Targeting Aged Astrocytes May Be a New Therapeutic Strategy in Parkinson's Disease.

Commentary on: Chinta, S. J. Woods, G. Demaria M. et al. Cellular Senescence Is Induced by the Environmental Neurotoxin Paraquat and Contributes to Neuropathology Linked to Parkinson’s Disease. Cell Reports 2018; 22: 930-940. Parkinson’s disease (PD) becomes increasingly common with advancing age. It is therefore possible that cell senescence contributes to its pathophysiology. In a recent paper in Cell Reports, Chinta et al1 have shown that astrocytes exhibiting an age-associated (senescent) phenotype are toxic to neurons in vitro, and their removal is associated with better outcomes in a mouse model of PD. This finding may be relevant to other neurodegenerative conditions such as Alzheimer’s and Amyotrophic Lateral Sclerosis (ALS) in which cellular senescence is also implicated.2CHWG holds a MRC Clinician Scientist fellowship, and receives grants from the Rosetrees Trust, the Evelyn Trust and Addenbrooke’s Charitable Trust. She is also supported by the NIHR Cambridge Biomedical Research Centre. KMS holds a fellowship from the Wellcome Trust and her work is also supported by the NIHR Cambridge Biomedical Research Centr

Prognosis Does not Change the Landscape: Palliative Home Care Clients Experience High Rates of Pain and Nausea, Regardless of Prognosis

Background: Most individuals who typically receive palliative care (PC) tend to have cancer and a relatively short prognosis (\u3c 6 months). People with other life-limiting illnesses can also benefit from a palliative care approach. However, little is known about those who receive palliative home care in Ontario, Canada\u27s largest province. To address this gap, the goal of this project was to understand the needs, symptoms and potential differences between those with a shorter (\u3c 6 months) and longer prognosis (6+ months) for individuals receiving PC in the community. Methods: A cross-sectional analysis was conducted using interRAI Palliative Care (interRAI PC) assessment data collected between 2011 and 2018. Individuals with a shorter prognosis (\u3c 6 months; n = 48,019 or 64.1%) were compared to those with a longer prognosis (6+ months; n = 26,945) across several clinical symptoms. The standardized difference (stdiff), between proportions, was calculated to identify statistically meaningful differences between those with a shorter and longer prognosis. Values of the stdiff of 0.2 or higher (absolute value) indicated a statistically significant difference. Results: Overall, cancer was the most prevalent diagnosis (83.2%). Those with a shorter prognosis were significantly more likely to experience fatigue (75.3% vs. 59.5%; stdiff = 0.34) and shortness of breath at rest (22.1% vs. 13.4%; stdiff = 0.23). However, the two groups were similar in terms of severe pain (73.5% vs. 66.5%; stdiff = - 0.15), depressive symptoms (13.2% vs. 10.7%; stdiff = 0.08) and nausea (35.7% vs. 29.4%; stdiff = 0.13). Conclusions: These results highlight the importance of earlier identification of individuals who could benefit from a palliative approach to their care as individuals with a longer prognosis also experience high rates of symptoms such as pain and nausea. Providing PC earlier in the illness trajectory has the potential to improve an individual\u27s overall quality of life throughout the duration of their illness

The interRAI CHESS Scale is Comparable to the Palliative Performance Scale in Predicting 90-day Mortality in a Palliative Home Care Population

Background: Prognostic accuracy is important throughout all stages of the illness trajectory as it has implications for the timing of important conversations and decisions around care. Physicians often tend to over-estimate prognosis and may under-recognize palliative care (PC) needs. It is therefore essential that all relevant stakeholders have as much information available to them as possible when estimating prognosis. Aims: The current study examined whether the interRAI Changes in Health, End-Stage Disease, Signs and Symptoms (CHESS) Scale is a good predictor of mortality in a known PC population and to see how it compares to the Palliative Performance Scale (PPS) in predicting 90-day mortality. Methods: This retrospective cohort study used data from 2011 to 2018 on 80,261 unique individuals receiving palliative home care and assessed with both the interRAI Palliative Care instrument and the PPS. Logistic regression models were used to evaluate the relationship between the main outcome, 90-day mortality and were then replicated for a secondary outcome examining the number of nursing visits. Comparison of survival time was examined using Kaplan-Meier survival curves. Results: The CHESS Scale was an acceptable predictor of 90-day mortality (c-statistic = 0.68; p \u3c 0.0001) and was associated with the number of nursing days (c = 0.61; p \u3c 0.0001) and had comparable performance to the PPS (c = 0.69; p \u3c 0.0001). The CHESS Scale performed slightly better than the PPS in predicting 90-day mortality when combined with other interRAI PC items (c = 0.72; p \u3c 0.0001). Conclusion: The interRAI CHESS Scale is an additional decision-support tool available to clinicians that can be used alongside the PPS when estimating prognosis. This additional information can assist with the development of care plans, discussions, and referrals to specialist PC teams

