Mechanism of Lck Activation in Driving Leukemia Cell Proliferation

Leukemia is a type of cancer that develops in blood-forming tissues of the immune system. These tissues can include the bone marrow or sites within the lymphatic system such as the lymph nodes. Leukemia progresses from a mutational event within a white blood cell. Often this mutation alters the cell’s normal life cycle, resulting in uninhibited cell division and growth. With this uncontrolled cell proliferation, mutated white blood cells accumulate and begin interfering with the functioning of healthy cells. Scientists are unsure of the exact mechanisms required for leukemia development. However, recently scientists identified four characteristic mutations in the protein tyrosine kinase, Lck, found specifically in the CTV-1 leukemia cell line. Lck is suspected to play an important regulatory role in immune system cell growth. In this honors project, I introduced these mutations into the Lck gene and produced the wildtype and the mutant enzymes. By comparing the mutated enzyme’s activity to the wild-type enzyme’s activity, we can potentially better understand how a mutation in Lck could stimulate cell proliferation. One of the mutations is an insertion mutation located in the linker region of the Lck’s structure. It is a potentially interesting alteration that could result in the enzyme’s constitutive activation. This inability for the enzyme to be turned off not only demonstrates how mutated Lck could be contributing to cancer progression but also reveals valuable knowledge about the functional importance of the linker region in Lck

Evidence for activated Lck protein tyrosine kinase as the driver of proliferation in acute myeloid leukemia cell, CTV-1

Acute myeloid leukemia (AML) is a heterogeneous group of fast growing cancers of myeloid progenitor cells, for which effective treatments are still lacking. Identification of signaling inhibitors that block their proliferation could reveal the proliferative mechanism of a given leukemia cell, and provide small molecule drugs for targeted therapy for AML. In this study, kinase inhibitors that block the majority of cancer signaling pathways are evaluated for their inhibition of two AML cell lines of the M5 subtypes, CTV-1 and THP-1. While THP-1 cells do not respond to any of these inhibitors, CTV-1 cells are potently inhibited by dasatinib, bosutinib, crizotinib, A-770041, and WH-4-23, all potent inhibitors for Lck, a Src family kinase. CTV-1 cells contain a kinase activity that phosphorylates an Lck-specific peptide substrate in an Lck inhibitor-sensitive manner. Furthermore, the Lck gene is over-expressed in CTV-1, and it contains four mutations, two of which are located in regions critical for Lck negative regulation, and are confirmed to activate Lck. Collectively, these results provide strong evidence that mutated and overexpressed Lck is driving CTV-1 proliferation. While Lck activation and overexpression is rare in AML, this study provides a potential therapeutic strategy for treating patients with a similar oncogenic mechanism

How to do it: Vitamin D supplementation

Vitamin D testing and supplementation is of great interest to neurologists and their patients. Recommended nutritional intakes of vitamin D in the UK remain focused on bone health, despite increasing evidence for a role outside this area. Here we discuss how neurologists might approach vitamin D testing and supplementation, focusing on two conditions associated with vitamin D deficiency that have an increased risk of downstream complications resulting from these: multiple sclerosis and epilepsy. We set out a rationale for testing serum 25-hydroxyvitamin D concentrations and discuss our personal practice in terms of supplementation, with evidence where available

Patterns of abundance across geographical ranges as a predictor for responses to climate change:Evidence from UK rocky shores

Aim: Understanding patterns in the abundance of species across thermal ranges can give useful insights into the potential impacts of climate change. The abundant-centre hypothesis suggests that species will reach peak abundance at the centre of their thermal range where conditions are optimal, but evidence in support of this hypothesis is mixed and limited in geographical and taxonomic scope. We tested the applicability of the abundant-centre hypothesis across a range of intertidal organisms using a large, citizen science-generated data set. Location: UK. Methods: Species' abundance records were matched with their location within their thermal range. Patterns in abundance distribution for individual species, and across aggregated species abundances, were analysed using Kruskal–Wallis tests and quantile general additive models. Results: Individually, invertebrate species showed increasing abundances in the cooler half of the thermal range and decreasing abundances in the warmer half of the thermal range. The overall shape for aggregated invertebrate species abundances reflected a broad peak, with a cool-skewed maximum abundance. Algal species showed little evidence for an abundant-centre distribution individually, but overall the aggregated species abundances suggested a hump-backed abundance distribution. Main Conclusions: Our study follows others in showing mixed support for the abundant-centre hypothesis at an individual species level, but demonstrates an increased predictability in species responses when an aggregated overall response is considered

A novel algorithmic approach to generate consensus treatment guidelines in adult Acute Myeloid Leukaemia

