Brain tumor masquerading as dengue in a three-year-old boy

Paediatric gliomas represent the most common brain tumour in children. Early diagnosis and treatment greatly improve survival. Paediatric gliomas depend on pathways and genes responsible for mitotic activity and cell proliferation as well as angiogenesis (mitogen-activated protein kinases, vascular endothelial growth factor, epidermal growth factor pathways). Symptoms seen as persistent headaches, behavior changes, early morning nausea, emesis, diplopia, and papilledema. Patients may also present with more specific localizing symptoms such as focal motor deficits, hemiplegia, pyramidal tract findings, dysmetria, and chorea; depending upon the tumor’s location can facilitate diagnosis, but they are not always present and therefore diagnosis is occasionally delayed. Here we report a case of a boy hailing from lower socioeconomic status with history of abdominal pain, irritability, fever and cough initially mimicking clinical features and symptoms of dengue encephalitis but subsequent deterioration of patient though on medication and review with MRI suggestive of a glioma.

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer's disease

Brain perfusion and normal blood brain barrier integrity are reduced early in Alzheimer's disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains to characterise pathological transcriptional signatures. We found that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. EC transcriptional signatures identified mechanisms for impaired b-amyloid clearance. Evidence for immune activation was found with upregulation of interferon signalling genes in EC and in pericytes (PC). Transcriptional signatures suggested dysregulation of vascular homeostasis and angiogenesis with upregulation of pro-angiogenic signals (HIF1A) and metabolism in EC, but downregulation of homeostatic growth factor pathways (VEGF, EGF, insulin) in EC and PC and of extracellular matrix genes in fibroblasts (FB). Our genomic dissection of vascular cell risk gene enrichment suggests a potentially causal role for EC and defines transcriptional signatures associated with microvascular dysfunction in AD.

Trajectories of frailty in aging: Prospective cohort study

Background Emerging evidence suggests that there is significant variability in the progression of frailty in aging. We aimed to identify latent subpopulations of frailty trajectories, and examine their clinical and biological correlates. Methods We characterized frailty using a 41-item cumulative deficit score at baseline and annual visits up to 12 years in 681 older adults (55% women, mean age 74·6 years). Clinical risk profile and walking while talking performance as a clinical marker of trajectories were examined. Mortality risk associated with trajectories was evaluated using Cox regression adjusted for established survival predictors, and reported as hazard ratios (HR). Proteome-wide analysis was done. Findings Latent class modeling identified 4 distinct frailty trajectories: relatively stable (34·4%) as well as mild (36·1%), moderate (24·1%) and severely frail (5·4%). Four distinct classes of frailty trajectories were also shown in an independent sample of 515 older adults (60% women, 68% White, 26% Black). The stable group took a median of 31 months to accumulate one additional deficit compared to 20 months in the severely frail group. The worst trajectories were associated with modifiable risk factors such as low education, living alone, obesity, and physical inactivity as well as slower walking while talking speed. In the pooled sample, mild (HR 2·33, 95% CI 1·30–4·18), moderate (HR 2·49, 95% CI 1·33–4·66), and severely frail trajectories (HR 5·28, 95% CI 2·68–10·41) had higher mortality compared to the stable group. Proteomic analysis showed 11 proteins in lipid metabolism and growth factor pathways associated with frailty trajectories. Conclusion Frailty shows both stable and accelerated patterns in aging, which can be distinguished clinically and biologically.

843 Reproducible, MoA-reflecting reporter-based bioassays to enable drug development of biosimilars and biobetters

BackgroundCytokines and growth factors are small immunomodulatory proteins secreted by a wide variety of cells (e.g. fibroblasts, endothelial and stromal cells) that regulate surrounding cells via autocrine, paracrine or endocrine mechanisms. Immunocytokines are a promising class of activators of the immune system, with the potential to be used alone or in combination with other therapeutic agents to treat a variety of disease including autoimmunity and cancer. This class of biologics includes FDA-approved cytokine therapies (e.g. IFN, IL-2 and Epo) as well as an increasing number of biologics designed to block cytokine activity. The latter class of biologics includes basiliximab (IL-2R), tocilizumab and sarilumabad (IL-6R), siltuximab (IL-6), ustekinumab and its biosimilars (IL-12/IL-23 p40), secukinumab (IL-17A), bevasizumab (VEGF), and denosumab (RANKL). Pharmaceutical pipelines include an increasing number of biosimilar and biobetter molecules with sustained and targeted activities with a goal to improve drug potency, patient tolerance and clinical response.MethodsQuantitative and reproducible functional bioassays are critical for the development and manufacture of biologics drugs targeting cytokine and growth factor pathways. In many cases, existing bioassays rely on the use of primary cells and measurement of complex endpoints. These assays are highly variable, difficult to implement, and often fail to yield data quality required for drug development in a quality-controlled environment. To address this problem, we have developed a suite of bioluminescent luciferase-based reporter bioassays that can be used to quantitatively measure the activity of specific cytokines and growth factors, including: IL-2, IL-6, IL-12, IL-15, IL-17, IL-23, VEGF and RANKL.ResultsThese mechanism of action (MOA) reflecting bioassays exhibit the required performance metrics for use in potency and stability studies. Importantly, these bioassays have been optimized in a thaw-and-use cell format, which eliminates the need for cell culture and ensures high reproducibility, convenience and transferability.ConclusionsIn summary, bioluminescent reporter-based bioassays offer significant advantages over primary cell-based bioassays and are valuable tools for the development and manufacturing of novel biologics targeting cytokine and growth factor pathways.

