Autologous adipose-derived regenerative cells are effective for chronic intractable radiation injuries

Effective therapy for chronic radiation injuries, such as ulcers, is prone to infection. Stiffness is expected since the therapeutic radiation often involves wider and deeper tissues and often requires extensive debridement and reconstruction, which are not sometimes appropriate for elderly and compromised hosts. Autologous adipose-derived regenerative cells (ADRCs) are highly yielding, forming relatively elderly aged consecutive 10 cases, 63.6±14.9 y (52-89 y), with mean radiation dose of 75.0±35.4 Gy (50-120 Gy) were included with at least 10-month follow-up. Minimal debridement and ADRC injection in the wound bed and margin along with the injection of mixture of fat and ADRCs in the periphery were tested for efficacy and regenerated tissue quality by clinically as well as imaging by computed tomography and magnetic resonance imaging. Uncultured ADRCs of 1.6±1.3×10. 7 cells were obtained. All cases healed uneventfully after 6.6±3.2 weeks (2-10 weeks) post-operatively. The done site morbidity was negligible and without major complications, such as paralysis or massive haematoma. The regenerated tissue quality was significantly superior to the pre-operative one and the mixture of fat and ADRCs connected to the intact tissue was very soft and pliable. Mean follow-up at 1.9±0.8 y (0.9-2.9 y) revealed no recurrence or new ulceration after treatment. Thus, the ADRCs treatment for decades-long radiation injuries is effective, safe and improves the quality of wounds

Engineering HIV-Resistant Human CD4+ T Cells with CXCR4-Specific Zinc-Finger Nucleases

HIV-1 entry requires the cell surface expression of CD4 and either the CCR5 or CXCR4 coreceptors on host cells. Individuals homozygous for the ccr5Δ32 polymorphism do not express CCR5 and are protected from infection by CCR5-tropic (R5) virus strains. As an approach to inactivating CCR5, we introduced CCR5-specific zinc-finger nucleases into human CD4+ T cells prior to adoptive transfer, but the need to protect cells from virus strains that use CXCR4 (X4) in place of or in addition to CCR5 (R5X4) remains. Here we describe engineering a pair of zinc finger nucleases that, when introduced into human T cells, efficiently disrupt cxcr4 by cleavage and error-prone non-homologous DNA end-joining. The resulting cells proliferated normally and were resistant to infection by X4-tropic HIV-1 strains. CXCR4 could also be inactivated in ccr5Δ32 CD4+ T cells, and we show that such cells were resistant to all strains of HIV-1 tested. Loss of CXCR4 also provided protection from X4 HIV-1 in a humanized mouse model, though this protection was lost over time due to the emergence of R5-tropic viral mutants. These data suggest that CXCR4-specific ZFNs may prove useful in establishing resistance to CXCR4-tropic HIV for autologous transplant in HIV-infected individuals

Induction of antigen-specific tolerance through hematopoietic stem cell-mediated gene therapy: the future for therapy of autoimmune disease?

Based on the principle that immune ablation followed by HSC-mediated recovery purges disease-causing leukocytes to interrupt autoimmune disease progression, hematopoietic stem cell transplantation (HSCT) has been increasingly used as a treatment for severe autoimmune diseases. Despite clinically-relevant outcomes, HSCT is associated with serious iatrogenic risks and is suitable only for the most serious and intractable diseases. A further limitation of autologous HSCT is that relapse rates can be high, suggesting disease-causing leukocytes are incompletely purged or the environmental and genetic determinants that drive disease remain active. Incorporation of antigen-specific tolerance approaches that synergise with autologous HSCT could reduce or prevent relapse. Further, by reducing the requirement for highly toxic immune-ablation and instead relying on antigen-specific tolerance, the clinical utility of HSCT could be significantly diversified. Substantial progress has been made exploring HSCT-mediated induction of antigen-specific tolerance in animal models but studies have focussed on primarily on prevention of autoimmune diseases. However, as diagnosis of autoimmune disease is often not made until autoimmune disease is well developed and populations of autoantigen-specific pathogenic effector and memory T cells have become well established, immunotherapies must be developed to address effector and memory T-cell responses which have traditionally been considered the key impediment to immunotherapy. Here, focusing on T-cell mediated autoimmune diseases we review progress made in antigen-specific immunotherapy using HSCT-mediated approaches, induction of tolerance in effector and memory T cells and the challenges for progression and clinical application of antigen-specific ‘tolerogenic’ HSCT therapy

The impact of transposable element activity on therapeutically relevant human stem cells

