bluuebunny/crossref_metadata_2025_split huggingface dataset:
P252 Treatment pathways for patients with axSpA: a retrospective UK database analysis
Authors: Morgan Christopher L. I , White Abigail , Tomlinson Mark , Scott Amie , Tian Haijun 
Published: April 2020

Abstract

Background
This UK study aimed to identify a population with axial spondyloarthritis (axSpA) and to describe the presence of prior reported symptoms and treatment pathways associated with the condition.

Methods
The study was performed using a large routine primary care database from the UK, the Clinical Practice Research Datalink. Only patients whose record could be linked to Hospital Episode Statistics (HES) were included for analysis. Patients with an incident diagnosis of axSpA recorded from 2003-2017 were identified. The date of first axSpA diagnosis defined the index date and patients were observed until the end of database follow up. Recordings of axSpA-related symptoms (back pain, rheumatoid arthritis and fatigue) in the 12 months prior to the index date, before and after attendance at orthopaedic or rheumatology outpatient clinics, and after inpatient contact with either a primary or secondary diagnosis of axSpA were flagged. The proportion of patients prescribed tumour necrosis factor inhibitors (TNFis), corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) or conventional systemic disease-modifying anti-rheumatic drugs (csDMARDs) subsequent to the index date and estimated first three lines of therapy were described.

Results
A total of 2,756 incident axSpA cases were identified. In the 12 months prior to the index date, 1,289 (46.8%) of these patients had at least one recorded symptom related to axSpA: back pain (1,195 [43.4%]), rheumatoid arthritis (140 [5.1%]) and fatigue (6 [0.2%]). Prior to the index date, 1,025 (37.2%) patients had been seen in an orthopaedic outpatient clinic and 1,274 (46.2%) in a rheumatology clinic. Subsequent to the index date, the respective figures were 815 (29.6%) and 1,641 (59.5%). In addition, 133 (4.8%) patients had a post-index inpatient admission with a primary diagnosis of axSpA and 895 (32.5%) had an inpatient admission with a secondary diagnosis. TNFis were prescribed for 97 (3.5%) patients, corticosteroids for 727 (26.4%), NSAIDs for 1,885 (68.4%) and csDMARDs for 461 (16.7%) patients. The most common first-line therapy was NSAIDs (1,579 [57.3%]) (Table).

Conclusion
This study describes the symptoms of and treatment pathways for axSpA patients within the UK. Issues regarding missing data within routine data should be considered when interpreting the results.

Disclosures
C.L.I. Morgan: Other; Employee of: Pharmatelligence. A. White: Shareholder/stock ownership; Novartis. Other; Employee of: Novartis. M. Tomlinson: Consultancies; Novartis. A. Scott: Consultancies; Novartis. H. Tian: Other; Employee of: Novartis.
P253 Secukinumab provides sustained improvements in tender and swollen joint counts: 5year results from the Phase 3 FUTURE 2 study
Authors: McInnes Iain , Chinoy Hector , Asquith Darren , White Abigail , Gaillez Corine 
Published: April 2020

Abstract

Background
Secukinumab, a fully human monoclonal antibody that neutralises interleukin-17A, demonstrated long-term efficacy and tolerability in psoriatic arthritis (PsA) patients in FUTURE 2. Tender joint count (TJC) and swollen joint count (SJC) scores are components of composite measures used to assess treatment response, which can include confounding factors. TJC and SJC were developed for rheumatoid arthritis, assessing 68 and 66 joints, respectively. Later, these scores evolved for use in PsA, which can affect small joints of the feet, assessing 78 and 76 joints. TJC and SJC measure synovitis, a key assessment of disease activity. Herein, we report the 5-year efficacy of secukinumab on reduction of 78 TJC and 76 SJC in FUTURE 2.

Methods
397 patients with active PsA were randomised to subcutaneous secukinumab loading dose (300, 150, 75 mg) or placebo at baseline, Weeks 1, 2, 3 and 4, and every 4 weeks thereafter. Placebo-treated patients were re-randomised to secukinumab 300 or 150 mg at Week 16 (non-responders) or 24 (responders). Secukinumab dose was escalated from 150 to 300 mg, and 75 to 150 or 300 mg starting at Week 128 and maintained thereafter, if active signs of disease were observed based on physician’s assessment. Data are reported as observed for secukinumab 300 and 150 mg (approved PsA doses) over 5 years (2 years of core study and 3-year extension).

