhi, Omar (2017) EXPLORING THE ROLE OF SULFORAPHANE IN PROSTATE METABOLISM. Doctoral thesis, University of East Anglia.
Prostate cancer is a worldwide health problem with a higher incidence in older men. Prostate cancer risk is lower in Asian countries compared to the west, this has largely been attributed to difference in diets between the two populations. To date evidence from casecontrol studies has indicated that cruciferous vegetables and regular exercise reduce the risk of prostate cancer progression; however, other similar studies have shown no association. These contrasting results may be due to study heterogeneity and the long latent period of prostate cancer.
The aim of the work presented in this thesis is to further understand the role of sulforaphane, an isothiocyanate derived from broccoli plants in preventing prostate cancer by exploring its effect on the metabolic microenvironment of the prostate. One of the key metabolic pathways that is altered in prostate cancer is the Krebs� cycle. Citrate, a product of the Krebs� cycle accumulates in healthy prostate tissue and is reduced in prostate cancer. It was demonstrated by using a novel liquid chromatography and tandem mass spectrometry method that the levels of citrate within in vitro models of prostate cancer are markedly different to those of human tissue. Furthermore, citrate levels altered when prostate cells were exposed to reactive oxygen species. The addition of physiological quantities of sulforaphane to prostate cells in culture inhibited the reactive oxygen speciesmediated changes on the Krebs� cycle.
A randomised, double-blinded human intervention study was undertaken to further understand the role of sulforaphane in prostate cancer by recruiting men with early prostate cancer into three different study arms delivering sulforaphane in increasing concentrations through naturally bred broccoli varieties. A subgroup analysis demonstrated significant metabolite changes in prostate tissue that were driven by the study diet with accumulation of sulfate common to all three arms. This was positively correlated with lower rates of cancer at 12 months.
The work presented here strengthens the argument that sulforaphane in physiologically achievable concentrations can alter the metabolic environment of the prostate and that this may contribute to the cancer preventing properties of cruciferous vegetables.


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Images of women vandalized as Kabul faces Taliban rule
A Taliban fighter walks past a beauty parlor with images of damaged women
Kabul, Afghanistan:
Statues of women have been covered or vandalized on shop windows around Kabul, a sign of the rapidly changing face of the Afghan capital in the days since the Taliban took charge.
The new regime's terrorists took control of the city on Sunday after a lightning strike that toppled the former government's provincial strongholds across the country like dominoes within days.
The advance was only surpassed by fears sweeping through areas yet to fall under their control from Afghans fearing a repeat of the notoriously harsh treatment of women during the last period of the Taliban rule.
In the two decades since the US-led invasion that ousted that government in 2001, hundreds of once-banned beauty salons have spread across Kabul.
They have traded in makeup and manicure, serving a clientele of women who had grown up forced to hide every inch of their bodies from the public.
But as Taliban forces approached the capital, at least one of these stores began whitewashing its exterior walls to obscure advertisements depicting the faces of smiling women in bridal regalia.
Another shuttered parlor, seen Tuesday when a Taliban fighter patrolled the street outside with an assault rifle slung over his shoulder, had its walls daubed with black spray paint to hide the faces of its models.
'They don't want women to work'
During their 1996-2001 rule, the Taliban were notorious for expelling girls from school, preventing women from coming into contact with men, and stoning women accused of adultery in public.
The ultra-strict interpretation of Sharia law also established a religious police force for the suppression of "vices".
Since returning to power, the group has pledged to respect women's rights.
A spokesperson for the group in Qatar told Britain's Sky News that women would not be required to wear the full-coverage burqa, although he did not say what clothing would be acceptable.
Suhail Shaheen also said the group would allow women to study in universities.
Another representative said the Taliban is "committed to making women work in accordance with the principles of Islam," without giving details.
But Afghans and the international community were skeptical of these promises.
The Taliban's advance was accompanied by reports of unmarried women and widows being forcibly married to terrorists – reports dismissed as "toxic propaganda" by a spokesman.
Demonstrations have been held in cities around the world in support of Afghan civilians, especially women and girls.
The United States, the European Union and other countries have said in a joint statement that they are "deeply concerned about Afghan women and girls" and have urged the new regime to ensure their safety.
A beauty salon owner in Kabul told AFP last month that she expected to be forced to close her business if the Taliban returned to power.
"If they come back, we will never have the freedom we have now," said Farida, 27, who asked not to be further identified.
"They don't want women to work."
(This story was not edited by NewsMadura staff and was generated automatically from a syndicated feed.)
Tags: facesimagesKabulNewsMaduraRuleTalibanvandalizedwomen
Nuvoco Vistas IPO: Here's How To Check Stock Allocation Status
"Taliban came to Gurdwara, assured Sikhs, Hindus of safety": Akali leader