Health Benefits of Polyphenols and Carotenoids in Age-Related Eye Diseases

Oxidative stress and inflammation play a critical role in the initiation and progression of age-related ocular abnormalities as cataract, glaucoma, diabetic retinopathy, and macular degeneration. Therefore, phytochemicals with proven antioxidant and anti-inflammatory activities, such as carotenoids and polyphenols, could be of benefit in these diseases. We searched PubMed and Web of Science databases for original studies investigating the benefits of different carotenoids and polyphenols in age-related ophthalmic diseases. Our results showed that several polyphenols (such as anthocyanins, Ginkgo biloba, quercetin, and resveratrol) and carotenoids (such as lutein, zeaxanthin, and mezoxanthin) have shown significant preventive and therapeutic benefits against the aforementioned conditions. The involved mechanisms in these findings include mitigating the production of reactive oxygen species, inhibiting the tumor necrosis factor-α and vascular endothelial growth factor pathways, suppressing p53-dependent apoptosis, and suppressing the production of inflammatory markers, such as interleukin- (IL-) 8, IL-6, IL-1a, and endothelial leucocyte adhesion molecule-1. Consumption of products containing these phytochemicals may be protective against these diseases; however, adequate human data are lacking. This review discusses the role and mechanisms of polyphenols and carotenoids and their possible synergistic effects on the prevention and treatment of age-related eye diseases that are induced or augmented by oxidative stress and inflammation.

40 YEARS OF IGF1: IGF-binding proteins

Insulin-like growth factor-binding proteins (IGFBPs) 1–6 bind IGFs but not insulin with high affinity. They were initially identified as serum carriers and passive inhibitors of IGF actions. However, subsequent studies showed that, although IGFBPs inhibit IGF actions in many circumstances, they may also potentiate these actions. IGFBPs are widely expressed in most tissues, and they are flexible endocrine and autocrine/paracrine regulators of IGF activity, which is essential for this important physiological system. More recently, individual IGFBPs have been shown to have IGF-independent actions. Mechanisms underlying these actions include (i) interaction with non-IGF proteins in compartments including the extracellular space and matrix, the cell surface and intracellular space, (ii) interaction with and modulation of other growth factor pathways including EGF, TGF-β and VEGF, and (iii) direct or indirect transcriptional effects following nuclear entry of IGFBPs. Through these IGF-dependent and IGF-independent actions, IGFBPs modulate essential cellular processes including proliferation, survival, migration, senescence, autophagy and angiogenesis. They have been implicated in a range of disorders including malignant, metabolic, neurological and immune diseases. A more complete understanding of their cellular roles may lead to the development of novel IGFBP-based therapeutic opportunities.

The PI3K Pathway at the Crossroads of Cancer and the Immune System: Strategies for Next Generation Immunotherapy Combinations

Immunotherapy has led to a paradigm shift in the treatment of some malignancies, providing long-term, durable responses for a subset of patients with advanced cancers. Increasingly, research has identified links between the immune system and critical oncogenic growth factor pathways. The phosphoinositide 3-kinase (PI3K)-AKT-mTOR cascade is frequently hyperactivated in cancer, and plays an integral role in many cellular processes including tumour growth and survival and can underlie resistance to therapies. In this review, we first summarize two key learnings from the initial studies of inhibitors of this pathway, including the profile of immune-related adverse events such as colitis, transaminitis and pneumonitis and the increased incidence of infections with the majority of agents that target the PI3K-AKT-mTOR pathway. We then discuss recent advances in our understanding of the role of this pathway in the tumour micro-environment, and in the regulation of innate and adaptive immune responses, and propose synergistic combination strategies with PI3K-network inhibitors and cancer immunotherapy.