Wnt5a induces ROR1 to recruit cortactin to promote breast-cancer migration and metastasis.

ROR1 is a conserved oncoembryonic surface protein expressed in breast cancer. Here we report that ROR1 associates with cortactin in primary breast-cancer cells or in MCF7 transfected to express ROR1. Wnt5a also induced ROR1-dependent tyrosine phosphorylation of cortactin (Y421), which recruited ARHGEF1 to activate RhoA and promote breast-cancer-cell migration; such effects could be inhibited by cirmtuzumab, a humanized mAb specific for ROR1. Furthermore, treatment of mice bearing breast-cancer xenograft with cirmtuzumab inhibited cortactin phosphorylation in vivo and impaired metastatic development. We established that the proline at 841 of ROR1 was required for it to recruit cortactin and ARHGEF1, activate RhoA, and enhance breast-cancer-cell migration in vitro or development of metastases in vivo. Collectively, these studies demonstrate that the interaction of ROR1 with cortactin plays an important role in breast-cancer-cell migration and metastasis

Peanut stunt virus and its satellite RNA trigger changes in phosphorylation in N-benthamiana infected plants at the early stage of the infection

Signaling in host plants is an integral part of a successful infection by pathogenic RNA viruses. Therefore, identifying early signaling events in host plants that play an important role in establishing the infection process will help our understanding of the disease process. In this context, phosphorylation constitutes one of the most important post-translational protein modifications, regulating many cellular signaling processes. In this study, we aimed to identify the processes affected by infection with Peanut stunt virus (PSV) and its satellite RNA (satRNA) in Nicotiana benthamiana at the early stage of pathogenesis. To achieve this, we performed proteome and phosphoproteome analyses on plants treated with PSV and its satRNA. The analysis of the number of differentially phosphorylated proteins showed strong down-regulation in phosphorylation in virus-treated plants (without satRNA). Moreover, proteome analysis revealed more down-regulated proteins in PSV and satRNA-treated plants, which indicated a complex dependence between proteins and their modifications. Apart from changes in photosynthesis and carbon metabolism, which are usually observed in virus-infected plants, alterations in proteins involved in RNA synthesis, transport, and turnover were observed. As a whole, this is the first community (phospho)proteome resource upon infection of N. benthamiana with a cucumovirus and its satRNA and this resource constitutes a valuable data set for future studies

Multiple cellular compartments engagement in Nicotiana benthamiana-peanut stunt virus-satRNA interactions revealed by systems biology approach

Abstract Key message PSV infection changed the abundance of host plant’s transcripts and proteins associated with various cellular compartments, including ribosomes, chloroplasts, mitochondria, the nucleus and cytosol, affecting photosynthesis, translation, transcription, and splicing. Abstract Virus infection is a process resulting in numerous molecular, cellular, and physiological changes, a wide range of which can be analyzed due to development of many high-throughput techniques. Plant RNA viruses are known to replicate in the cytoplasm; however, the roles of chloroplasts and other cellular structures in the viral replication cycle and in plant antiviral defense have been recently emphasized. Therefore, the aim of this study was to analyze the small RNAs, transcripts, proteins, and phosphoproteins affected during peanut stunt virus strain P (PSV-P)–Nicotiana benthamiana interactions with or without satellite RNA (satRNA) in the context of their cellular localization or functional connections with particular cellular compartments to elucidate the compartments most affected during pathogenesis at the early stages of infection. Moreover, the processes associated with particular cell compartments were determined. The ‘omic’ results were subjected to comparative data analyses. Transcriptomic and small RNA (sRNA)–seq data were obtained to provide new insights into PSV-P–satRNA–plant interactions, whereas previously obtained proteomic and phosphoproteomic data were used to broaden the analysis to terms associated with cellular compartments affected by virus infection. Based on the collected results, infection with PSV-P contributed to changes in the abundance of transcripts and proteins associated with various cellular compartments, including ribosomes, chloroplasts, mitochondria, the nucleus and the cytosol, and the most affected processes were photosynthesis, translation, transcription, and mRNA splicing. Furthermore, sRNA-seq and phosphoproteomic analyses indicated that kinase regulation resulted in decreases in phosphorylation levels. The kinases were associated with the membrane, cytoplasm, and nucleus components. </jats:sec

The effect of oral omega-3 polyunsaturated fatty acid supplementation on muscle maintenance and quality of life in patients with cancer: A systematic review and meta-analysis