Add, subtract multiply or divide feet and inches fractions.
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Handles operations for feet whole numbers and inches in mixed numbers for adding, subtracting, dividing or multiplying whole numbers, fractions or mixed numbers and returns an answer in a reduced fraction and a mixed number, if it exists.
Enter feet in whole numbers.
Mixed numbers as 1 1/2 which is one and one half or 25 3/32 which is twenty five and three thirty-secondths. Keep exactly one space between the whole number and the fraction.
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Furey, Edward "Feet and Inches Calculator"; from https://www.calculatorsoup.com - Online Calculator Resource.


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Kokoi and Yemo had received their orders from the council elders, and now had to plan for the journey a head.
Their instructions were simple enough. Journey to villages over a considerable distance from the city and report back on the well-being of the council's subjects in each village.
Yemo and Kokoi began their trek the following day at dawn. The council required them to take the shortest journey through the surrounding forests. This would lead them to the few sparsely populated villages on the other side. The first village they encountered had only the remnants of a civilisation which had long gone and had probably migrated to the bigger towns and cities. However the second village some miles further was different. It was barren but their tracking skills revealed someone was still living there.
As the pair emerged from a forest edge, they made their way over towards the huts in the middle of a clearing. At first they could see no one, but it didn't take long before shadows began appearing with-in the huts. Kokoi moved closer to Yemo who was the eldest and the most experienced of the two, and Yemo encouraged her to stick real close.
Yemo began to speak loudly and requested that the leader of village show themselves, so she may memorise and bring word to the council. Some of the dark shadows retreated back into the huts whilst others began to approach.
Both rangers looked at each other when they saw the leader, who approached in a crouched manner as if unable to use her legs to stand upright. The leader was a female-Nyem and she turned her head nervously, as if to check behind her as she squatted away from her hut into the open space before them. Yemo, observed the leader as she approached and noticed the scars on her body.
The leaders tone of voice sinisterly changed and as she continued her story the Tribal Rangers sensed something was dreadfully wrong. Shadows were stalking in the nearby forest. As if synchronised by telepathy they both turned to meet their attackers charging towards them, it was a trap, and fell for for it.


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Brexit – What Now?
Following the consistent support from the construction sector to remain in the EU, the referendum result was a surprise to many. This has been followed by substantial concerns over the effect on client confidence, the project pipeline, the flow of…
More Industry Card Schemes Meet CLC Requirements
Following the publication of the Build UK Training Standard which implements the Construction Leadership Council's recommendation on industry card schemes, Build UK Trade Association Members continue to work with industry to bring their cards schemes in line with CSCS requirements.…
CIJC Confirms Increased Pay Rates
Construction employers and unions have reached agreement on an improved two year pay and conditions deal for workers covered by the Construction Industry Joint Council (CIJC) Working Rule Agreement. The first 2.5% increase on basic rates of pay will be…
Record Numbers Get Inspired By Open Doors 2016
Open Doors proved a fantastic success with 130 Build UK member sites opening their gates to over 3000 visitors to inspire them to find out more about construction and the extensive range of careers that the industry has to offer.…
Build UK Surveys Members on the State of the Industry
Build UK has launched its first State of Trade Survey to obtain a detailed picture of the state of trade within the construction industry. The new survey has been created in partnership with Glenigan, the trusted provider of UK construction…


