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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a median lifespan of 2–3 years after diagnosis. There are few meaningful treatments that alter progression in this disease. Preclinical and clinical studies have demonstrated that neuroinflammation may play a key role in the progression rate of ALS. Despite this, there are no validated biomarkers of neuroinflammation for use in clinical practice or clinical trials. Biomarkers of neuroinflammation could improve patient management, provide new therapeutic targets, and possibly help stratify clinical trial selection and monitoring. However, attempts to identify a singular cause of neuroinflammation have not been successful. Here, we performed multi-parameter flow cytometry to comprehensively assess 116 leukocyte populations and phenotypes from lymphocytes, monocytes, and granulocytes in a cohort of 80 ALS patients. We identified 32 leukocyte phenotypes that were altered in ALS patients compared to age and gender matched healthy volunteers (HV) that included phenotypes of both inflammation and immune suppression. Unsupervised hierarchical clustering and principle component analysis of ALS and HV immunophenotypes revealed two distinct immune profiles of ALS patients. ALS patients were clustered into a profile distinct from HVs primarily due to differences in a multiple T cell phenotypes, CD3+CD56+ T cells and HLA-DR on monocytes. Patients clustered into an abnormal immune profile were younger, more likely to have a familial form of the disease, and survived longer than those patients who clustered similarly with healthy volunteers (344 weeks versus 184 weeks; p = 0.012). The data set generated from this study establishes an extensive accounting of immunophenotypic changes readily suitable for biomarker validation studies. The extensive immune system changes measured in this study indicate that normal immune homeostatic mechanisms are disrupted in ALS patients, and that multiple immune states likely exist within a population of patients with ALS. [ABSTRACT FROM AUTHOR]

Background There are no effective treatments that slow the progression of neurodegenerative diseases. A major challenge of treatment in neurodegenerative diseases is appropriate delivery of pharmaceuticals into the cerebrospinal fluid ( CSF) of affected individuals. Mesenchymal stromal cells ( MSCs-either naïve or modified) are a promising therapy in neurodegenerative diseases and may be delivered directly into the CSF where they can reside for months. In this preclinical study, we evaluated the safety of intrathecal autologous MSCs in a rabbit model. Study Design and Methods Autologous adipose-derived MSCs (or artificial CSF) were delivered intrathecally, either with single or with repeated injections into the foramen magnum of healthy rabbits and monitored for 4 and 12 weeks, respectively. Results Rabbits tolerated injections well and no definitive MSC-related side effects were observed apart from three rabbits that had delayed death secondary to traumatic foramen magnum puncture. Functional assessments and body weights were equivalent between groups. Gross pathology and histology did not reveal any abnormalities or tumor growth. Complete blood count data were normal and there were no differences in CSF interleukin-6 levels in all groups tested. Conclusion Our data suggest that intrathecal delivery of autologous MSCs is safe in a rabbit model. Data from this study have supported two successful investigational new drug applications to the Food and Drug Administration, resulting in the initiation of two clinical trials using autologous MSCs in amyotrophic lateral sclerosis and multiple system atrophy. [ABSTRACT FROM AUTHOR]

• Selected trifluoromethoxy-containing drugs and agrochemicals were profiled. • General aspects of the biological properties of these compounds were briefly introduced. • Synthetic methods for preparation of these compounds were presented. Trifluoromethoxy-containing molecules represent still underdeveloped, but highly promising group of biologically active compounds. The first part of this review profiles five known pharmaceuticals Riluzole (myotrophic sclerosis), Delamanid (tuberculosis), Sonidegib (cancer), Pretomanid (tuberculosis), and Celikalim (blood pressure). The second part of this article covers five marketed agrochemicals featuring trifluoromethoxy group. These include pesticides No-valuron and Flometoquin; herbicides Flucarbazone-sodium and Flurprimidol; and fungicide Thifluzamide. For each compound, we discuss the detailed chemical synthesis and general aspects of biological activity. In this review, the biological properties and the synthetic method of the selected five known pharmaceuticals and five marketed agrochemicals featuring trifluoromethoxy group have been presented. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Biofuels produced from biomass are considered to be promising sustainable alternatives to fossil fuels. The conversion of lignocellulose into fermentable sugars for biofuels production requires the use of enzyme cocktails that can efficiently and economically hydrolyze lignocellulosic biomass. As many fungi naturally break down lignocellulose, the identification and characterization of the enzymes involved is a key challenge in the research and development of biomass-derived products and fuels. One approach to meeting this challenge is to mine the rapidly-expanding repertoire of microbial genomes for enzymes with the appropriate catalytic properties. Results: Semantic technologies, including natural language processing, ontologies, semantic Web services and Web-based collaboration tools, promise to support users in handling complex data, thereby facilitating knowledgeintensive tasks. An ongoing challenge is to select the appropriate technologies and combine them in a coherent system that brings measurable improvements to the users. We present our ongoing development of a semantic infrastructure in support of genomics-based lignocellulose research. Part of this effort is the automated curation of knowledge from information on fungal enzymes that is available in the literature and genome resources. Conclusions: Working closely with fungal biology researchers who manually curate the existing literature, we developed ontological natural language processing pipelines integrated in a Web-based interface to assist them in two main tasks: mining the literature for relevant knowledge, and at the same time providing rich and semantically linked information. [ABSTRACT FROM AUTHOR]