Human stem cells harbor significant potential for basic and clinical translational research as well as regenerative medicine. Currently ~ 3000 adult and ~ 30 pluripotent stem cell-based, interventional clinical trials are ongoing worldwide, and numbers are increasing continuously. Although stem cells are promising cell sources to treat a wide range of human diseases, there are also concerns regarding potential risks associated with their clinical use, including genomic instability and tumorigenesis concerns. Thus, a deeper understanding of the factors and molecular mechanisms contributing to stem cell genome stability are a prerequisite to harnessing their therapeutic potential for degenerative diseases. Chemical and physical factors are known to influence the stability of stem cell genomes, together with random mutations and Copy Number Variants (CNVs) that accumulated in cultured human stem cells. Here we review the activity of endogenous transposable elements (TEs) in human multipotent and pluripotent stem cells, and the consequences of their mobility for genomic integrity and host gene expression. We describe transcriptional and post-transcriptional mechanisms antagonizing the spread of TEs in the human genome, and highlight those that are more prevalent in multipotent and pluripotent stem cells. Notably, TEs do not only represent a source of mutations/CNVs in genomes, but are also often harnessed as tools to engineer the stem cell genome; thus, we also describe and discuss the most widely applied transposon-based tools and highlight the most relevant areas of their biomedical applications in stem cells. Taken together, this review will contribute to the assessment of the risk that endogenous TE activity and the application of genetically engineered TEs constitute for the biosafety of stem cells to be used for substitutive and regenerative cell therapiesS.R.H. and P.T.R. are funded by the Government of Spain (MINECO, RYC-2016- 21395 and SAF2015–71589-P [S.R.H.]; PEJ-2014-A-31985 and SAF2015–71589- P [P.T.R.]). GGS is supported by a grant from the Ministry of Health of the Federal Republic of Germany (FKZ2518FSB403)

The International Natural Product Sciences Taskforce (INPST) and the power of Twitter networking exemplified through #INPST hashtag analysis

Background: The development of digital technologies and the evolution of open innovation approaches have enabled the creation of diverse virtual organizations and enterprises coordinating their activities primarily online. The open innovation platform titled "International Natural Product Sciences Taskforce" (INPST) was established in 2018, to bring together in collaborative environment individuals and organizations interested in natural product scientific research, and to empower their interactions by using digital communication tools. Methods: In this work, we present a general overview of INPST activities and showcase the specific use of Twitter as a powerful networking tool that was used to host a one-week "2021 INPST Twitter Networking Event" (spanning from 31st May 2021 to 6th June 2021) based on the application of the Twitter hashtag #INPST. Results and Conclusion: The use of this hashtag during the networking event period was analyzed with Symplur Signals (https://www.symplur.com/), revealing a total of 6,036 tweets, shared by 686 users, which generated a total of 65,004,773 impressions (views of the respective tweets). This networking event's achieved high visibility and participation rate showcases a convincing example of how this social media platform can be used as a highly effective tool to host virtual Twitter-based international biomedical research events

Alarm prediction in industrial machines using autoregressive LS-SVM models

© 2014 IEEE. In industrial machines different alarms are embedded in machines controllers. They make use of sensors and machine states to indicate to end-users various information (e.g. diagnostics or need of maintenance) or to put machines in a specific mode (e.g. shut-down when thermal protection is activated). More specifically, the alarms are often triggered based on comparing sensors data to a threshold defined in the controllers software. In batch production machines, triggering an alarm (e.g. thermal protection) in the middle of a batch production is crucial for the quality of the produced batch and results into a high production loss. This situation can be avoided if the settings of the production machine (e.g. production speed) is adjusted accordingly based on the temperature monitoring. Therefore, predicting a temperature alarm and adjusting the production speed to avoid triggering the alarm seems logical. In this paper we show the effectiveness of Least Squares Support Vector Machines (LS-SVMs) in predicting the evolution of the temperature in a steel production machine and, as a consequence, possible alarms due to overheating. Firstly, in an offline fashion, we develop a nonlinear autoregressive (NAR) model, where a systematic model selection procedure allows to carefully tune the model parameters. Afterwards, the NAR model is used online to forecast the future temperature trend. Finally, a classifier which uses as input the outcomes of the NAR model allows to foresee future alarms.status: publishe