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"Wire" Actress Arrested in Drug Raid
"The Wire's" Snoop gets busted on drug charges.
By Michael Preston	• Published at 2:14 am on March 11, 2011
In a sad case of life imitating art, a former convict turned notable actress was arrested in a massive drug raid this week.
Felicia "Snoop" Pearson, who played a hit man for a drug dealer on HBO's critically acclaimed crime saga "The Wire," was one of sixty people swept up by police in Baltimore on heroin-related and aiding and abetting charges, reports the Los Angeles Times.
Pearson, who is not a trained thespian, won acclaim for her work as an emotionless enforcer on the streets of Charm City.
"She's a real coldhearted person," she said in a 2007 interview. "I love playing her."
Earlier in her life, she had repeated run ins with the law for dealing drugs and was eventually landed in prison for killing another woman in self-defense.
The show's creator, former Baltimore Sun reporter and media critic David Simon, released a statement about his former star's predicament.
"First of all, Felicia's entitled to the presumption of innocence," he wrote in a posting on Slate. "And I would note that a previous, but recent drug arrest that targeted her was later found to be unwarranted and the charges were dropped. Nevertheless, I'm certainly sad at the news today. This young lady has, from her earliest moments, had one of the hardest lives imaginable. And whatever good fortune came from her role in 'The Wire,' seems, in retrospect, limited to that project. She worked hard as an actor and was entirely professional, but the entertainment industry does not offer a great many roles for those who can portray people from the other America. There are, in fact, relatively few stories told about the other America."
Selected Reading: Los Angeles Times, Washington Post, Slate


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What: Conducting the research, study, examination, inquiry or exploration that you need. Gathering the information necessary to take the next step or solve a problem when you do not have the time, desire or expertise.
What are my customers, clients, constituents, members looking for? What makes them take action?
What are the needs of my constituents?
What and how are my competitors doing?
Who are my potential partners and what are the best arrangements?
What are the resources, training, processes, funding sources, systems available to help me accomplish my objectives?
How do I qualify as a vendor; for a grant or other funding; or for a license, certification or accreditation?
Is there a market for my product, service or organization?
Am I meeting the requirements of the grant or contract or am I in danger or losing it?


Bloomville Lions Club is to host the 53rd annual ox roast 11 a.m.-1 p.m. Sept. 9 at Bloomville Fire Station.
The menu features pit beef sandwiches, macaroni or potato salad, applesauce, ice cream and a drink. Patrons can dine in or use the drive-through.
Proceeds are to support eyeglasses and community projects benefiting those in the local area. Along with the Lions International mission of promoting and protecting eyesight, some important local causes the club supports include the junior fair livestock sales at the Attica and Seneca County Fairs, the Seneca County Park District, several Red Cross Bloodmobiles and providing support to local families in need.
Tiffin-Seneca Public Library is to be closed Monday in observance of the Labor Day holiday.
The library is to re-open with regular hours Tuesday.
The library also is to be re-opening 1-5 p.m. Sundays starting Sept. 9 through Memorial Day.
The junior department at Tiffin-Seneca Public Library is to host Playtime @ the Library at 10 a.m. Friday and Sept. 21 in the Frost Kalnow Room of the library, 77 Jefferson St.
The program is hosted with Seneca County's Ohio Early Intervention. Toys and activities are to be offered to children ages 18 months to 5 years old, to interact with their caregivers in an unstructured, creative play.
September at Tiffin-Seneca Public Library is to be Library Card Sign-up Month.
The perks of owning a library card are to be highlighted and there are to be opportunities for those who wish to sign up for a card.
All month long, new patroons are to be entered into a drawing for a gift basket. Current patrons also can be entered to win if they refer someone.
For more information, call (419) 447-3751 or visit www.tifffinsenecalibrary.org.
Titles include "Walking Shadows" by Faye Kellerman, "Tear Me Apart" by J.T. Ellison, "Trust Me" by Ryan Hank Phillippi, "Face Off" by Brenda Novak, "Shattered at Sea" by Cheryl Hollon, "Safe and Sound" by Fern Michaels and "Don't Look Back" by Dawn Ryder.
FOSTORIA — Kaubisch Memorial Public Library is to host the program Baby & Toddler Story Time at 2 p.m. Tuesday at the library, 205 Perry St.
The program is geared toward babies and toddlers along with their caregivers.
The event is to feature stories for preschoolers ages 2-5 years old.
CLYDE — Clyde Public Library is to host the Book Babies program at 10 a.m. Thursday at the library, 222 W. Buckeye St.
The program is for infants through 24 months with a caregiver. The event features stories, baby games and musical activities to create a playful learning experience.
CAREY — The After School Bunch is to meet at 3:30 p.m. Tuesday at Dorcas Carey Public Library, 236 E. Findlay St.
CAREY — Dorcas Carey Public Library is to host a movie day at 3:30 p.m. Thursday at the library, 236 E. Findlay St.
The National Machinery Foundation has warded North Central Academy a $10,000 grant to be used to implement a county-wide career education program — REACH.
The grant is to be used to work with seven local school districts including Fostoria, Hopewell-Loudon, Mohawk, New Riegel, North Central Academy, Old Fort and Seneca East.
TOLEDO — Mercy College of Ohio has announced students who have been named to the 2018 summer semester honors lists.
Local students named to the list include Kourtney Elswick of Attica; Amber Gonyer of Bradner; Olivia Zimmerman of Carey; Laura Galvan of Fostoria; Nicole Hanlon of New Washington; and Melissa Lang of Tiffin.
Tiffin University announced it has been selected by the Council of Independent Colleges, in partnership with the Association of College and University Educators, to join the national Consortium for Instructional Excellence and Career Guidance.
This is a new initiative that is to prepare up to 500 faculty members to use evidence-based teaching practices shown to promote student success while embedding career guidance into their existing courses.
Kristina Collins, vice provost of academic excellence, distinctiveness and effectiveness at TU, is to lead the cohort in 25 learning modules beginning in fall.