The article discusses the study on the ecology of ontologies in the public domain. It assesses and reviews the general characteristics of existing Web Ontology Language (OWL) ontologies paying attention to features such as their abundance, continuing availability, originating sources, and domain covered. It also explores the criteria and related work for ontology evaluation. It presents the findings from the survey of ontologies in the public domain and on their domain dependent and domain independent features.

This review provides a short summary of the traditional methods for synthesis of CF3-O-containing compounds, followed by a critical overview of known trifluoromethoxylating reagents, focusing on their preparation, synthetic generality and limitations. [ABSTRACT FROM AUTHOR]

• Application of HF-THF/PhIO for electrophilic fluorination has been developed. • A series of carbonyl compounds and aromatic olefins were fluorinated under mild conditions. • High reactivity and good yield augur well of this reagent for the large-scale commercial application. New electrophilic fluorination reagent HF·THF/PhIO was introduced and tested on three general classes of compounds. Compared with the literature data reported for basic reagents, such as HF/TEA/PhIO and HF/Py/PhIO, the new reagent showed superior performance in fluorination of aromatic alkenes, subpar reactivity with ketones and malonates, while in the reactions with 1,3-unsaturated carbonyl compounds the results were much the same as the literature data. [ABSTRACT FROM AUTHOR]

This review describes the discovery, preparation and properties of perfluoro-3-ethyl-2,4-dimethyl-3-pentyl persistent radical (PPFR). Novel areas of application of this new reagent for radical trifluoromethylation, trifluoromethylation/fluorination and polymer initiation are emphasized. • Recent advances about perfluoro-3-ethyl-2,4-dimethyl-3-pentyl persistent radical (PPFR) were presented. • Several types of reactions on this fluorinated persistent radical were profiled. • This new reagent used as the radical trifluoromethyl source was emphasized. This review comprehensively profiles perfluoro-3-ethyl-2,4-dimethyl-3-pentyl persistent radical (PPFR) as a new reagent for radical trifluoromethylation, trifluoromethylation/fluorination and polymer initiation. The PPFR is perfectly stable at ambient conditions, but at temperatures above 80 °C undergoes β-scission to generate trifluoromethyl radical. This property can be used to initiate various chain-polymerization or trifluoromethylation reactions. The unique feature of this process, distinguishing it from all other known methods for ·CF 3 -radical generation, is that the radical is produced under neutral, inert and additive-free conditions. Hopefully, the mild reaction conditions and commercial availability of PPFR will generate research interest for practical applications of this novel perfluorination reagent for fluorination and polymerization processes. [ABSTRACT FROM AUTHOR]

Introduction: The use of motorized scooters is gaining popularity in Canada and elsewhere. This study aims to summarize characteristics of injuries related to use of motorized scooters using data from the electronic Canadian Hospitals Injury Reporting and Prevention Program (eCHIRPP) and to analyze trends. The eCHIRPP collects information associated with the injury event and clinical information related to treatment (the injured body part, the nature of the injury, injury intent and treatment received) from 11 pediatric and 9 general hospitals across Canada., Results: A free-text search using keywords identified 523 cases related to motorized scooter injuries between January 2012 and December 2019. Most of the injuries reported were among males (62.7%). Fracture/dislocation was the most frequent injury (36.9%), and 14.3% of all patients were admitted to hospital. Joinpoint regression showed a statistically significant increase in injuries related to motorized scooter use between 2012 and 2017 (annual percent change of 18.4%)., Conclusion: Study findings indicate the need for continued preventive efforts and improved educational messages on safe riding and the importance of the use of protective equipment to prevent injuries among riders., Competing Interests: The authors have no conflicts to declare.

