Targeting SLMAP-ALK—a novel gene fusion in lung adenocarcinoma

Assessment of ALK gene rearrangements is strongly recommended by the Molecular Testing Guideline for Selection of Lung Cancer Patients proposed by IASLC, AMP, and CAP at the time of diagnosis for patients with advanced stage disease. Non- small-cell lung cancer (NSCLC) with ALK gene rearrangements or the resulting fusion pro- teins have been, for the most part, successfully targeted with ALK tyrosine kinase inhibitors (TKIs). The most frequent rearrangement, the EML4-ALK oncogenic fusion, has more than 10 distinct variants, each with a discrete breakpoint in EML4. Recent studies have suggested that EML4-ALK variants may have differential responses to TKIs. Additionally, non-EML4- ALK fusions that result from ALK rearrangements with diverse 5′ partners could possibly have varied biologic and clinical implications in their therapeutic responses and outcomes of patients with NSCLC. Existing literature documents at least 20 non-EML4 fusion partners for ALK, and the clinical responsiveness to crizotinib ranges from increased sensitivity to re- sistance. This underscores the importance of identifying the precise 5′ fusion partner to ALK before initiation of therapy. Herein we report the identification of a novel SLMAP-ALK fusion in a patient with NSCLC

Modelling outcomes after paediatric brain injury with admission laboratory values: a machine-learning approach.

BACKGROUND: Severe traumatic brain injury (TBI) is a leading cause of mortality in children, but the accurate prediction of outcomes at the point of admission remains very challenging. Admission laboratory results are a promising potential source of prognostic data, but have not been widely explored in paediatric cohorts. Herein, we use machine-learning methods to analyse 14 different serum parameters together and develop a prognostic model to predict 6-month outcomes in children with severe TBI. METHODS: A retrospective review of patients admitted to Cambridge University Hospital's Paediatric Intensive Care Unit between 2009 and 2013 with a TBI. The data for 14 admission serum parameters were recorded. Logistic regression and a support vector machine (SVM) were trained with these data against dichotimised outcomes from the recorded 6-month Glasgow Outcome Scale. RESULTS: Ninety-four patients were identified. Admission levels of lactate, H+, and glucose were identified as being the most informative of 6-month outcomes. Four different models were produced. The SVM using just the three most informative parameters was the best able to predict favourable outcomes at 6 months (sensitivity = 80%, specificity = 99%). CONCLUSIONS: Our results demonstrate the potential for highly accurate outcome prediction after severe paediatric TBI using admission laboratory data

Analysis of three epoetin alpha products by LC and LC-MS indicates differences in glycosylation critical quality attributes, including sialic acid content

Erythropoietin (EPO) is one of the main therapeutics used to treat anaemic patients, greatly improving their quality of life. In this study, biosimilars Binocrit and a development product, called here CIGB-EPO, were compared to the originator product, Eprex. All three are epoetin alpha products, reputed to have similar glycosylation profiles. The quality, safety and efficacy of this biotherapeutic depend on the following glycosylation critical quality attributes (GCQAs): sialylation, N-glycolyl-neuraminic acid (Neu5Gc) content, branching, N-acetyl-lactosamine (LacNAc) extensions and O-acetylation pattern. Reverse-phase ultra high pressure liquid chromatography (RP-UHPLC) analysis of acid-released, 1,2-diamino-4,5-methylenedioxybenzene (DMB) labelled sialic acid derivatives and hydrophilic interaction liquid chromatography (HILIC) in combination with mass spectrometry (HILIC-UHPLC-MS) of procainamide (PROC) labelled N-glycans were the analytical tools used. An automated method for enzymatic release and PROC labelling was applied for the first time to the erythropoiesis stimulating agent (ESA) products, which facilitated novel, in-depth characterisation, and allowed identification of precise structural features including the location of O-acetyl groups on sialic acid (SA) moie-ties. Samples were digested by a sialate-O-acetylesterase (NanS) to confirm the presence of O-acetyl groups. It was found that Eprex contained the greatest relative abundance of O-acetylated derivatives, Binocrit expressed the least Neu5Gc, and CIGB-EPO showed the greatest variety of high-mannose-phosphate structures. The sialylation and LacNAc extension patterns of the three ESAs were similar, with a maximum of four N-acetyl-neuraminic acid (Neu5Ac) moieties detected per glycan. Such differences in SA derivatisation, particularly O-acetylation, could have consequences for the quality and safety of a biotherapeutic, as well as its efficacy

Partial Failure of Milk Pasteurization as a Risk for the Transmission of Campylobacter From Cattle to Humans

