Transcriptional characterization of iPSC-derived microglia as a model for therapeutic development in neurodegeneration.

Microglia are the resident immune cells in the brain that play a key role in driving neuroinflammation, a hallmark of neurodegenerative disorders. Inducible microglia-like cells have been developed as an in vitro platform for molecular and therapeutic hypothesis generation and testing. However, there has been no systematic assessment of similarity of these cells to primary human microglia along with their responsiveness to external cues expected of primary cells in the brain. In this study, we performed transcriptional characterization of commercially available human inducible pluripotent stem cell (iPSC)-derived microglia-like (iMGL) cells by bulk and single cell RNA sequencing to assess their similarity with primary human microglia. To evaluate their stimulation responsiveness, iMGL cells were treated with Liver X Receptor (LXR) pathway agonists and their transcriptional responses characterized by bulk and single cell RNA sequencing. Bulk transcriptome analyses demonstrate that iMGL cells have a similar overall expression profile to freshly isolated human primary microglia and express many key microglial transcription factors and functional and disease-associated genes. Notably, at the single-cell level, iMGL cells exhibit distinct transcriptional subpopulations, representing both homeostatic and activated states present in normal and diseased primary microglia. Treatment of iMGL cells with LXR pathway agonists induces robust transcriptional changes in lipid metabolism and cell cycle at the bulk level. At the single cell level, we observe heterogeneity in responses between cell subpopulations in homeostatic and activated states and deconvolute bulk expression changes into their corresponding single cell states. In summary, our results demonstrate that iMGL cells exhibit a complex transcriptional profile and responsiveness, reminiscent of in vivo microglia, and thus represent a promising model system for therapeutic development in neurodegeneration.

Lipidomic Analysis Reveals Differences in the Extent of Remyelination in the Brain and Spinal Cord.

During demyelination, lipid-rich myelin debris is released in the central nervous system (CNS) and must be phagocytosed and processed before new myelin can form. Although myelin comprises over 70% lipids, relatively little is known about how the CNS lipidome changes during demyelination and remyelination. In this study, we obtained a longitudinal lipidomic profile of the brain, spinal cord, and serum using a genetic mouse model of demyelination, known as Plp1-iCKO-Myrf. The mass spectrometry data is available at the Metabolomics Workbench, where it has been assigned Study ID ST002958. This model has distinct phases of demyelination and remyelination over the course of 24 weeks, in which loss of motor function peaks during demyelination. Using principal component analysis (PCA) and volcano plots, we have demonstrated that the brain and spinal cord have different remyelination capabilities and that this is reflected in different lipidomic profiles over time. We observed that plasmalogens (ether-linked phosphatidylserine and ether-linked phosphatidylcholine) were elevated specifically during the early stages of active demyelination. In addition, we identified lipids in the brain that were altered when mice were treated with a remyelinating drug, which may be CNS biomarkers of remyelination. The results of this study provide new insights into how the lipidome changes in response to demyelination, which will enable future studies to elucidate mechanisms of lipid regulation during demyelination and remyelination.

Lipidomic analysis reveals differences in the extent of remyelination in the brain and spinal cord.

During demyelination, lipid-rich myelin debris is released in the central nervous system (CNS) and must be phagocytosed and processed before new myelin can form. Although myelin comprises over 70% lipids, relatively little is known about how the CNS lipidome changes during demyelination and remyelination. In this study, we obtained a longitudinal lipidomic profile of the brain, spinal cord, and serum using a genetic mouse model of demyelination, known as Plp1 -iCKO- Myrf mice. This model has distinct phases of demyelination and remyelination over the course of 24 weeks, in which loss of motor function peaks during demyelination. Using principal component analysis (PCA) and volcano plots, we have demonstrated that the brain and spinal cord have different remyelination capabilities and that this is reflected in different lipidomic profiles over time. We observed that plasmalogens (ether-linked phosphatidylserine and ether-linked phosphatidylcholine) were elevated specifically during the early stages of active demyelination. In addition, we identified lipids in the brain that were altered when mice were treated with a remyelinating drug, which may be CNS biomarkers of remyelination. The results of this study provide new insights into how the lipidome changes in response to demyelination, which will enable future studies to elucidate mechanisms of lipid regulation during demyelination and remyelination.

Concurrent versus sequential chemoradiotherapy for unresectable locally advanced stage III non-small cell lung cancer: Retrospective analysis in a single United Kingdom cancer centre.

INTRODUCTION: Stage III unresectable locally advanced non-small cell lung cancer (NSCLC) is a complex disease group with poor long-term survival. Clinical data suggests curative intent concurrent chemoradiotherapy (CCRT) is superior to a sequential (SCRT) approach but comes with additional toxicities. We report real world data regarding overall survival and toxicity to aid clinical decision making in balancing optimal management and treatment tolerability. METHODS: Retrospective analysis of survival data, treatment toxicities, and rates of treatment completion were performed for 241 patients who underwent chemoradiotherapy for unresectable stage III NSCLC within Leeds Cancer Centre from January 2011 to December 2014. RESULTS: Median survival was 18.8 months following SCRT compared to 22.7 months following CCRT HR 0.90 (95% CI 0.67-1.20, P = 0.46). Median follow up was 21 months. The clinical benefit rate for CCRT compared to SCRT was 22.7% versus 24%. In the CCRT group 63.8% patients completed treatment compared to 46% in the SCRT arm (P < 0.01). 90-day mortality rates were low in CCRT and SCRT cohorts at 4.3% and 1% respectively. There was greater pulmonary toxicity following CCRT versus SCRT (13.5% versus 1.0%, P < 0.01). CONCLUSION: This study provides real world data regarding the radical treatment of unresectable stage III NSCLC. Increased hospital admissions and pneumonitis toxicities did not adversely affect treatment completion for those undergoing CCRT; this was likely due to careful patient selection based on performance status. SCRT still remains an important treatment modality for patients who cannot tolerate the upfront CCRT approach but could still be treated with curative intent.