Prenatal predictors and physical fitness in Spanish Youth: the UP&DOWN study

BACKGROUND: Physical fitness outcomes are considered major health biomarkers to assess and monitor exercise-based interventions across the lifespan. Recent studies provide evidence that many adult and childhood chronic diseases should have their origins in gestational or fetal life. To date, a few pioneering studies have showed associations between prenatal predictors and selected physical fitness tests (strength and cardiorespiratory). Nevertheless, there is a lack of knowledge about the influence of prenatal factors on childhood performance on a comprehensive fitness test battery including speed and coordination. The innovative purpose of the current study is to analyse the relative weight of prenatal predictors on schoolchildren's physical fitness outcomes. METHODS: We obtain data from1188 children (571 girls) aged 6-11 years and 1020 adolescents (495 girls) aged 12-17 years. Prenatal predictors (gestational anemia, gestational diabetes and length of gestation) were self-reported from offspring's mothers. The ALPHA fitness test battery for youth was used to assess offsprinǵs physical fitness (muscular strength, motor fitness and cardiorespiratory fitness). Regression analysis were performed to predict the different physical fitness outcomes. RESULTS: The main findings of the present study indicate that the presence of gestational anemia significantly predicted lower scores of lower-body explosive muscular strength (standing long jump) and motor fitness (4x10-m shuttle run) and predicted moderately lower scores of upper-body isometric muscular strength (handgrip strength test). (p>.005; p>.008; p>.075 respectively). Moreover, gestational anemia better predicted lower scores of muscular strength and motor fitness in children than in adolescents (standing long jump, handgrip strength test, 4x10-m shuttle run) (p>.001; p>.051; p > 0.18, respectively). While gestational age and length of gestation (>34- ?42 weeks) predict better cardiorespiratory fitness (20 m shuttle-run test) (p>.023; p>.023 respectively) and motor fitness (4x10 m shuttle; moderately for length of gestation). (p>.020; p > 0.55 respectively). CONCLUSION: This evidence suggests that preventive strategies by health-care institutions, policy makers and technicians must be two-fold: a) to effectively reduce gestational anemia in order to prevent offsprinǵs predisposition to low levels of physical fitness, and b) to intervene with toddlers and children at risk to provide tailored physical activity programs and regular physical fitness evaluation

Cardiorespiratory Fitness Cutoff Points for Early Detection of Present and Future Cardiovascular Risk in Children: A 2-Year Follow-up Study

Objective To examine the association between cardiorespiratory fitness (CRF) at baseline and cardiovascular disease (CVD) risk in 6- to 10-year-olds (cross-sectional) and 2 years later (8- to 12-year-olds [longitudinal]) and whether changes with age in CRF are associated with CVD risk in children aged 8 to 12 years. Patients and Methods Spanish primary schoolchildren (n=236) aged 6 to 10 years participated at baseline. Of the 23 participating primary schools, 22% (n=5) were private schools and 78% (n=18) were public schools. The dropout rate at 2-year follow-up was 9.7% (n=23). The 20-m shuttle run test was used to estimate CRF. The CVD risk score was computed as the mean of 5 CVD risk factor standardized scores: sum of 2 skinfolds, systolic blood pressure, insulin/glucose, triglycerides, and total cholesterol/high-density lipoprotein cholesterol. Results At baseline, CRF was inversely associated with single CVD risk factors (all P0.85; P<.001) and to predict CVD risk 2 years later (P=.004). Persistent low CRF or the decline of CRF from 6-10 to 8-12 years of age is associated with increased CVD risk at age 8 to 12 years (P<.001). Conclusion During childhood, CRF is a strong predictor of CVD risk and should be monitored to identify children with potential CVD risk

Predictive Validity of Motor Fitness and Flexibility Tests in Adults and Older Adults: A Systematic Review.

Motor fitness and flexibility have been linked to several health issues. We aimed to investigate the predictive validity of motor fitness and flexibility tests in relation to health outcomes in adults and older adults. Web of Science and PubMed databases were screened for studies published from inception to November 2020. Two authors systematically searched, evaluated, and extracted data from identified original studies and systematic reviews/meta-analysis. Three levels of evidence were constructed: strong, moderate, and limited/inconclusive evidence. In total, 1182 studies were identified, and 70 studies and 6 systematic reviews/meta-analysis were summarized. Strong evidence indicated that (i) slower gait speed predicts falls and institutionalization/hospitalization in adults over 60 years old, cognitive decline/impairment over 55 years old, mobility disability over 50 years old, disability in instrumental activities of daily living (IADL) over 54 years old, cardiovascular disease risk over 45 years old, and all-cause mortality over 35 years old; (ii) impaired balance predicts falls and disability in IADL/mobility disability in adults over 40 years old and all-cause mortality over 53 years old; (iii) worse timed up&go test (TUG) predicts falls and fear of falling over 40 years old. Evidence supports that slower gait speed, impaired balance, and worse TUG performance are significantly associated with an increased risk of adverse health outcomes in adults