An HLA-G/SPAG9/STAT3 axis promotes brain metastases

Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastatic cascade-the "premetastatic" or early stage when they first colonize the brain and the established macrometastatic stage. RNA sequencing was used to obtain the transcriptional profiles of premetastatic and macrometastatic (non-premetastatic) lung, breast, and melanoma BMICs. We identified that lung, breast, and melanoma premetastatic BMICs share a common transcriptomic signature that is distinct from their non-premetastatic counterparts. Importantly, we show that premetastatic BMICs exhibit increased expression of HLA-G, which we further demonstrate functions in an HLA-G/SPAG9/STAT3 axis to promote the establishment of brain metastatic lesions. Our findings suggest that unraveling the molecular landscape of premetastatic BMICs allows for the identification of clinically relevant targets that can possibly inform the development of preventive and/or more efficacious BM therapies

The discourse dynamics approach to metaphor and metaphor-led discourse analysis

The use of metaphor as a tool to uncover people's ideas, attitudes, and values through analysis of discourse is demonstrated and illustrated with data collected in a social science research project. A 'discourse dynamics' approach to metaphor situated within a complexity/dynamic systems perspective is developed. This approach is turned into a method of 'metaphor-led discourse analysis' which is described in detail, using a focus group discussion to illustrate the procedure: transcription, metaphor identification, coding metaphors and using software, and finding patterns of metaphor use from coded data. The reasoning that justifies decisions at each stage of the procedure is made explicit so that the trustworthiness of the method can be maximized. The method of metaphor-led discourse analysis has been developed through a series of empirical projects to be accessible and relevant to social science researchers as well as to metaphor scholars

How Subjective Is the Subject?

This article re-examines the issue of grammatical relations in Mandarin Chinese in light of the results of recent large-scale typological research on grammatical relations (henceforth GRs) worldwide. Specifically, it discusses three syntactic operations and constructions that are cross-linguistically relevant to the definition of grammatical relations, namely relativisation, reflexivisation, and quantifier float. The study adopts a strictly language-internal typological approach and avails itself of natural linguistic data or sentences sanity-checked by native speakers. The aim of this paper is twofold: first, it explores the hypothesis that, in line with various other languages, GRs in Mandarin Chinese are construction-specific. Second, it proposes an alternative approach capable of explaining the conflicting evidence often pointed out in the literature on GRs and subjecthood in Mandarin Chinese

A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study

BackgroundBrivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients.MethodsEligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response.ResultsOf 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension.ConclusionsBased on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability

Improving the Treatment and Assessment of Moderate and Severe Pain in a Pediatric Emergency Department

Background. The Janeway Children’s Hospital previously enacted a number of measures to improve pain management for patients in its emergency department (ED). While improvements were demonstrated, rates for the timely assessment and treatment of pain remain below standards of care. Objectives. The study objectives are to investigate the impact of the previous attempts to improve the treatment of pain and to explore ways to further improve pain management in the ED. Methods. Key informant interviews and a focus group were conducted with nurses, physicians, and parents whose children were identified as having severe pain. Results. Interviews were conducted with 31 parents or children, 9 physicians, and 8 nurses. The focus group was attended by 15 nurses. Previous initiatives were viewed as improvements. Continued barriers include difficulties in accurately capturing the level of pain, issues in treating pain for specific types of patients, and inadequacy in addressing patients in severe pain. Conclusion. Changes in pain treatment protocols can result in positive impacts but are likely insufficient on their own to achieve desired standards of care. Consistent measurement and engagement with staff can identify additional opportunities for improving pain management within an ED setting

Delayed diagnosis and issues with pump usage are the leading causes of diabetic ketoacidosis in children with diabetes living in Newfoundland and Labrador, Canada

Background Newfoundland and Labrador (NL) has a very high incidence of type 1 diabetes (T1DM) and admission rate for diabetic ketoacidosis (DKA). The purpose of this study was to identify characteristics and precipitating factors associated with pediatric DKA in this population. Methods This was a retrospective study on children diagnosed with DKA from 2007–2011 admitted to the province’s only tertiary care pediatric hospital. Demographics, biochemical characteristics, and reasons for DKA diagnosis were analyzed. Chi-square and Fisher Exact tests were performed for categorical variables; t- and non-parametric Kruskal-Wallis tests were performed for continuous variables. Results A total of 90 children were admitted with DKA (39.5% newly diagnosed; 60.5% were previously diagnosed). The rate of DKA on presentation for incident cases was 22.1%. More severe cases of DKA occurred in younger, newly diagnosed patients. Almost half of preexisting diabetes cases were recurrent DKA (49.1%). The most common presenting characteristics of newly diagnosed patients were weight loss, bedwetting, polyuria, polydipsia, and neurologic symptoms. Pre-existing diabetes patients most often presented with abdominal pain and vomiting. Diagnosis of diabetes in new patients and issues related to interrupted insulin delivery in pre-existing patients using insulin pump therapy were the most common factors associated with DKA. Of the newly diagnosed patients presenting in DKA, 64% had seen a physician in the weeks leading up to diagnosis. Conclusions Pediatric patients have predictable patterns associated with a diagnosis of DKA. Most cases of DKA could be prevented with earlier diagnosis and improved education and problem-solving by families and health care providers. DKA preventative strategies are recommended and should be aimed at patients, their families, and health care professionals especially those outside of pediatric centers