Results
Baseline characteristics were comparable across treatment arms (Table 1). Overall, 62.5% (248/397) of all patients randomised completed 260 weeks of treatment. Of these, 48/65 (73.8%) and 49/66 (74.2%) patients randomised to secukinumab 300 and 150 mg achieved ACR20 at Week 260, respectively. Improvements in adjusted 78 TJC and 76 SJC change from baseline were sustained from Week 16 to Week 260 in all treatment groups (Table 1). At Week 260, mean change from baseline in adjusted 78 TJC/76 SJC was −12.8/−9.3 and −15.1/−8.5 for the secukinumab 300 mg and 150 mg group (including patients up-titrated to 300 mg), respectively. Numerical differences were comparable between secukinumab doses.

Conclusion
Secukinumab 300 and 150 mg provided sustained improvements in 78 TJC and 76 SJC scores over 5 years; numerical differences were comparable between secukinumab doses.

Disclosures
I. McInnes: Consultancies; AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, UCB. Honoraria; AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, UCB. Grants/research support; AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Lilly, Novartis, Pfizer, UCB. H. Chinoy: Honoraria; Novartis. D. Asquith: Shareholder/stock ownership; Novartis. Other; Employee of Novartis. A. White: Shareholder/stock ownership; Novartis. Other; Employee of Novartis. C. Gaillez: Shareholder/stock ownership; Novartis, Bristol-Myers Squibb. Other; Employee of Novartis.
Gender Equality and the EU's Economic Governance: The Strategic Use of Women’s Employment Within Labor Market Reforms in Italy
Authors: Chieregato Elisa 
Published: April 2020

AbstractThis article aims to evaluate the political implications of post-crisis governance in the European Union for national gender-equality strategies and policies. It presents a study of recent reforms of the labor market in Italy, where the response to the Eurozone crisis has increased concerns over the low rate of female employment. Through an analysis of policy documents and legislative reforms informed by discursive politics, the article argues that the Italian case provides evidence of the trend toward the further instrumentalization of gender equality, which has been strategically used in order to provide additional legitimation for labor market deregulation.
Indemnities and modern corporate structures
Authors: Watson Jack 
Published: April 2020

Abstract
This article considers the issue of trustee indemnity clauses and their interaction with the corporate structures which underlie many modern trusts. It considers the problems which can arise in relation to such clauses and the recent decision of First National Trustco (UK) Ltd v McQuitty [2020] EWCA Civ 107, in which the Court of Appeal gave guidance as to the construction of such clauses. Finally, it will conclude by addressing the wider impact of the decision on the ability of trustees to compel beneficiaries to make payment in respect of liabilities of underlying companies in order to ensure that taxes and other liabilities are paid.
11‐Keto‐a‐Boswellic Acid, a Novel Triterpenoid from Boswellia spp., with Cytotoxic Efficacy against Treatment‐Resistant Triple Negative Breast Cancer Cell Lines
Authors: Schmiech Michael , Lang Sophia Johanna , Paetz Christian , Ulrich Judith , Büchele Berthold , Syrovets Tatiana , Simmet Thomas 
Published: April 2020

Triterpenoids including biologically active boswellic acids constitute about twenty percent of frankincense, the oleogum resin of Boswellia spp. trees from the Burseraceae family
[1–
2]. Frankincense as well as extracts thereof have been traditionally used by folk medicines, such as Ayurveda, African, Arab, and Chinese medicine, for the treatment of fever and pain. Several clinical pilot trials provided evidence for a potential therapeutic efficacy of frankincense preparations in various chronic inflammatory diseases. Moreover, preclinical studies have demonstrated that boswellic acids may be beneficial for treatment of human cancers because they also inhibit tumor growth in different animal models. We have performed a comparative analysis of more than 40 oleogum resins from different Boswellia species grown in different geographic locations
[1] and we have shown that frankincense extracts induce apoptosis in triple negative breast cancer cell lines in vitro and in vivo
[1–
2]. Moreover, the cytotoxic efficacy of the extracts correlated positively with the contents of boswellic acids
[2]. Boswellic acids exist as two structural isomers, α‐boswellic acids (oleanane‐type skeleton) and β‐boswellic acids (ursane‐type skeleton). In the current study, we have identified the novel oleanane‐type 11‐keto‐α‐boswellic acid (αKBA) in oleogum resins of different Boswellia species. The structure of αKBA was elucidated by 1D and 2D 1H and 13C NMR analysis. The contents of the individual boswellic acid isomers was quantified in different frankincense extracts by high performance reversed‐phase liquid chromatography coupled with tandem mass spectrometric detection (HPLC‐MS/MS) and the help of fluorinated stationary phases. We have compared the toxicities of different known boswellic acids and of the newly identified αKBA against tthe reatment‐resistant, triple negative human breast cancer cell lines MDA‐MB‐231 and CAL‐148. αKBA exhibited cytotoxic activity against the cancer cells and was less toxic to normal peripheral blood mononuclear cells (PBMC) and non‐malignant human breast epithelial cells indicating tumor selectivity. Structure‐activity‐relationship between the cytotoxic activities of different boswellic acid were analyzed. Hence, the study provides evidence for the existence of a novel biologically active boswellic acid with cytotoxic activity against triple negative human breast cancer cell lines in the oleogum resin of Boswellia spp. Additionally, it offers new clues for possible structural modifications of boswellic acids to increase their cytotoxicity against cancer cells.Support or Funding InformationThis work was supported by the Academic Center for Complementary and Integrative Medicine (AZKIM), State Ministry of Baden‐Württemberg for Sciences, Research and Arts.
Novel Treatment of Human Melanoma Cells that Express BRAF or NRAS Mutations by Antifungal Agents
Authors: Koh David W. , Jira Lukas R. , McKamey Shelby G. 
Published: April 2020