The Build a Bug feature is designed to provide you with a general concept of how Bug-O's Modular Drive System can help you mechanize your cutting and welding efficiently.
This is only a suggestion. For a detailed solution and to schedule a visit or live demonstration, click on one of the buttons below or call Bug-O Systems today.


text:
#include <memory>
#include <string>
#include <unordered_map>
#include <vector>

#include "tensorflow/contrib/lite/toco/graph_transformations/graph_transformations.h"
#include "tensorflow/contrib/lite/toco/model.h"
#include "tensorflow/contrib/lite/toco/tooling_util.h"
#include "tensorflow/core/platform/logging.h"

namespace toco {

namespace {

// Returns true if the given op is strictly a broadcasting operation.
// This is commonly seen as a Concat of the same input multiple times, and is
// often generated from Tile ops that were converted via the
// convert_trivial_tile_to_concat transformation.
bool IsBroadcastingOp(const Model& model, Operator* op) {
  // Concatenation of identical inputs is usually a broadcast.
  if (op->type == OperatorType::kConcatenation) {
    // Verify that all inputs are the same.
    for (int i = 1; i < op->inputs.size(); ++i) {
      if (op->inputs[i] != op->inputs[0]) {
        return false;
      }
    }
    return true;
  }

  // There are other things we could look for (Stack/etc) when needed.
  return false;
}

}  // namespace

// Finds an operation that looks like a broadcast (concat of the same sources
// along the last dimension) and drops it by relying on the ability of certain
// binary ops to perform an implicit broadcast.
::tensorflow::Status FuseBroadcastIntoFollowingBinary::Run(Model* model,
                                                           std::size_t op_index,
                                                           bool* modified) {
  *modified = false;
  const auto binary_it = model->operators.begin() + op_index;
  auto* binary_op = binary_it->get();

  // Test for binary ops of types that we know how to resolve
  if (binary_op->inputs.size() != 2) {
    return ::tensorflow::Status::OK();
  }
  if (binary_op->type != OperatorType::kAdd &&
      binary_op->type != OperatorType::kMul &&
      binary_op->type != OperatorType::kSub &&
      binary_op->type != OperatorType::kDiv) {
    return ::tensorflow::Status::OK();
  }

  // NOTE: either of these ops may be nullptr if the input array is constant.
  Operator* const op[2] = {
      GetOpWithOutput(*model, binary_op->inputs[0]),
      GetOpWithOutput(*model, binary_op->inputs[1]),
  };

  // Check whether either input is a broadcast-like concat.
  bool is_op_0_broadcast = op[0] && IsBroadcastingOp(*model, op[0]);
  bool is_op_1_broadcast = op[1] && IsBroadcastingOp(*model, op[1]);
  if (!is_op_0_broadcast && !is_op_1_broadcast) {
    // Neither input is a broadcast-looking thing.
    AddMessageF("Neither input looks broadcasty");
    return ::tensorflow::Status::OK();
  } else if (is_op_0_broadcast && is_op_1_broadcast) {
    AddMessageF(
        "Unable to fuse broadcast into %s as both inputs (%s, %s) are "
        "broadcasts",
        LogName(*binary_op), op[0] ? LogName(*op[0]) : "(?)",
        op[1] ? LogName(*op[1]) : "(?)");
    return ::tensorflow::Status::OK();
  }
  int broadcast_index = is_op_0_broadcast ? 0 : 1;