Nowadays, the selective introduction of fluorine into bioactive compounds is a mature strategy in the design of drugs allowing to increase efficiency, biological half-life and bio-absorption. On the other hand, amino acids (AAs) represent one of the most ubiquitious classes of naturally occurring organic compounds, which are found in over 40% of newly marked small-molecule pharmaceutical drugs and medical formulations. The primary goal of this work is to underscore two major trends in the design of modern pharmaceuticals. The first is dealing with the unique structural characteristics provided by the structure of amino acids featuring an abundance of functionality and the presence of a stereogenic center, all of which bodes well for the successful development of targeted bioactivity. The second is related to fine-tuning the desired activity and pharmacokinetics by selective introduction of fluorine. Historically, both trends were developed separately as innovative and prolific approaches in modern drug design. However, in recent decades, these approaches are clearly converging leading to an ever-increasing number of newly approved pharmaceuticals containing both structural features of amino acids and fluorine.

This review article focused on the innovative procedure for electrophilic fluorination using HF and in situ generation of the required electrophilic species derived from hypervalent iodine compounds. The areas of synthetic application of this approach include fluorination of 1,3-dicarbonyl compounds, aryl-alkyl ketones, styrene derivatives, α,β-unsaturated ketones and alcohols, homoallyl amine and homoallyl alcohol derivatives, 3-butenoic acids and alkynes., Competing Interests: The authors declare no conflict of interest.

Background: Crohn's rectovaginal fistulizing disease remains notoriously difficult to treat. A phase I clinical trial to evaluate the safety and feasibility of a novel protocol using a mesenchymal stem cell (MSC)-coated Gore Bio-A fistula plug for the treatment of medically and surgically refractory Crohn's rectovaginal fistulas was conducted., Methods: Five patients underwent an autologous subcutaneous adipose tissue harvest via a 2-cm abdominal wall incision at time of exam under anesthesia (EUA) with seton placement. MSCs were isolated, expanded, and impregnated on the plug. After 6 weeks, patients returned to the operating room for placement of the MSC-coated plug. The primary end points were safety and feasibility; the secondary end point was clinical and radiographic healing at 6 months., Results: Five female patients (median age [range], 49 [38-53] years) with a median disease duration (range) of 23 (7-34) years who were on biologic (n = 5) or combination therapy (n = 3) had successful harvest and expansion of MSCs and delivery of the Gore Bio-A plug. There were no serious adverse events or adverse events related to the MSCs or plug during the 6-month follow-up. At 6 months, 3 patients had complete cessation of drainage, and 2 had >50% reduction in drainage; all had a persistent fistula tract identified on magnetic resonance imaging and EUA at 6 months., Conclusions: Surgical placement of an autologous adipose-derived MSC-coated fistula plug in diverted patients with Crohn's rectovaginal fistulas was safe and feasible. All patients had a reduction in the size of their fistula tract, and 3 of 5 had cessation of drainage, but none achieved complete healing.This was a phase I clinical trial of autologous mesenchymal stem cells on a plug for rectovaginal Crohn's fistulas., (© 2019 Crohn’s & Colitis Foundation. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Management of transsphincteric cryptoglandular fistulas remains a challenging problem and the optimal surgical approach remains elusive. Mesenchymal stem cells, increasingly being utilized for perianal Crohn's disease, offer a novel therapy to treat cryptoglandular fistulas., Objectives: This study aimed to determine safety and feasibility of using an autologous mesenchymal stem cell-coated fistula plug in patients with transsphincteric cryptoglandular fistulas., Design: This study is a phase I clinical trial., Setting: This study was conducted at a tertiary academic medical center., Patients: Adult (>18 years) male and female patients with transsphincteric cryptoglandular fistulas were selected., Main Outcomes Measures: The primary outcomes measured were the safety, feasibility, and efficacy of a mesenchymal stem cell-coated fistula plug in patients with transsphincteric fistulas., Results: Fifteen patients (8 women, mean age 39.8 years) with a single-tract transsphincteric fistula received a mesenchymal stem cell-loaded fistula plug and were followed for 6 months. Duration of disease at the time of study enrollment was a median of 3.0 years (range, 1-13 years) with a median of 3.5 (range, 1-20) prior surgical interventions. Adverse events included 1 plug extrusion, 1 abdominal wall seroma, 3 perianal abscesses requiring drainage, and 1 patient with perianal cellulitis. There were no serious adverse events. At 6 months, 3 patients had complete clinical healing, 8 had partial healing, and 4 patients showed no clinical improvement. Radiographic improvement was seen in 11 of 15 patients., Limitations: This study was limited by the small cohort and short follow-up., Conclusions: Autologous mesenchymal stem cell-coated fistula plug treatment of transsphincteric cryptoglandular fistulas was safe and feasible and resulted in complete or partial healing in a majority of patients. See Video Abstract at http://links.lww.com/DCR/A897.