Approximately 70% of all melanomas are characterized by mutations in the BRAF or NRAS genes. Although targeted therapy exists for BRAF mutations, this therapy is not commonly used in wild‐type melanoma, no such treatment is available for NRAS mutations, and resistance to all available treatments is increasing. These observations indicate that new strategies and targets are needed to improve melanoma therapy. We previously reported the potential for the antifungal agents, clotrimazole and econazole, to treat melanoma. Our objective here was to analyze the ability of these agents to treat human melanoma cell lines expressing the BRAF or NRAS mutations. Cell growth and cell death were investigated via flow cytometry, cell proliferation assays, and cell death assays after treatments.Wild‐type human melanoma cell lines or those possessing the BRAF V600E mutation or the NRAS Q61R mutation were analyzed. A dose of 25 μM clotrimazole led to profound decreases in cell growth in wild‐type and NRAS mutant melanoma cells. Significant, but lesser effects were observed in BRAF mutants. However, treatment with 25 μM econazole caused substantial reductions in cell growth in BRAF mutant cells, as well as one line of wild‐type melanoma cells. These results were corroborated by cell death analyses, where clotrimazole treatment caused up to 50% cell death in wild‐type and NRAS mutant cells after 3 days. In BRAF mutants after 3 days, econazole treatment caused up to 45% cell death. Taken together, these preliminary studies indicated that clotrimazole was more effective in the treatment of wild‐type and NRAS mutant melanoma cells, while econazole demonstrated greater effects in melanoma cells expressing the BRAF mutation.In conclusion, this study demonstrated the ability of antifungal agents to successfully treat human melanoma cell lines that possess BRAF and NRAS mutations. Since each agent displayed differential effects for each type of mutation, it is possible that these antifungal agents affect different molecular targets in each mutant melanoma cell line. These antifungal agents thus appear to be potential alternative treatments for wild‐type melanoma or melanoma characterized with the BRAF V600E or NRAS Q61R mutation.
Development of a Novel ω‐6 Polyunsaturated Fatty Acid Based Treatment Strategy for Non‐Melanoma Skin Cancer by Inhibiting Delta‐5‐Desaturase
Authors: Shah Harshit , Pang Lizhi , Qian Steven , Zhao Pinjing , Sathish Venkatachalem 
Published: April 2020