Rationale: Omega-3 polyunsaturated fatty acid (PUFA) supplementation is a promising therapy for cancer-relatedmalnutrition, which affects 20-70% of patients with cancer1,2. This systematic review aimed to examine the effects of oralomega-3 PUFA supplementation on muscle maintenance and quality of life in patients with cancer. Methods: Randomised controlled trials in cancer patients aged >18 years were retrieved from 5 electronic databases;MEDLINE (via PubMed), EMBASE, CENTRAL, CINAHL (via EBSCOhost), and Web of Science, from database inceptionuntil 31st of December 2019. Trials supplementing ≥600 mg/d omega-3 PUFA (oral capsules, pure fish oil or oralnutritional supplements) or a control intervention for ≥3 weeks were included. Meta-analyses were performed in RevManto determine the mean differences (MD) in muscle mass and quality of life between omega-3 PUFA and control groupswith 95% confidence intervals (CI) and I2 for heterogeneity. Results: We included 33 studies in patients with various types of cancers and degrees of malnutrition. The Cochrane riskof bias tool graded most trials as ‘unclear’ or ‘high’ risk of bias. Meta-analyses showed oral omega-3 PUFA supplementsimproved physical functioning (MD: 6.33; 95% CI: 0.32, 12.34, p=0.04; I2=0%) and potentially reduced fatigue (MD: -6.21;95% CI: -13.473, 1.05, p=0.09; I2=14%). However, there was no significant effect of omega-3 PUFA supplements on muscle mass, global health status, emotional functioning and symptoms (nausea and vomiting, loss of appetite anddiarrhoea). Conclusion: This review provides evidence for the benefits of oral omega-3 PUFA supplementation on quality of life butnot on muscle maintenance in patients with cancer. Well-designed large-scale randomised controlled trials inhomogenous patient cohorts are required to confirm these findings

Conceptualizing Machine Learning for Dynamic Information Retrieval of Electronic Health Record Notes

The large amount of time clinicians spend sifting through patient notes and documenting in electronic health records (EHRs) is a leading cause of clinician burnout. By proactively and dynamically retrieving relevant notes during the documentation process, we can reduce the effort required to find relevant patient history. In this work, we conceptualize the use of EHR audit logs for machine learning as a source of supervision of note relevance in a specific clinical context, at a particular point in time. Our evaluation focuses on the dynamic retrieval in the emergency department, a high acuity setting with unique patterns of information retrieval and note writing. We show that our methods can achieve an AUC of 0.963 for predicting which notes will be read in an individual note writing session. We additionally conduct a user study with several clinicians and find that our framework can help clinicians retrieve relevant information more efficiently. Demonstrating that our framework and methods can perform well in this demanding setting is a promising proof of concept that they will translate to other clinical settings and data modalities (e.g., labs, medications, imaging).Comment: To be published in Proceedings of Machine Learning Research Volume 219; accepted to the Machine Learning for Healthcare 2023 conferenc

Inhibition of chemotherapy resistant breast cancer stem cells by a ROR1 specific antibody.

Breast cancers enduring treatment with chemotherapy may be enriched for cancer stem cells or tumor-initiating cells, which have an enhanced capacity for self-renewal, tumor initiation, and/or metastasis. Breast cancer cells that express the type I tyrosine kinaselike orphan receptor ROR1 also may have such features. Here we find that the expression of ROR1 increased in breast cancer cells following treatment with chemotherapy, which also enhanced expression of genes induced by the activation of Rho-GTPases, Hippo-YAP/TAZ, or B lymphoma Mo-MLV insertion region 1 homolog (BMI1). Expression of ROR1 also enhanced the capacity of breast cancer cells to invade Matrigel, form spheroids, engraft in Rag2-/-[Formula: see text] mice, or survive treatment with paclitaxel. Treatment of mice bearing breast cancer patient-derived xenografts (PDXs) with the humanized anti-ROR1 monoclonal antibody cirmtuzumab repressed expression of genes associated with breast cancer stemness, reduced activation of Rho-GTPases, Hippo-YAP/TAZ, or BMI1, and impaired the capacity of breast cancer PDXs to metastasize or reengraft Rag2-/-[Formula: see text] mice. Finally, treatment of PDX-bearing mice with cirmtuzumab and paclitaxel was more effective than treatment with either alone in eradicating breast cancer PDXs. These results indicate that targeting ROR1 may improve the response to chemotherapy of patients with breast cancer

Inconsistent Adoption of World Health Organization V (2010) Semen Analysis Reference Ranges in the United States Six Years After Publication

Objective To determine the percentage of laboratories in the United States that have adopted the World Health Organization 2010 (WHO 5) semen analysis (SA) reference values six years after their publication. Methods Laboratories were identified via three approaches: using the Clinical Laboratory Improvement Amendments (CLIA) website, the CDC's 2015 Assisted Reproductive Technology Fertility Clinical Success Rate Report, and automated web searches. Laboratories were contacted by phone or email to obtain de-identified SA reports and reference ranges. Results We contacted 617 laboratories in 46 states, of which 208 (26.7%) laboratories in 45 states were included in our analysis. 132 (63.5%) laboratories used WHO 5 criteria, 57 (27.4%) used WHO 4 criteria, and 19 (9.1%) used other criteria. WHO 5 criteria adoption rates varied by geographic region, ranging from 87.5% (35/40) in the Midwest to 50.0% (33/66) in the West. There was a greater adoption rate of WHO 5 reference values in academic affiliated (23/26, 88.5%) compared to non-academic affiliated laboratories (110/182, 60.4%) (P=0.028). Conclusion While the majority of laboratories have adopted WHO 5 criteria following its release six years ago, a large percentage (36.5%) use what is now considered outdated criteria. This variability could result in the characterization of a male's semen values as being “within reference range” at one center and “outside of reference range” at another. This inconsistency in classification may result in confusion for the both patient and physician and potentially shift the burden of infertility evaluation and treatment to the female partner