Cytokine-Induced and Stretch-Induced Sphingosine 1-Phosphate Production by Enthesis Cells Could Favor Abnormal Ossification in Spondyloarthritis

Spondyloarthritis (SpA) is a common rheumatic disease characterized by enthesis inflammation (enthesitis) and ectopic ossification (enthesophytes). The current pathogenesis model suggests that inflammation and mechanical stress are both strongly involved in SpA pathophysiology. We have previously observed that the levels of sphingosine 1-phosphate (S1P), a bone anabolic molecule, were particularly high in SpA patients' serum compared to healthy donors. Therefore, we wondered how this deregulation was related to SpA molecular mechanisms. Mouse primary osteoblasts, chondrocytes, and tenocytes were used as cell culture models. The sphingosine kinase 1 (Sphk1) gene expression and S1P secretion were significantly enhanced by cyclic stretch in osteoblasts and chondrocytes. Further, TNF-α and IL-17, cytokines implicated in enthesitis, increased Sphk1 mRNA in chondrocytes in an additive manner when combined to stretch. The immunochemistry on mouse ankles showed that sphingosine kinase 1 (SK1) was localized in some chondrocytes; the addition of a pro-inflammatory cocktail augmented Sphk1 expression in cultured ankles. Subsequently, fingolimod was used to block S1P metabolism in cell cultures. It inhibited S1P receptors (S1PRs) signaling and SK1 and SK2 activity in both osteoblasts and chondrocytes. Fingolimod also reduced S1PR-induced activation by SpA patients' synovial fluid (SF), demonstrating that the stimulation of chondrocytes by SFs from SpA patients involves S1P. In addition, when the osteogenic culture medium was supplemented with fingolimod, alkaline phosphatase activity, matrix mineralization, and bone formation markers were significantly reduced in osteoblasts and hypertrophic chondrocytes. Osteogenic differentiation was accompanied by an increase in S1prs mRNA, especially S1P_1/3, but their contribution to S1P-impact on mineralization seemed limited. Our results suggest that S1P might be overproduced in SpA enthesis in response to cytokines and mechanical stress, most likely by chondrocytes. Moreover, S1P could locally favor the abnormal ossification of the enthesis; therefore, blocking the S1P metabolic pathway could be a potential therapeutic approach for the treatment of SpA. © 2019 American Society for Bone and Mineral Research.     

Atypical case of perimesencephalic subarachnoid hemorrhage

Perimesencephalic subarachnoid hemorrhage (PM‐SAH) refers to intracranial hemorrhage located in the perimesencephalic cistern. The etiology remains mainly unclear, although venous leakage or rupture has been postulated. We report an interesting case of a 57‐year‐old healthy man who presented initially with PM‐SAH with worsening of subcortical lesions on follow‐up neuroimaging. Histopathological examination demonstrated cerebral amyloid angiopathy with perivascular inflammation.     

Risk of COVID-19 in Patients with Cancer Receiving Immune Checkpoint Inhibitors

ObjectiveThe aim of this study was to determine the rate of coronavirus disease‐19 (COVID‐19) among patients with cancer treated with immune checkpoint inhibitors (ICIs).Materials and MethodsThis was a retrospective study of 1,545 patients with cancer treated with ICIs between July 1, 2019, and February 29, 2020, and 20,418 age‐, sex‐, and cancer category‐matched controls in a large referral hospital system. Confirmed COVID‐19 case and mortality data were obtained with Massachusetts Department of Public Health from March 1 through June 19, 2020.ResultsThe mean age was 66.6 years, and 41.9% were female. There were 22 (1.4%) and 213 (1.0%) COVID‐19 cases in the ICI and control groups, respectively. When adjusting for demographics, medical comorbidities, and local infection rates, ICIs did not increase COVID‐19 susceptibility.ConclusionICIs did not increase the rate of COVID‐19. This information may assist patients and their oncologists in decision‐making surrounding cancer treatment during this pandemic.     

Thermal Ablation,Embolization, and Selective Internal Radiation Therapy Combined with Checkpoint Inhibitor Cancer Immunotherapy: Safety Analysis

PurposeTo describe interventional oncology therapies combined with immune checkpoint inhibitor (ICI) therapy targeting the programmed death 1 pathway in patients with different neoplasms.Materials and MethodsThis was a retrospective cohort study of patients who underwent tumor-directed thermal ablation, embolization, or selective internal radiation therapy (SIRT) between January 1, 2011, and May 1, 2019, and received anti–programmed death 1/PD-L1 agents ≤ 90 days before or ≤ 30 days after the interventional procedure. Immune-related adverse events (irAEs) and procedural complications ≤ 90 days after the procedure were graded according to the Common Terminology Criteria for Adverse Events version 5.0. The study included 65 eligible patients (49% female; age 63 years ± 11.1). The most common tumors were metastatic melanoma (n = 28) and non–small cell lung cancer (NSCLC) (n = 12). Patients underwent 78 procedures (12 patients underwent > 1 procedure), most frequently SIRT (35.9%) and cryoablation (28.2%). The most common target organs were liver (46.2%), bone (24.4%), and lung (9.0%). Most patients received ICI monotherapy with pembrolizumab (n = 30), nivolumab (n = 22), and atezolizumab (n = 6); 7 patients received ipilimumab and nivolumab.ResultsSeven (10.8%) patients experienced an irAE (71.4% grade 1–2), mostly affecting the skin. Median time to irAE was 33 days (interquartile range, 19–38 days). Five irAEs occurred in patients with melanoma, and no irAEs occurred in patients with NSCLC. Management required corticosteroids (n = 3) and immunotherapy discontinuation (n = 1); all irAEs resolved to grade ≤ 1. There were 4 intraprocedural and 32 postprocedural complications (77.8% grade < 3). No grade 5 irAEs and/or procedural complications occurred.ConclusionsNo unmanageable or unanticipated toxicities occurred within 90 days after interventional oncology therapies combined with ICIs.     