BackgroundCyclooxygenase‐2 (COX‐2) overexpression has been considered as one of the culprits for cancer progression, due to precancerous prostaglandin production from downstream ω‐6 polyunsaturated fatty acid (PUFA), arachidonic acid (AA), in the majority of the cancers including, Nonmelanoma skin cancer (NMSC). However, COX‐2 inhibitors have failed to provide protection against cancer in clinics. As per the recent studies from our lab, manipulation of ω‐6 PUFA metabolism by genetically inhibiting delta‐5‐desaturase (D5D), requires for metabolism of an upstream ω‐6 PUFA, dihomo gamma‐linolenic acid (DGLA), to AA, results in accumulation of DGLA which undergo peroxidation by COX‐2 to produce an anti‐cancer product, 8‐Hydroxyoctanoic acid (8‐HOA) in pancreatic and colon cancer model. However, this approach was associated with limitations, such as the degradation of D5D siRNA by endonuclease and the inability to cross the cell membrane. Hence in order to overcome the limitation and to get a sustained production of 8‐HOA inside the tumor, we developed a novel D5D inhibitor (D5Di) and hypothesized that D5Di could stimulate 8‐HOA production, which exerts anti‐cancer activity in NMSC.MethodsIn vitro studies like colony formation assay for proliferation analysis and PI Annexin V double staining assay for apoptosis analysis using A431 cell line and in vivo studies using xenograft mouse model evaluating the protective effect of D5Di against NMSC were performed. In order to dissect the molecular pathway, Western blot analysis, and immunohistochemistry studies were performed.ResultsD5Di treatment in the presence of DGLA resulted in a significant increase in apoptosis by 14.23±1.01% and reduction in survival fraction by 29.91±0.70%. Similar to the in vitro study, treatment with D5Di in animals receiving the DGLA supplement displayed a significant reduction in tumor size. The reduction in tumor size was due to a significantly high level of 8‐HOA (1.32±0.122μM) and a low PGE2/PGE1 ratio. In addition, an increase in cleaved PARP and reduction in Ki‐67 were observed by immunohistochemistry, which were indicating inhibitory effect of D5Di on tumor growth. Moreover, treatment with D5Di also caused downregulation of anti‐apoptotic factors such as procaspase‐3, procaspase‐9, and increased DNA damage marker, γH2Ax, both in vitro and in vivo.ConclusionThese results concluded that the novel strategy of providing D5Di with DGLA could be a new therapeutic approach for advanced and high‐risk NMSC.Support or Funding InformationThis research work is supported by NIH R15CA195499.
Exploring opioid receptor dependent biased agonism in the PreBötzinger Complex
Authors: Szujewski Caroline C. , Campbell Chrishon , Garcia Alfredo J. 
Published: April 2020

Respiratory depression is a hallmark of opiate overdose and is mediated by activation of μ‐opioid receptors (MORs) to suppress the drive for breathing. Agonist binding to MOR can preferentially activate Gi or β‐arrestin‐2 (β‐arr2) signaling. Although a large body of literature suggests that activation of the β‐arr2 pathway is involved with respiratory depression, emerging evidence has challenged this perspective. This raises the question of whether the development of biased agonist opiates is valuable for mitigating adverse respiratory side effects. The preBötzinger complex (preBötC) is area in the respiratory network expressing MORs and is responsible for inspiratory rhythm generation. This ongoing study examines the role of MORs biased agonism on opioid modulation of rhythmogenesis in the preBötC. Extracellular population recordings were made in preBötC slices prepared from wildtype mice and β‐arr2 knock out mice (β‐arr2−/−). No differences were observed between genotypes in the degree of inhibition caused by the opiate agonist DAMGO. Additionally, no differences were observed with Endmorphin‐2 application, an opioid receptor agonist biased for β‐arr2 signaling. These findings indicate that β‐arr2 signaling in the preBötC is not responsible for the inhibition of rhythmogenesis caused by activation of MORs. Thus, developing biased agonist opiates to mitigate depressive respiratory side effects may not be an effective strategy.Support or Funding InformationNIH T32DA043469, NIH PO 1 HL 144454, NIH R01 NS10742101
Effect of Hydrogen Sulfide‐Releasing Compounds on Proliferation of Human Colon Cancer HT29 Cells
Authors: Yakubu Momoh A. , Keita Djene , Ngele Kalu K. , Mbye Ya Fatou N. , Ohia Sunny E. 
Published: April 2020