Induction therapy for acute myeloid leukaemia (AML) has changed with the approval of a number of new agents. Clinical guidelines can struggle to keep pace with an evolving treatment and evidence landscape and therefore identifying the most appropriate front-line treatment is challenging for clinicians. Here, we combined drug eligibility criteria and genetic risk stratification into a digital format, allowing the full range of possible treatment eligibility scenarios to be defined. Using exemplar cases representing each of the 22 identified scenarios, we sought to generate consensus on treatment choice from a panel of nine aUK AML experts. We then analysed >2500 real-world cases using the same algorithm, confirming the existence of 21/22 of these scenarios and demonstrating that our novel approach could generate a consensus AML induction treatment in 98% of cases. Our approach, driven by the use of decision trees, is an efficient way to develop consensus guidance rapidly and could be applied to other disease areas. It has the potential to be updated frequently to capture changes in eligibility criteria, novel therapies and emerging trial data. An interactive digital version of the consensus guideline is available

Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders

OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings

Experimentally assessing the effect of search effort on snare detectability

Reducing threats to biodiversity is the key objective of ranger patrols in protected areas. However, efforts can be hampered by rangers' inability to detect threats, and poor understanding of threat abundance and distribution in a landscape. Snares are particularly problematic due to their cryptic nature and limited selectivity with respect to captured animals' species, sex, or age. Using an experimental approach, we investigated the effect of search effort, habitat, season, and team on rangers' detection of snares in a tropical forest landscape. We provide an effort-detection curve, and use our findings to make preliminary predictions about snare detection under different scenarios of patrol effort. Results suggest that the overall probability of a searcher detecting any given snare in a 0.25/km2 area, assuming 60 min (or approximately 2 km) of search effort is 20% (95% CI ± 15–25%), with no significant effect of season, habitat or team. Our models suggested this would increase by approximately 10% with an additional 30mins/1 km of search effort. Our preliminary predictions of the effectiveness of different patrolling scenarios show that detection opportunities are maximised at low effort levels by deploying multiple teams to a single area, but at high effort levels deploying single teams becomes more efficient. Our results suggest that snare detectability in tropical forest landscapes is likely to be low, and may not improve dramatically with increased search effort. Given this, managers need to consider whether intensive snare-removal efforts are the best use of limited resources; the answer will depend on their underlying objectives

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Exposure to secondhand and thirdhand smoke in private vehicles: Measurements in air and dust samples

Background: This study aimed to estimate airborne nicotine concentrations and nicotine, cotinine, and tobaccospecific nitrosamines (TSNAs) in settled dust from private cars in Spain and the UK. Methods: We measured vapor-phase nicotine concentrations in a convenience sample of 45 private cars from Spain (N = 30) and the UK (N = 15) in 2017-2018. We recruited non-smoking drivers (n = 20), smoking drivers who do not smoke inside the car (n = 15), and smoking drivers who smoke inside (n = 10). Nicotine, cotinine, and three TSNAs (NNK, NNN, NNA) were also measured in settled dust in a random subsample (n = 20). We computed medians and interquartile ranges (IQR) of secondhand smoke (SHS) and thirdhand smoke (THS) compounds according to the drivers' profile. Results: 24-h samples yielded median airborne nicotine concentrations below the limit of quantification (LOQ) (IQR

The WHO-ITU MyopiaEd Programme: A Digital Message Programme Targeting Education on Myopia and Its Prevention

The objective of this paper is to provide an overview of the World Health Organization - International Telecommunication Union MyopiaEd programme - a digital message programme targeting education on myopia and its prevention. The development of the MyopiaEd programme included 4 key steps: (1) Conceptualization and consultation with experts in the field of myopia, mHealth and health behavior change; (2) Creation of SMS message libraries and programme algorithm; (3) Review of the message libraries to ensure relevance to the target audience; and (4) Pre-testing amongst end-user groups to ensure that the design of the programme and the message content were understandable. After reviewing the available evidence and considering input of the experts, the aims, end users and key themes of the programme were finalized. Separate SMS-adapted message libraries were developed, reviewed and pre-tested for four target end-user groups; (1) general population involved in the care of children (2) parents or caregivers of children with myopia; (3) adolescents with myopia; and (4) adults with myopia. The message libraries are part of a comprehensive toolkit, developed through a consultative process with experts in digital health, to support implementation within countries. The development of the MyopiaEd programme aims to provide a basis for Member States and other stakeholders to develop, implement and monitor large-scale mHealth programmes. It is aimed at raising awareness of good eye care behaviors and addressing common reasons for non-compliance to spectacle wear. The next steps will involve adapting and evaluating the MyopiaEd programme in selected settings