Relationship of the degree of physical activity, blood pressure and body fat among teenagers in Madrid

BACKGROUND: It is throughout childhood and adolescence that many behavior patterns which are going to have a powerful influence on health during adult life are established. This study is aimed at analysing the influence physical activity has on the health of adolescents and at determining the relationship thereof with blood pressure (BP) and body composition. METHODS: The research was conducted from November 2002 to February 2003, using the Modifiable Physical Activity Questionnaire for Adolescents, which measures the degree of physical activity. The anthropometric variables and blood pressure were also measured for the sample comprised of 554 adolescents within the 12-18 age range from 35 schools in Madrid. RESULTS: A total of 13.2% of the males and 36.4% of the females were found to be inactive. The averages for the systolic/diastolic BP were 125.6/71.3 mmHg in the males and 118/69.4 mmHg in the females, but physical activity was found to have an influence solely on the diastolic BP for the males. A total of 48.27% of the females showed a tendency toward being overweight, as compared to 13.53% of the males. In the case of the females, a relationship was found to exist between body fat and degree of physical activity. CONCLUSIONS: The degree of physical activity shows itself to be a factor related to the health of adolescents, although taking on a different focus in each gender. Among the males, it has a significant bearing on the diastolic BP, whilst among the females, its influence is seen in the degree of body fat.     

One‐year clinical experience of perampanel in Spain: a multicentre study of efficacy and tolerability

Perampanel, a non‐competitive antagonist of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptors, is the most recent antiepileptic drug available in Spain, marketed in January 2014. It was initially approved by the European Medicines Agency as adjunctive treatment for partial‐onset seizures in patients 12 years and older, but recently also for primary generalized tonic‐clonic seizures. Although clinical trials provide essential information about the drug, they do not reflect daily clinical practice. This retrospective study shows the initial experience with perampanel in 11 Spanish hospitals during its first year post‐commercialisation. All patients who started perampanel treatment were included, but efficacy and tolerability were only assessed in those patients with a minimum follow‐up period of six months. In total, 256 patients were treated with perampanel before September 2014, and 253 had an observational period of one year. After six months, 216/256 patients (84%) continued on perampanel and 180/253 (71.1%) completed one year of treatment. The mean number of previous antiepileptic drugs used was 6.83 and the median number of concomitant antiepileptic drugs was 2. The mean perampanel dose was 7.06 mg and 8.26 mg at six and 12 months, respectively. The responder rate was 39.5% and 35.9% at both follow‐up points, respectively. Adverse events were experienced by 91/253 (35.5%) and resulted in withdrawal in 37 (14.6%). The most common adverse events were somnolence, dizziness, and irritability. We found no significant differences between concomitant use of enzyme‐inducing and non‐inducing antiepileptic drugs, regarding efficacy, adverse effects, or withdrawals. Irritability was not influenced by concomitant use of levetiracetam, relative to other drugs, but was more frequently observed in patients with a history of psychiatric problems or learning disabilities.     

Critical role for sphingosine kinase-1 in regulating survival of neuroblastoma cells exposed to amyloid-beta peptide

We examined the role of sphingosine kinase-1 (SphK1), a critical regulator of the ceramide/sphingosine 1-phosphate (S1P) biostat, in the regulation of death and survival of SH-SY5Y neuroblastoma cells in response to amyloid beta (Abeta) peptide (25-35). Upon incubation with Abeta, SH-SY5Y cells displayed a marked down-regulation of SphK1 activity coupled with an increase in the ceramide/S1P ratio followed by cell death. This mechanism was redox-sensitive; N-acetylcysteine totally abrogated the down-regulation of SphK1 activity and strongly inhibited Abeta-induced cell death. SphK1 overexpression impaired the cytotoxicity of Abeta, whereas SphK1 silencing by RNA interference mimicked Abeta-induced cell death, thereby establishing a critical role for SphK1. We further demonstrated that SphK1 could mediate the well established cytoprotective action of insulin-like growth factor (IGF-I) against Abeta toxicity. A dominant-negative form of SphK1 or its pharmacological inhibition not only abrogated IGF-I-triggered stimulation of SphK1 but also hampered IGF-I protective effect. Similarly to IGF-I, the neuroprotective action of TGF-beta1 was also dependent on SphK1 activity; activation of SphK1 as well as cell survival were impeded by a dominant-negative form of SphK1. Taken together, these results provide the first illustration of SphK1 role as a critical regulator of death and survival of Abeta-treated cells.