Skeletal Muscle Measures as Predictors of Toxicity, Hospitalization, and Survival in Patients with Metastatic Breast Cancer Receiving Taxane-Based Chemotherapy

Severe skeletal muscle (SM) loss (sarcopenia), is associated with poor cancer outcomes including reduced survival and increased toxicity. This study investigates SM measures in metastatic breast cancer (MBC) patients receiving first line taxane-based chemotherapy and evaluates associations with treatment toxicity and other outcomes

RefSoil: A reference database of soil microbial genomes

A database of curated genomes is needed to better assess soil microbial communities and their processes associated with differing land management and environmental impacts. Interpreting soil metagenomic datasets with existing sequence databases is challenging because these datasets are biased towards medical and biotechnology research and can result in misleading annotations. We have curated a database of 922 genomes of soil-associated organisms (888 bacteria and 34 archaea). Using this database, we evaluated phyla and functions that are enriched in soils as well as those that may be underrepresented in RefSoil. Our comparison of RefSoil to soil amplicon datasets allowed us to identify targets that if cultured or sequenced would significantly increase the biodiversity represented within RefSoil. To demonstrate the opportunities to access these underrepresented targets, we employed single cell genomics in a pilot experiment to sequence 14 genomes. This effort demonstrates the value of RefSoil in the guidance of future research efforts and the capability of single cell genomics as a practical means to fill the existing genomic data gaps

Peripheral blood marker of residual acute leukemia after hematopoietic cell transplantation using multi-plex digital droplet PCR

BACKGROUND Relapse remains the primary cause of death after hematopoietic cell transplantation (HCT) for acute leukemia. The ability to identify minimal/measurable residual disease (MRD) via the blood could identify patients earlier when immunologic interventions may be more successful. We evaluated a new test that could quantify blood tumor mRNA as leukemia MRD surveillance using droplet digital PCR (ddPCR). METHODS The multiplex ddPCR assay was developed using tumor cell lines positive for the tumor associated antigens (TAA: WT1, PRAME, BIRC5), with homeostatic ABL1. On IRB-approved protocols, RNA was isolated from mononuclear cells from acute leukemia patients after HCT (n = 31 subjects; n = 91 specimens) and healthy donors (n = 20). ddPCR simultaneously quantitated mRNA expression of WT1, PRAME, BIRC5, and ABL1 and the TAA/ABL1 blood ratio was measured in patients with and without active leukemia after HCT. RESULTS Tumor cell lines confirmed quantitation of TAAs. In patients with active acute leukemia after HCT (MRD+ or relapse; n=19), the blood levels of WT1/ABL1, PRAME/ABL1, and BIRC5/ABL1 exceeded healthy donors (p<0.0001, p=0.0286, and p=0.0064 respectively). Active disease status was associated with TAA positivity (1+ TAA vs 0 TAA) with an odds ratio=10.67, (p=0.0070, 95% confidence interval 1.91 - 59.62). The area under the curve is 0.7544. Changes in ddPCR correlated with disease response captured on standard of care tests, accurately denoting positive or negative disease burden in 15/16 (95%). Of patients with MRD+ or relapsed leukemia after HCT, 84% were positive for at least one TAA/ABL1 in the peripheral blood. In summary, we have developed a new method for blood MRD monitoring of leukemia after HCT and present preliminary data that the TAA/ABL1 ratio may may serve as a novel surrogate biomarker for relapse of acute leukemia after HCT

Body Composition as a Predictor of Toxicity in Patients Receiving Anthracycline and Taxane–Based Chemotherapy for Early-Stage Breast Cancer

Poor body composition metrics (BCM) are associated with inferior cancer outcomes; however, in early breast cancer (EBC) there is a paucity of evidence regarding BCM’s impact on toxicities. This study investigates associations between BCM and treatment-related toxicity in EBC patients receiving anthracyclines-taxane based chemotherapy

Skeletal muscle measures and physical function in older adults with cancer: sarcopenia or myopenia?