A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity.

AIMS: To assess the pharmacokinetic (PK) and pharmacodynamic characteristics of VI-0521, a fixed-dose combination of immediate-release phentermine (PHEN) and extended-release topiramate (TPM) in adolescents aged 12 to 17 years with obesity, and to report weight loss and adverse events using this drug combination. MATERIALS AND METHODS: This was a multicentre, randomized, double-blind, parallel-design, placebo-controlled study in adolescents with obesity. A total of 42 adolescents were randomly assigned in a 1:1:1 ratio to placebo, or to a mid-dose (PHEN/TPM 7.5 mg/46 mg), or a top-dose (PHEN/TPM 15 mg/92 mg) of VI-0521. A total of 26 adolescents were included in the PK analysis (14 from the mid-dose group and 12 from the top-dose group). RESULTS: On day 56, arithmetic means of terminal elimination half-life, apparent clearance (CL/F) and apparent central volume of distribution (Vc/F) were consistent across dose levels for both PHEN and TPM. Arithmetic means of CL/F and Vc/F for PHEN and TPM administered as a combination in adolescents with obesity were within 10% to 30% of those previously assessed in adults with obesity enrolled in phase II and III studies. A higher proportion of adolescents in both the mid- and top-dose groups (13.3% and 50.0%, respectively) compared with placebo (0.0%) reached ≥5% weight loss at day 56. The least squares (LS) mean change in systolic blood pressure from baseline to day 56 was -5.2 mmHg for the placebo group, -2.5 mmHg for the mid-dose group, and - 5.5 mmHg for the top-dose group. The LS mean change in diastolic blood pressure from baseline to day 56 was -2.4 mmHg for the placebo group, +3.8 mmHg for the mid-dose group, and + 2.0 mmHg for the top-dose group. Participants in the top-dose group had increases in heart rate from baseline of 4.1 bpm, while participants in the mid-dose group experienced a mean decrease in heart rate of 4.5 bpm at day 56. Both PHEN/TPM dose combinations were safe and well tolerated. CONCLUSIONS: Treatment of adolescents with obesity using a fixed-dose combination of PHEN/TPM for 8 weeks resulted in exposure to PHEN and TPM that was comparable to that observed in adults, statistically significant weight loss, and a tolerable safety profile. These data indicate that both mid- and top-dose levels are appropriate for longer-term safety and efficacy studies in adolescents.

Telomere length is an independent prognostic marker in MDS but not in de novo AML.

Telomere dysfunction is implicated in the generation of large-scale genomic rearrangements that drive progression to malignancy. In this study we used high-resolution single telomere length analysis (STELA) to examine the potential role of telomere dysfunction in 80 myelodysplastic syndrome (MDS) and 95 de novo acute myeloid leukaemia (AML) patients. Despite the MDS cohort being older, they had significantly longer telomeres than the AML cohort (P < 0·0001) where telomere length was also significantly shorter in younger AML patients (age <60 years) (P = 0·02) and in FLT3 internal tandem duplication-mutated AML patients (P = 0·03). Using a previously determined telomere length threshold for telomere dysfunction (3·81 kb) did not provide prognostic resolution in AML [Hazard ratio (HR) = 0·68, P = 0·2]. In contrast, the same length threshold was highly prognostic for overall survival in the MDS cohort (HR = 5·0, P < 0·0001). Furthermore, this telomere length threshold was an independent parameter in multivariate analysis when adjusted for age, gender, cytogenetic risk group, number of cytopenias and International Prognostic Scoring System (IPSS) score (HR = 2·27, P < 0·0001). Therefore, telomere length should be assessed in a larger prospective study to confirm its prognostic role in MDS with a view to integrating this variable into a revised IPSS.

Relationships with Peers and Use of the School Environment of Mainstream Secondary School Pupils with Asperger Syndrome (High-Functioning Autism): A Case-Control Study

This study is of the in-school social relationships with peers of mainstream secondary school pupils with Asperger syndrome/high-functioning autism (AS/HFA) and of matched controls. Fifty-seven pupils participated in the study (30 with AS/HFA and 27 controls), ranging from school years 7-13 (age 11-18 years). By comparison with controls, pupils with AS/HFA engaged in fewer social interactions during the school day, both in and out of lessons, spent break and lunch times inside in quieter more closely adult supervised areas of the school, reported having fewer friends, were less physically active, were more likely to be the targets of bullying but had equally good school attendance records. Implications for further research are discussed (AU)

Este estudio trata de las relaciones sociales con los iguales dentro de las escuelas integradas de secundaria por parte, por un lado, de alumnos con síndrome de Asperger/ autismo de alto funcionamiento (SA/AAF) y por otro, de sus casos controles emparejados. Han participado 57 alumnos (30 con SA/AAF y 27 controles), entre los cursos 7 y 13 (11-18 años). Los resultados sugieren que en comparación con los casos control, los alumnos con SA/AAF participan en menos interacciones sociales durante la jornada escolar, tanto dentro como fuera de clase, pasan los recreos y las horas de comida dentro, en áreas más tranquilas y más supervisadas por adultos, reconocen tener menos amigos que los casos control, son significativamente menos activos físicamente y son blanco más probable de maltrato por los iguales, pero sus registros de asistencia son igual de buenos que los de sus compañeros. Se discuten las implicaciones para investigaciones futuras (AU)