Reciprocal priming between receptor tyrosine kinases at recycling endosomes orchestrates cellular signalling outputs.

Integration of signalling downstream of individual receptor tyrosine kinases (RTKs) is crucial to fine-tune cellular homeostasis during development and in pathological conditions, including breast cancer. However, how signalling integration is regulated and whether the endocytic fate of single receptors controls such signalling integration remains poorly elucidated. Combining quantitative phosphoproteomics and targeted assays, we generated a detailed picture of recycling-dependent fibroblast growth factor (FGF) signalling in breast cancer cells, with a focus on distinct FGF receptors (FGFRs). We discovered reciprocal priming between FGFRs and epidermal growth factor (EGF) receptor (EGFR) that is coordinated at recycling endosomes. FGFR recycling ligands induce EGFR phosphorylation on threonine 693. This phosphorylation event alters both FGFR and EGFR trafficking and primes FGFR-mediated proliferation but not cell invasion. In turn, FGFR signalling primes EGF-mediated outputs via EGFR threonine 693 phosphorylation. This reciprocal priming between distinct families of RTKs from recycling endosomes exemplifies a novel signalling integration hub where recycling endosomes orchestrate cellular behaviour. Therefore, targeting reciprocal priming over individual receptors may improve personalized therapies in breast and other cancers.

Indwelling medical device use and sepsis risk at a health professional shortage area hospital: Possible interaction with length of hospitalization.

BACKGROUND: We aimed to identify risk factors for sepsis diagnosis and possible interaction with length of hospital stay (LOS) among inpatients at a rural Health Professional Shortage Area hospital. METHODS: This case-control study examined 600 adult patients (300 cases and 300 controls) admitted to a rural health system in North Carolina between 2012 and 2018. Case selection was based on assignment of ICD-9-CM diagnostic codes for sepsis. Controls were patients with a medical diagnosis other than sepsis during the observational period. Logistic regression was used to model sepsis diagnosis as a function of indwelling medical device use and stratified by LOS. RESULTS: Indwelling medical device use preadmission and postadmission were significantly associated with increased risk of sepsis diagnosis among patients with extended hospital stays (LOS ≥ 5 days) (odds ratio [OR] = 5.51; 95% confidence interval [CI] = 1.95-15.62; P = .001 and OR = 3.28; 95% CI = 1.24-8.68; P = .017, respectively). Among patients with LOS <5 days, association with sepsis diagnosis was only significant for indwelling medical device use preadmission (OR = 9.61; 95% CI = 3.68-25.08; P < .0001). CONCLUSIONS: Indwelling medical device use was significantly associated with increased risk of sepsis diagnosis and the risk was higher with longer hospitalization.

Chemical Derivatization Enables MALDI-TOF-Based High-Throughput Screening for Microbial Trimethylamine (TMA)-Lyase Inhibitors.

Microbial-dependent trimethylamine (TMA) generation from dietary precursors such as choline was recently linked to cardiovascular diseases (CVDs) as well as chronic kidney disease (CKD). Inhibition of TMA-generating enzymes in gut bacteria would be an innovative approach to treat these diseases. The potential to accurately quantify secreted TMA levels highlights the capacity of mass spectrometry (MS) for tracking microbial TMA-lyase activity. However, high-throughput screening (HTS) by conventional MS instrumentation is hampered by limited sample throughput. Recent advancement in liquid handling and instrumentation of matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS provides an HTS-compatible MS technology. The deciphering of enzymatic reactions using this label-free readout has been successfully applied but has thus far been limited to peptide/protein-centric activity assays. Here, we demonstrate the versatile applicability of MALDI-TOF by tracking a small molecule within a highly complex sample background. The key to success for this concept was chemical derivatization of the target molecule enabling quantitative assessment of microbial TMA formation. Further, its potential was demonstrated in a side-by-side comparison to RapidFire-MS in a primary screen and subsequent dose-response experiments. Overall, the established assay enables the screening for microbial TMA-lyase inhibitors and serves as a proof of concept for the applicability of MALDI-TOF for demanding assay concepts per se.

What do pauses in narrative production reveal about the nature of word retrieval deficits in PPA?

Naming and word-retrieval deficits, which are common characteristics of primary progressive aphasia (PPA), differentially affect production across word classes (e.g., nouns, verbs) in some patients. Individuals with the agrammatic variant (PPA-G) often show greater difficulty producing verbs whereas those with the semantic variant (PPA-S) show greater noun deficits and those with logopenic PPA (PPA-L) evince no clear-cut differences in production of the two word classes. To determine the source of these production patterns, the present study examined word-finding pauses as conditioned by lexical variables (i.e., word class, frequency, length) in narrative speech samples of individuals with PPA-S (n=12), PPA-G (n=12), PPA-L (n=11), and cognitively healthy controls (n=12). We also examined the relation between pause distribution and cortical atrophy (i.e., cortical thickness) in nine left hemisphere regions of interest (ROIs) linked to word production. Results showed higher overall pause rates for PPA compared to unimpaired controls; however, greater naming severity was not associated with increased pause rate. Across all groups, more pauses were produced before lower vs. higher frequency words, with no independent effects of word length after controlling for frequency. With regard to word class, the PPA-L group showed a higher rate of pauses prior to production of nouns compared to verbs, consistent with noun-retrieval deficits arising at the lemma level of word production. Those with PPA-G and PPA-S, like controls, produced similar pause rates across word classes; however, lexical simplification (i.e., production of higher-frequency and/or shorter words) was evident in the more-impaired word class: nouns for PPA-S and verbs for PPA-G. These patterns are consistent with conceptual and/or lemma-level impairments for PPA-S, predominantly affecting objects/nouns, and a lemma-level verb-retrieval deficit for PPA-G, with a concomitant impairment in phonological encoding and articulation affecting overall pause rates. The greater tendency to pause before nouns was correlated with atrophy in the left precentral gyrus, inferior frontal gyrus and inferior parietal lobule, whereas the greater tendency to pause before less frequent and longer words was associated with atrophy in left precentral and inferior parietal regions.

Interprofessional learning for medication safety.

BACKGROUND: Patient safety is a worldwide priority. Recommendations have been made that doctors, nurses and pharmacists could interact more effectively to improve patient outcomes, and that interprofessional education should be encouraged. In 2009, the North East Strategic Health Authority awarded Workforce Development Initiative funding to Northumbria Healthcare National Health Service (NHS) Foundation Trust to develop an undergraduate interprofessional training activity in medication safety for medicine, pharmacy and nursing students. CONTEXT: Interprofessional seminars for medication safety and therapeutics were developed that were delivered across the North East of England. The initial seminars took place between January and April 2011 at 10 teaching hospitals, and were attended by over 400 students (from medicine, pharmacy and nursing). INNOVATION: The majority of the workshops were facilitated by an interprofessional team comprised of pharmacists, doctors and nurses, with all students working in small groups with participants from each of the professional groups, where possible. All seminars had standardised materials, but it was up to individual facilitators to choose which of the five case studies were used within the seminar. The seminars lasted between 2 and 3 hours, and depending on which case studies were used, two or three cases could be discussed. Student feedback showed that the seminar was particularly successful in highlighting and improving the students' understanding of each other's roles and responsibilities in relation to medication safety. There are considerable organisational challenges in arranging interprofessional groups. Scenarios need to provide tasks that engage and challenge all of the professions involved. Facilitation is an important element. Interprofessional education should be encouraged.