BACKGROUND: Skeletal muscle loss, commonly known as sarcopenia, is highly prevalent in older adults and linked with adverse outcomes in cancer, yet the definition and role of sarcopenia remains uncertain. The aim of this study was to examine the association of Computerized Tomography (CT) assessed skeletal muscle measures with physical function in older adults with cancer. RESULTS: CTs for 185 patients were available. Median age 73 (IQR 68-76) and 56.5% female. After controlling for sex and BMI, we found no evidence that SMI was associated with physical function impairments. Both SMD and SMG were associated physical function impairments and higher values were associated with decreased limitations in instrumental activities of daily living (RR 0.84 [CI 0.73-0.96] and 0.94 [CI 0.89-0.99], respectively), climbing stairs (RR 0.84 [CI 0.76-0.94] and 0.91 [CI 0.87-0.96]), walking 1 block (RR 0.77 [CI 0.67-0.90] and 0.91 [CI 0.85-0.97]), and prolonged Timed Up and Go (RR 0.83 [CI 0.75-0.92] and 0.92 [CI 0.88-0.96]). MATERIALS AND METHODS: Using the Carolina Senior Registry, we identified patients with CT imaging performed within 60 days +/- of baseline geriatric assessment (GA). Skeletal muscle area and density (SMD) were analyzed from L3 lumbar segments. Muscle area and height (m2) were used to calculate skeletal muscle index (SMI). Skeletal Muscle Gauge (SMG) was created by multiplying SMI x SMD. CONCLUSIONS: Skeletal muscle mass as assessed from CT imaging was not associated with physical function impairments. Skeletal muscle radiodensity was more associated with physical function and may aid in identifying older adults at risk for functional impairments

The Panchromatic Hubble Andromeda Treasury I: Bright UV Stars in the Bulge of M31

As part of the Panchromatic Hubble Andromeda Treasury (PHAT) multi-cycle program, we observed a 12' \times 6.5' area of the bulge of M31 with the WFC3/UVIS filters F275W and F336W. From these data we have assembled a sample of \sim4000 UV-bright, old stars, vastly larger than previously available. We use updated Padova stellar evolutionary tracks to classify these hot stars into three classes: Post-AGB stars (P-AGB), Post-Early AGB (PE-AGB) stars and AGB-manqu\'e stars. P-AGB stars are the end result of the asymptotic giant branch (AGB) phase and are expected in a wide range of stellar populations, whereas PE-AGB and AGB-manqu\'e (together referred to as the hot post-horizontal branch; HP-HB) stars are the result of insufficient envelope masses to allow a full AGB phase, and are expected to be particularly prominent at high helium or {\alpha} abundances when the mass loss on the RGB is high. Our data support previous claims that most UV-bright sources in the bulge are likely hot (extreme) horizontal branch stars (EHB) and their progeny. We construct the first radial profiles of these stellar populations, and show that they are highly centrally concentrated, even more so than the integrated UV or optical light. However, we find that this UV-bright population does not dominate the total UV luminosity at any radius, as we are detecting only the progeny of the EHB stars that are the likely source of the UVX. We calculate that only a few percent of MS stars in the central bulge can have gone through the HP-HB phase and that this percentage decreases strongly with distance from the center. We also find that the surface density of hot UV-bright stars has the same radial variation as that of low-mass X-ray binaries. We discuss age, metallicity, and abundance variations as possible explanations for the observed radial variation in the UV-bright population.Comment: Accepted for publication in Ap

Linking energy sensing to suppression of JAK-STAT signalling: a potential route for repurposing AMPK activators?

YesExaggerated Janus kinase-signal transducer and activator of transcription (JAKSTAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5′-monophosphate (AMP)–activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAKSTAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.British Heart Foundation; Diabetes UK; Chief Scientist Office; NHS Greater Glasgow and Clyde Research Endowment Fund; Chest, Heart and Stroke Scotlan