Background. Cattle are the second most common source of human campylobacteriosis. However, routes to account for this scale of transmission have not been identified. In contrast to chicken, red meat is not heavily contaminated at point of sale. Although effective pasteurization prevents milk-borne infection, apparently sporadic infections may include undetected outbreaks from raw or perhaps incompletely pasteurized milk.Methods. A rise in Campylobacter gastroenteritis in an isolated population was investigated using whole-genome sequencing (WGS), an epidemiological study, and environmental investigations.Results. A single strain was identified in 20 cases, clearly distinguishable from other local strains and a reference population by WGS. A case-case analysis showed association of infection with the outbreak strain and milk from a single dairy (odds ratio, 8; Fisher exact test P value = .023). Despite temperature records indicating effective pasteurization, mechanical faults likely to lead to incomplete pasteurization of part of the milk were identified by further testing and examination of internal components of dairy equipment.Conclusions. Here, milk distribution concentrated on a small area, including school-aged children with low background incidence of campylobacteriosis, facilitated outbreak identification. Low-level contamination of widely distributed milk would not produce as detectable an outbreak signal. Such hidden outbreaks may contribute to the substantial burden of apparently sporadic Campylobacter from cattle where transmission routes are not certain. The effective discrimination of outbreak isolates from a reference population using WGS shows that integrating these data and approaches into surveillance could support the detection as well as investigation of such outbreaks

Thresholds for identifying pathological intracranial pressure in paediatric traumatic brain injury.

Intracranial pressure (ICP) monitoring forms an integral part of the management of severe traumatic brain injury (TBI) in children. The prediction of elevated ICP from imaging is important when deciding on whether to implement invasive ICP monitoring for a patient. However, the radiological markers of pathologically elevated ICP have not been specifically validated in paediatric studies. Here in, we describe an objective, non-invasive, quantitative method of stratifying which patients are likely to require invasive monitoring. A retrospective review of patients admitted to Cambridge University Hospital's Paediatric Intensive Care Unit between January 2009 and December 2016 with a TBI requiring invasive neurosurgical monitoring was performed. Radiological biomarkers of TBI (basal cistern volume, ventricular volume, volume of extra-axial haematomas) from CT scans were measured and correlated with epochs of continuous high frequency variables of pressure monitoring around the time of imaging. 38 patients were identified. Basal cistern volume was found to correlate significantly with opening ICP (r = -0.53, p < 0.001). The optimal threshold of basal cistern volume for predicting high ICP ([Formula: see text]20 mmHg) was a relative volume of 0.0055 (sensitivity 79%, specificity 80%). Ventricular volume and extra-axial haematoma volume did not correlate significantly with opening ICP. Our results show that the features of pathologically elevated ICP in children may differ considerably from those validated in adults. The development of quantitative parameters can help to predict which patients would most benefit from invasive neurosurgical monitoring and we present a novel radiological threshold for this.We gratefully acknowledge financial support as follows. Research support: the Medical Research Council (MRC, Grant Nos. G0600986 ID79068 and G1002277 ID98489) and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: Peter J Hutchinson – NIHR Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship, NIHR Global Health Research Group on Neurotrauma, and NIHR Cambridge BRC. Joseph Donnelly is supported by a Woolf Fisher Scholarship. MC- NIHR BRC

Scaling up experimental ocean acidification and warming research: from individuals to the ecosystem

NERC UK Ocean Acidification Research Programme NE/HO1747X/1 The full text is under embargo until 17.08.1

Detection of STRN-ALK fusion in thyroid nodules with indeterminate cytopathology facilitates papillary thyroid cancer diagnosis

Thyroid cancer is the most common endocrine malignancy. Approximately 70% of cases of papillary thyroid carcinoma and 50% of poorly differentiated and anaplastic thyroid carcinoma harbor well-characterized driver mutations and chromosomal rearrangements that drive tumorigenesis. Molecular profiling has been helpful in identifying and informing follow-up strategies in tumors with more aggressive trajectories. Here, we report a case of papillary thyroid cancer (PTC) discovered in a patient with thyroid nodules with relatively benign ultrasound and fine needle aspiration (FNA) findings. Molecular testing in this patient identified a rare STRN-ALK fusion in two thyroid nodules with indeterminate and/or benign cytology. This led to the patient undergoing a thyroid lobectomy and a subsequent confirmation of papillary thyroid carcinoma upon resection. The report highlights the role of comprehensive molecular testing in thyroid lesions of indeterminate cytology

High-resolution dietary reconstruction of victims of the 79 CE Vesuvius eruption at Herculaneum by compound-specific isotope analysis.

The remains of those who perished at Herculaneum in 79 CE offer a unique opportunity to examine lifeways across an ancient community who lived and died together. Historical sources often allude to differential access to foodstuffs across Roman society but provide no direct or quantitative information. By determining the stable isotope values of amino acids from bone collagen and deploying Bayesian models that incorporate knowledge of protein synthesis, we were able to reconstruct the diets of 17 adults from Herculaneum with unprecedented resolution. Significant differences in the proportions of marine and terrestrial foods consumed were observed between males and females, implying that access to food was differentiated according to gender. The approach also provided dietary data of sufficient precision for comparison with assessments of food supply to modern populations, opening up the possibility of benchmarking ancient diets against contemporary settings where the consequences for health are better understood