  // Just pull out the input of the broadcast op and pass it directly to the
  // binary op.
  AddMessageF("Fusing broadcast op %s into the following binary %s",
              LogName(*op[broadcast_index]), LogName(*binary_op));
  binary_op->inputs[broadcast_index] = op[broadcast_index]->inputs[0];

  // We leave the broadcast op in; it'll get cleaned up if it's not used later.
  *modified = true;
  return ::tensorflow::Status::OK();
}

}  // namespace toco

redpajama_set_name: RedPajamaGithub


text:
Preview: Eagles at Plymouth City Patriots
Newcastle Eagles/News/BBL/Preview: Eagles at Plymouth City Patriots
October 9, 2022 3:00 pm BBL Cup 2022-23
The winless Newcastle Eagles take a break from BBL Championship duties this afternoon and turn their attention to picking up a first win of the season in the BBL Cup.
They have made the long journey to the South-West to take on Plymouth City Patriots this afternoon.
Coach Marc Steutel will be desperate to get the "monkey off his side's back" when they face the Patriots at The Pavilions which is always a tough place to take a road win from.
The BBL Cup is a competition that the Eagles have won on no fewer than six occasions and a win down and Plymouth would set themselves off another possible run to glory and at the same time kick-start their season.
On Friday night Newcastle lost their third league game of the fledgling season but there were signs of positivity to take from the game. Not least that but for one poor quarter, the third, they were right there competing against the BBL's strongest side, London Lions.
Preview: Eagles vs Manchester Giants – SOLD-OUT
Preview: Eagles at Caledonia Gladiators (BBL Trophy First Round)
One of the bright spots for Newcastle on the night was forward Jermel Kennedy. The Canadian born, British passport holder made his home debut and showed he has plenty to offer his new side this season. He gave his post game thoughts and looked forward to the trip to Plymouth.
"We fought. First half we did great things, pushed our tempo got into great spots and we went into the locker rooms at the half pretty confident. Javion (Hamlet) getting into foul trouble early in the second half didn't help."
"It increased the pressure on us taking us out of our actions but we tried to stay disciplined and true to what we're good at but there were a couple of mental lapses in the third and we struggled to get back to them."
"London definitely had a lot of depth but we don't focus on those things. We come with what we have and had prepared the whole week for this and it is just is what it is. I think we can take some positives about the way we played especially in the first half."
Turning his attentions to today's game Kennedy well remembers the trips he made to Plymouth from his former time in The BBL with Worcester Wolves.
"I've played their a few times and it's definitely one of the hardest places to make adjustments to what you're facing up to. But we have a day's rest and travelling and we're not going to make excuses. We're 0 – 3 right now so we've got to find a way to make those adjustments."
"Sunday (today) is about doing a bit more of the good things we're doing and minimise some of the bad possessions and decisions with the ball. Plus it's important that we play together and stick together."
"We definitely feel we have a chance to get the win and get ourselves going if we can just do that."
The game at Plymouth tips-off at 3:00pm and is the first of two games Newcastle face on the road this week as they go to arch-rivals Sheffield Sharks this coming Friday night in the Championship on Sky Sports and hopefully with a Cup win behind them.
Fans can watch live on the BBL's YouTube channel with coverage building up from 2:45pm.
Jermel Kennedy,Plymouth City Patriots,Preview
About the Author: Jeff King
Jeff King is our Press Officer and live commentator in our games shown on YouTube