Background Aims: Light chain (AL) amyloidosis is a protein misfolding disease characterized by extracellular deposition of immunoglobulin light chains (LC) as amyloid fibrils. Patients with LC amyloid involvement of the heart have the worst morbidity and mortality. Current treatments target the plasma cells to reduce further production of amyloid proteins. There is dire need to understand the mechanisms of cardiac tissue damage from amyloid to develop novel therapies. We recently reported that LC soluble and fibrillar species cause apoptosis and inhibit cell growth in human cardiomyocytes. Mesenchymal stromal cells (MSCs) can promote wound healing and tissue remodeling. The objective of this study was to evaluate MSCs to protect cardiomyocytes affected by AL amyloid fibrils., Methods: We used live cell imaging and proteomics to analyze the effect of MSCs in the growth arrest caused by AL amyloid fibrils., Results: We evaluated the growth of human cardiomyocytes (RFP-AC16 cells) in the presence of cytotoxic LC amyloid fibrils. MSCs reversed the cell growth arrest caused by LC fibrils. We also demonstrated that this effect requires cell contact and may be mediated through paracrine factors modulating cell adhesion and extracellular matrix remodeling. To our knowledge, this is the first report of MSC protection of human cardiomyocytes in amyloid disease., Conclusions: This important proof of concept study will inform future rational development of MSC therapy in cardiac LC amyloid., (Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

In patients with Crohn's disease, perianal fistulas recur frequently, causing substantial morbidity. We performed a 12-patient, 6-month, phase 1 trial to determine whether autologous mesenchymal stem cells, applied in a bioabsorbable matrix, can heal the fistula. Fistula repair was not associated with any serious adverse events related to mesenchymal stem cells or plug placement. At 6 months, 10 of 12 patients (83%) had complete clinical healing and radiographic markers of response. We found placement of mesenchymal stem cell-coated matrix fistula plugs in 12 patients with chronic perianal fistulas to be safe and lead to clinical healing and radiographic response in 10 patients. ClinicalTrials.gov Identifier: NCT01915927., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the safety of intrathecal autologous adipose-derived mesenchymal stromal cell treatment for amyotrophic lateral sclerosis (ALS)., Methods: Participants with ALS were enrolled and treated in this phase I dose-escalation safety trial, ranging from 1 × 10 7 (single dose) to 1 × 10 8 cells (2 monthly doses). After intrathecal treatments, participants underwent standardized follow-up, which included clinical examinations, revised ALS Functional Rating Scale (ALSFRS-R) questionnaire, blood and CSF sampling, and MRI of the neuroaxis., Results: Twenty-seven patients with ALS were enrolled and treated in this study. The safety profile was positive, with the most common side effects reported being temporary low back and radicular leg pain at the highest dose level. These clinical findings were associated with elevated CSF protein and nucleated cells with MRI of thickened lumbosacral nerve roots. Autopsies from 4 treated patients did not show evidence of tumor formation. Longitudinal ALSFRS-R questionnaires confirmed continued progression of disease in all treated patients., Conclusions: Intrathecal treatment of autologous adipose-derived mesenchymal stromal cells appears safe at the tested doses in ALS. These results warrant further exploration of efficacy in phase II trials., Classification of Evidence: This phase I study provides Class IV evidence that in patient with ALS, intrathecal autologous adipose-derived mesenchymal stromal cell therapy is safe., (© 2016 American Academy of Neurology.)