Both natural and synthetic compounds that release hydrogen sulfide (H2S) such as diallyl trisulfide and naproxen‐H2S hybrids growth and proliferation of human colon HT29 cells (Lai et al. J. Cell. Mol. Med 19: 474, 2014; Kodela et al. Drug Des. Dev. Ther. 9:4873, 2015). Aims of the present study were: (a) to investigate the pharmacological action of L‐cysteine (substrate for the biosynthesis of H2S) and NaHS (H2S‐releasing compound) on proliferation of HT29 cells at different time‐points, and (b) to study the role of enzymes (cystathionine β‐synthase, CBS and cystathionine γ‐lyase, CSE) and K+‐ATP channels on the response elicited by H2S‐producing compounds in HT29 cells. The colon adenoma HT29 cells were treated with different concentrations of L‐cysteine (1 μM – 1 mM) and NaHS (1 μM – 1 mM) for 24 and 48 hours, in the absence and presence of inhibitors of CBS and CSE, amino‐oxyacetic acid (AOA, 1 mM), an inhibitor of K+‐ATP channels, glibenclamide (GLB, 10 μM). After incubation, the anti‐proliferative response on cells caused by various agents was determined by MTT Assay. At equimolar concentrations (10 μM and 1 mM), both L‐cysteine and NaHS caused concentration‐dependent inhibitions of cell proliferation after incubation for 24 h, but increased cell growth at these same concentrations after 48 h of incubation. For instance, at 10 μM, both L‐cysteine and NaHS increased cell proliferation by 37% and 51% after 48 h of incubation. Pretreatment of cells with AOA (1 mM) had no significant (P>0.05) effect on the inhibitory response caused by L‐cysteine and NaHS after 24 h incubation. Interestingly, AOA blocked and even reversed the increase in proliferation caused by L‐cysteine (10 μM and 1 mM) and NaHS (10 μM and 1 mM) after 48 h incubation. After 24 h, both L‐cysteine and NaHS caused additional inhibitory effects on cell proliferation in HT 29 cells pretreated with GLB (10 μM). GLB blocked and even reversed the increase in proliferation caused by L‐cysteine and NaHS in HT29 cells after 48 h incubation. We conclude that H2S‐releasing compounds can elicit a time‐dependent inhibitory or excitatory action on the proliferation of HT29 cells. The inhibitory/excitatory effects caused by these compounds depends, at least in part, on endogenous biosynthesis of new gas and the activity of K+‐ATP channels in HT29 cells.Support or Funding InformationThis research is supported by Tittle III under the Award Number P031B090216;Title III, Part B, Historically Black Graduate Institutions (HBGI) (CFDA No. 84.031B).
Motor Neuron Pathology Leads to Respiratory Deficiency in Optn−/− Mice
Authors: McCall Angela L. , Dhindsa Justin S. , Pucci Logan A. , Strickland Laura M. , Kahn Amanda F. , Fusco Anna F. , Tseng Henry , ElMallah Mai K. 
Published: April 2020

Amyotrophic Lateral Sclerosis (ALS) is a devastating and fatal neurodegenerative disease with no current cure. Respiratory failure is the leading cause of death in ALS. Death occurs3–5 years after diagnosis when patients with ALS ultimately succumb to inadequate ventilation, hypoxia, and respiratory failure. Several genes are associated with ALS. One of these genes encodes optineurin (OPTN) which is associated with neurodegeneration in both ALS and glaucoma. Optineurin has multiple roles in various biochemical pathways such as regulation of inflammation and autophagy. However, the exact mechanism by which loss of OPTN results in progressive neural degeneration and respiratory failure in ALS is still unclear.In order to understand the impact of OPTN deficiency on respiratory function, our goal was to study the respiratory pathophysiology in the Optn−/− mouse. The hypothesis driving this work is that the Optn−/− mouse has respiratory insufficiency due to degeneration of the respiratory motor unit – motor neuron, nerve, neuromuscular junction and muscle. Physiological, histological and molecular outcome measures were used to assess the impact of OPTN on the respiratory system. We used whole body plethysmography (WBP) to assess breathing at baseline and during a respiratory challenge with hypercapnic and hypoxic conditions (FiCO2: 0.07, FiO2: 0.10; nitrogen balance). During the respiratory challenge, compared to the WT mice, Optn−/− mice had significantly lower tidal volume, minute ventilation, peak inspiratory flow, and peak expiratory flow starting at 6 months of age indicating weakened muscle strength. Furthermore, throughout the challenge period Optn−/− mice spent a greater amount of time in apnea indicating pathology in the respiratory control centers. The weakness and pathology in control of breathing during the respiratory challenge progresses as the mice age. At 1 year of age, Optn−/− mice have stunted growth accompanied by reduced diaphragm size compared to WT mice. Postmortem immunohistochemical studies of the medulla reveal Optn−/− mice have fewer hypoglossal motor neurons. Finally, the hypoglossal (XII) nerves of Optn−/− mice had significantly reduced g‐ratio which indicates pathology and decompaction of myelin sheaths. Within the XII nerve, there are an increase in both the number of mitochondria and area of mitochondria. These along with elevated levels of LC3‐II to LC3‐I indicate reduced mitophagy. In conclusion, the Optn−/− ALS mouse model displays motor neuron pathology, increased nerve demyelination and aberrant control of breathing leading to respiratory insufficiency.