Recently I had the good fortune to pick up a cheap second hand copy of Orwell: The Observer Years, a wonderful collection of essays and reviews written for the London Observer newspaper from 1942 until 1949. It is a fascinating collection of thoughts by the great man written at such a key time in world history, an undertaking which would help form a close friendship with the paper's proprietor, David Astor who was looking to push The Observer in a new direction.
Many of the articles were written during his writing of Animal Farm (1945) and it shows the bravery of Astor to give voice to an author who was repeatedly rejected by publishers (particularly for Animal Farm) for his increasingly hostile views on politics which found him alienated by those on both the left and the right.
It was Astor who sent Orwell to cover the Allied advance into Germany in 1945 which subsequently lead to him meeting Hemingway in Paris. Orwell was as good for Astor as he was for Orwell, the one hundred articles were written for Astor who in turn did much to help Orwell in his later years including finding him a grave in Oxfordshire.
One particular article caught my eye; The Uncertain Fate of Displaced Persons from June 10th 1945. Here Orwell covers the problems associated with the resettling of foreign workers forced into labour in Germany during the war. Orwell details the work being done in 230 camps across Germany to deal with 4,500,000 displaced foreign nationals in Germany alone. The figure was broken down thus; 1,500,000 Russians, 1,200,000 Frenchmen, 600,000 Belgians along with some 100,000 Dutchmen (by then nearly all repatriated) and smaller groups of Czechs, Scandinavians, Greeks and Yugoslavs.
As the authorities worked to register and relocate them they realised a great number had already taken flight, going to the countryside where they begged and stole or sought work on farms. There was the real issue of food shortages and the dilemma of how much food should be rationed to the Germans. Interestingly, Orwell describes the level of food wasted by American troops and the depth of ill feeling it caused to starving onlookers who could see for themselves the might of the American dollar.
He finishes the article with a very interesting and relevant question; 'One point that does not seem to have been decided -or at least, no authoritative pronouncement has been made-is whether a Displaced Person who does not wish to go home is obliged to do so'…one cannot help but wonder what he would have made of the refugees 'flooding' (as per David Cameron) into Europe from Africa and the Middle East and the question of their status should they not wish to return to Iraq, Syria, Libya or Afghanistan. Whilst they are not foreign workers they are very much 'Displaced Persons' and that is a question begging to be answered by many.


text:
Release:LAURA REED TO RELEASE NEW SONG "DON'T SHOOT" AUGUST 19th
SINGER/SONGWRITER LAURA REED TO RELEASE HEARTFELT NEW SONG "DON'T SHOOT" ON AUGUST 19 IN RESPONSE TO POLICE AND RACE-RELATED GUN VIOLENCE
NEW COMMUNITY- INSPIRED VIDEO FOR "DON'T SHOOT" OUT NOW
VIDEO FILMED IN REED'S NATIVE NORTH CAROLINA
PORTION OF PROCEEDS FOR SONG TO GO TO N.C. ORG SPIRITHOUSE ADVOCATES FOR LOW WEALTH FAMILIES AND COMMUNITY SOCIAL JUSTICE
(New York, New York; August 8, 2016) Acclaimed singer/songwriter Laura Reed www.laurareed.com has released the video for her impassioned new song "Don't Shoot," which will be available everywhere as a single on August 19th in response to police and race-related gun violence and the questionable use of deadly force in altercations within the black community.
The moving video for the song filmed in black and white in Laura Reed's native Raleigh, NC, and the city of Durham, NC, features local members of the community, social activists, musicians, and other artists holding up cue card-lyrics of the poignant song https://www.youtube.com/watch?v=nXiayndh738 Part of the clip was filmed in a rally in Durham where community members and social activists gathered to advocate community-led policing and other solutions in an effort to fully engage the issue purposefully. Laura has designated that a portion of all proceeds from "Don't Shoot" be donated to the Durham, NC organization SpiritHouse, http://www.spirithouse-nc.org, a thriving cultural arts and organizing network that outreaches with low-wealth families and community members to uncover and uproot systemic barriers that prevent communities from gaining the resources, leverage and capacity for long- term self-sufficiency.
This is the first single from Laura since her acclaimed debut album The Awakening was released in 2014, and she commented on the motivation behind "Don't Shoot" and the opportunity to work with such dedicated artists and community activists. "It was beautiful to have the human element in this video and song," says Laura. "Behind the words, the faces, the stories, the smiles, the pain…all of it is part of this story and message. I have been unable to turn my head from the violence and discrimination that is plaguing not only the United States but our world. I felt compelled to do something as an artist and it starts with a song and hopefully turns into considerable donations and community activism. I really hope to inspire others to get involved, to speak out, and to look at the systematic injustice that has become the status quo. I think a lot of violence stems from apathy, we become detached….I want to plant a seed of empathy."
"Don't Shoot" was produced by and co-written with Will Edwards at Copperline Ranch. Will's diverse music career spans records, television, and film and includes 41 gold and platinum albums, multiple Grammy Award winning records and five Prime Time Emmys. He says, "This is a timely message that I am proud to be part of."
The video was directed by André Leon Gray, (also serving as the video producer and cinematographer) who has been a key figure in Raleigh's art scene for years. The self-trained artist's mixed-media assemblages, which have been showcased at the Nasher, NC Museum of Art, 21C, and other exhibits, are considered devastating critiques of structural racism, whitewashed history, and pop-culture myths.
Director Andre Leon Gray stated: "For Laura Reed's "Don't Shoot" music video, my goal was to display the humanity of those who are concerned about their safety in a world that doesn't seem to value their lives, along with those who recognize their humanity and love and support them despite an environment of hatred that is fueled by fear."
Laura has recently performed "Don't Shoot" in her live show, engaging audiences to become active in their community and vote. Her most recent album The Awakening (which she recorded in Nashville) was a musical transformation for her, after earning her stripes as lead vocalist for the southeastern R&B/Soul-tinged band Laura Reed And Deep Pocket. She tabled the funk/Reggae-informed shadings for a more intimate but accessible exploration on The Awakening, but returns to a reggae-infused sound on "Don't Shoot.". Her years of fronting a working band, combined with her unique and empowering outlook on life served her well in crafting the cornerstone album of her career, and the socially conscious "Don't Shoot."
She has toured the country extensively in support of her most recent album and turned heads at noted South By Southwest performances as well as other spotlight events over the years. The in-demand performer has been joined by some stellar singers and musicians on multiple past projects, including George Clinton, Killer Mike, Karl Denson, Kendra Foster, and Jewel. She's also shared stages with a star-studded list of artists including India.Arie, Mali Music, Miguel, Daley, Valerie June and Anthony Hamilton, among others. Laura won the 2016 Summerfest Emerging Artist Series and was nominated for two 2015 Nashville Industry Music Awards (NIMA) – Best Female R&B Performer and Best Female R&B Vocalist. She was awarded her first NIMA in 2014 for Best R&B Solo Artist.
More information please contact Tracey Miller, TMA , tracey@tmapublicity.com / 609-383-2323