Self-limited Langerhans cell histiocytosis (LCH) represents a rare, congenital, cutaneous form of LCH associated with a good prognosis. Only 35 cases of solitary lesion self-limited LCH have been reported. Herein, we present an additional case in a 3-month-old boy who presented with an isolated pigmented nodule on his left posterior shoulder, which had been present since birth. Punch biopsy showed histopathologic features of LCH with positive CD1a and CD68 stains. Further examination and investigation showed no features of systemic involvement. The lesion spontaneously resolved within 2 months, and there has been no evidence of recurrence on follow up. As several cases of recurrence and complications have been reported in self-limited LCH, we emphasize the need for long-term, and perhaps indefinite, follow up for symptoms and signs associated with LCH in these patients., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Mesenchymal stem cells (MSC) can serve as carriers to deliver oncolytic measles virus (MV) to ovarian tumors. In preparation for a clinical trial to use MSC as MV carriers, we obtained cells from ovarian cancer patients and evaluated feasibility and safety of this approach., Methods: MSC from adipose tissues of healthy donors (hMSC) and nine ovarian cancer patients (ovMSC) were characterized for susceptibility to virus infection and tumor homing abilities., Results: Adipose tissue (range 0.16-3.96 grams) from newly diagnosed and recurrent ovarian cancer patients yielded about 7.41×106 cells at passage 1 (range 4-9 days). Phenotype and doubling times of MSC were similar between ovarian patients and healthy controls. The time to harvest of 3.0×108 cells (clinical dose) could be achieved by day 14 (range, 9-17 days). Two of nine samples tested had an abnormal karyotype represented by trisomy 20. Despite receiving up to 1.6×109 MSC/kg, no tumors were seen in SCID beige mice and MSC did not promote the growth of SKOV3 human ovarian cancer cells in mice. The ovMSC migrated towards primary ovarian cancer samples in chemotaxis assays and to ovarian tumors in athymic mice. Using non-invasive SPECT-CT imaging, we saw rapid co-localization, within 5-8 minutes of intraperitoneal administration of MV infected MSC to the ovarian tumors. Importantly, MSC can be pre-infected with MV, stored in liquid nitrogen and thawed on the day of infusion into mice without loss of activity. MV infected MSC, but not virus alone, significantly prolonged the survival of measles immune ovarian cancer bearing animals., Conclusions: These studies confirmed the feasibility of using patient derived MSC as carriers for oncolytic MV therapy. We propose an approach where MSC from ovarian cancer patients will be expanded, frozen and validated to ensure compliance with the release criteria. On the treatment day, the cells will be thawed, washed, mixed with virus, briefly centrifuged and incubated for 2 hours with virus prior to infusion of the virus/MSC cocktail into patients.

Fungi produce a wide range of extracellular enzymes to break down plant cell walls, which are composed mainly of cellulose, lignin and hemicellulose. Among them are the glycoside hydrolases (GH), the largest and most diverse family of enzymes active on these substrates. To facilitate research and development of enzymes for the conversion of cell-wall polysaccharides into fermentable sugars, we have manually curated a comprehensive set of characterized fungal glycoside hydrolases. Characterized glycoside hydrolases were retrieved from protein and enzyme databases, as well as literature repositories. A total of 453 characterized glycoside hydrolases have been cataloged. They come from 131 different fungal species, most of which belong to the phylum Ascomycota. These enzymes represent 46 different GH activities and cover 44 of the 115 CAZy GH families. In addition to enzyme source and enzyme family, available biochemical properties such as temperature and pH optima, specific activity, kinetic parameters and substrate specificities were recorded. To simplify comparative studies, enzyme and species abbreviations have been standardized, Gene Ontology terms assigned and reference to supporting evidence provided. The annotated genes have been organized in a searchable, online database called mycoCLAP (Characterized Lignocellulose-Active Proteins of fungal origin). It is anticipated that this manually curated collection of biochemically characterized fungal proteins will be used to enhance functional annotation of novel GH genes. Database URL: http://mycoCLAP.fungalgenomics.ca/.