Laser & Skin Surgery Center of Richmond, P.C.
Mohs' Micrographic surgical treatment of skin cancers that are in delicate locations such as the nose, ears, lips,, hand/finger, genitalia, are poorly defined, recurrent from previous treatment or occurring in the young patient. As of January 2014 I have treated approximately 13,000 skin cancers with Mohs' surgery and achieved a local recurrence rate of approximately 1 case per 1,000 treated.
11.) Galen H. Fisher and William Joel Cook "The Interpolated paranasal flap as a novel and advantageous reconstructive option for nasal-alar reconstruction." Dermatol Surg. 2009 Apr;35(4):656-61.
12.) Galen H. Fisher, "Opaque Titanium and Zinc Sunscreen as an effective and versatile masking agent during laser hair removal, "the batik-masking approach"". Dermatol Surg. 2009 Jun;35(6):985-6.
13.) Galen H. Fisher, "Medium sized lower eyelid defect reconstructed with a bilobed flap". Dermatol Surg. 2010 May;36(5):683-6.
1.) October, 2003, New Orleans,LA. American Society for Dermatologic Surgery and American College of Mohs Micrographic Surgery and Cutaneous Oncology Combined Annual Meeting. Poster Presentation entitled "Treatment of melanoma in situ on sun-damaged skin with topical 5% imiquimod cream complicated by the development of invasive disease"
2.) April 2004, Lake Buena Vista FL, American Society of Lasers in Medicine and Surgery. Main Platform presentation entitled "Treatment of acneiform scars with fractional photothermolysis: a series of 17 patients"
3.) October 2005, Atlanta GA, American Society for Dermatologic Surgery and American College of Mohs Micrographic Surgery and Cutaneous Oncology Combined Annual Meeting. Main Platform presentation entitled "Treatment of acneiform scars with fractional photothermolysis: a series of 17 patients"
presentation entitled "Treatment of acneiform scars with fractional photothermolysis"


1. No flaming. This is important- this thread can go anywhere and if an argument starts, someone (me ) is gonna crack down on everything hard.
3. Don't kill anyone unless it's super important to the story, and I mean super important; see the end of Chapter 3 (page bottom of page 5) for details.
4. Keep your own name. So no, you can't be "Raging Bulldozer Knight of the Fifth Order".
5. Don't stop the adventure unless we've come to a resolution.
So pretty much you can go anywhere with this story. Make it happen in space in the year 4995 with mecha-monkeys if you so please. So...without further ado...let Channel-Ai's adventures begin!
01. The Beginning...of the End!
04. Scenario: It's Party Time!
Ok...can we change rule number 3????
It was a nice day on the Channel-Ai mansion.
No Rodri The mods will descend from heaven and smite you.
It was a nice day on the Channel-Ai mansion. Smily leaned back on his executive directores chair and contemplated the Love is Born 6th Concert which was showing on the big screen covering the wall in front of him when all of a sudden an alert flashed up on his screen. It was an invitation to a party which was going to be held on the Channel-Ai farm on Sapporo.
An alarm, louder than the one before, shattered through the mansion. A mechanized voice was blaring: Meltdown meltdown!
Then Ashley entered Smily's room to see if he was alright, but when she opened the door, she saw that he wasn't there! Where could he be?
ALRIGHT HOLD UP. Some new rules are coming into play here. Read the first post, which I edited, for the new rules.


Overlooking Vivonne Bay and jetty. Enjoy looking at the view which continually changes or just relax, do nothing!!
Sleeps 6 in two bedrooms, front - queen bed, second - double bed and bunk. All linen included. Full kitchen inc microwave and dishwasher. Separate toilet, full laundry. Two lounge areas, one with Flat screen 46" TV, other with views over Vivonne Bay. Babies & Children welcome.
Toys, books, games, to suit from birth to family. Travel cot & High Chair available on request. Wallabies, possums, echidnas just outside. Little penguin walk nearby.
Ingredients provided to make a loaf of bread in our breadmaker on the first night.
NB: 'Room only' means accommodation only (in this case whole house) but no meals included.
Cancellations notified more than 30 days prior to departure will be entitled to a full refund, less 25%.
Bookings commencing within 48 hours, please phone us (details on your invoice) to ensure house is ready for your arrival.
**Flexible check in time from 3 pm onwards**. Check out by 10 am.
Koopalanda Dreaming is at Vivonne Bay, 60 kms from Kingscote, 100 kms from Penneshaw (where ferry lands), 45 kms from airport, so you will need your own transport. To get to Koopalanda Dreaming, proceed to Vivonne Bay on South Coast Road, once you reach Vivonne Bay Store, stay on South Coast Rd, continue west over Harriet River bridge, turn left onto Jetty Road, after 3 km, you will be at the jetty, observing the directional road signs, Koopalanda Dreaming is one of four cottages.
.** Flexible check-in from 3 pm onwards** Check out by 10 am.


River City Bank's Maximum checking is currently paying an APY of 2.27% on all qualifying accounts. APY is accurate as of 04/15/2019, and the rate may change after the account is opened.
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text:
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h2 {
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h3 {
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* other top-level elements *
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*/
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@media only screen and (min-width: 500px) {
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*****************/
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#page-content {
  /* div containing everything after the header */
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@media only screen and (max-width: 500px) {
  #page-content {
    /* div containing everything after the header */
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/* ⬇ thanks to https://css-tricks.com/snippets/css/prevent-long-urls-from-breaking-out-of-container/ */
#post-content {
  /* These are technically the same, but use both */
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  word-wrap: break-word;
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  /* This is the dangerous one in WebKit, as it breaks things wherever */
  word-break: break-all;
  /* Instead use this non-standard one: */
  word-break: break-word;
  /* Adds a hyphen where the word breaks, if supported (No Blink) */
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  -ms-hyphens: auto;
  -moz-hyphens: auto;
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  */ }

/* ⬆ thanks to https://css-tricks.com/snippets/css/prevent-long-urls-from-breaking-out-of-container/ */
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blockquote p {
  font: 200 11pt "Verdana", "Helvetica", "Arial", sans-serif;
  font-style: italic;
  padding: 10px 20px 10px 20px;
  border-left: 5px grey solid;
  background-color: #EEE; }

@media only screen and (max-width: 500px) {
  blockquote p {
    font: 200 11pt "Verdana", "Helvetica", "Arial", sans-serif;
    font-style: italic;
    margin: 0px 10px 0px 10px; } }

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