Human Factors in Automated and Robotic Space Systems: Proceedings of a symposium. Part 1

Human factors research likely to produce results applicable to the development of a NASA space station is discussed. The particular sessions covered in Part 1 include: (1) system productivity -- people and machines; (2) expert systems and their use; (3) language and displays for human-computer communication; and (4) computer aided monitoring and decision making. Papers from each subject area are reproduced and the discussions from each area are summarized

Engineered Bivalent Ligands to Bias ErbB Receptor-mediated Signaling and Phenotypes

The ErbB receptor family is dysregulated in many cancers, and its therapeutic manipulation by targeted antibodies and kinase inhibitors has resulted in effective chemotherapies. However, many malignancies remain refractory to current interventions. We describe a new approach that directs ErbB receptor interactions, resulting in biased signaling and phenotypes. Due to known receptor-ligand affinities and the necessity of ErbB receptors to dimerize to signal, bivalent ligands, formed by the synthetic linkage of two neuregulin-1β (NRG) moieties, two epidermal growth factor (EGF) moieties, or an EGF and a NRG moiety, can potentially drive homotypic receptor interactions and diminish formation of HER2-containing heterodimers, which are implicated in many malignancies and are a prevalent outcome of stimulation by native, monovalent EGF, or NRG. We demonstrate the therapeutic potential of this approach by showing that bivalent NRG (NN) can bias signaling in HER3-expressing cancer cells, resulting in some cases in decreased migration, inhibited proliferation, and increased apoptosis, whereas native NRG stimulation increased the malignant potential of the same cells. Hence, this new approach may have therapeutic relevance in ovarian, breast, lung, and other cancers in which HER3 has been implicated

Cancer Stem Cells and Side Population Cells in Breast Cancer and Metastasis

In breast cancer it is never the primary tumour that is fatal; instead it is the development of metastatic disease which is the major cause of cancer related mortality. There is accumulating evidence that suggests that Cancer Stem Cells (CSC) may play a role in breast cancer development and progression. Breast cancer stem cell populations, including side population cells (SP), have been shown to be primitive stem cell-like populations, being long-lived, self-renewing and highly proliferative. SP cells are identified using dual wavelength flow cytometry combined with Hoechst 33342 dye efflux, this ability is due to expression of one or more members of the ABC transporter family. They have increased resistance to chemotherapeutic agents and apoptotic stimuli and have increased migratory potential above that of the bulk tumour cells making them strong candidates for the metastatic spread of breast cancer. Treatment of nearly all cancers usually involves one first-line agent known to be a substrate of an ABC transporter thereby increasing the risk of developing drug resistant tumours. At present there is no marker available to identify SP cells using immunohistochemistry on breast cancer patient samples. If SP cells do play a role in breast cancer progression/Metastatic Breast Cancer (MBC), combining chemotherapy with ABC inhibitors may be able to destroy both the cells making up the bulk tumour and the cancer stem cell population thus preventing the risk of drug resistant disease, recurrence or metastasis

Study protocol for a randomized controlled trial: Integrating the Time-limited Trial in the emergency department.

INTRODUCTION: Time-limited trial (TLT) is a structured approach between clinicians and seriously ill patients or their surrogates to discuss patients values and preferences, prognosis, and shared decision-making to use specific therapies for a prespecified period of time in the face of prognostic uncertainty. Some evidence exists that this approach may lead to more patient-centered care in the intensive care unit; however, it has never been evaluated in the emergency department (ED). The study protocol aims to assess the feasibility and acceptability of TLTs initiated in the ED. METHODS AND ANALYSIS: We will conduct a parallel group, clinician-level, pilot randomized clinical trial among 40 ED clinicians. We will measure feasibility (e.g., the time it takes to conduct the TLTs by ED clinicians) and clinician and patient-reported acceptability of the TLT, and also track patients clinical outcomes via medical record review. DISCUSSION: This study protocol will investigate the potential of TLT initiated in the ED to lead to patient-centered intensive care utilization. By doing so, the study intends to improve palliative care integration for seriously ill older adults in the ED and intensive care unit. TRIAL IDENTIFIER AND REGISTRY NAME: ClinicalTrials.gov ID: NCT06378151 https://clinicaltrials.gov/study/NCT06378151; Pre-results; a randomized controlled trial: Time-limited Trials in the Emergency Department

Prognostic factors for outcomes after whole-brain irradiation of brain metastases from relatively radioresistant tumors: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>This study investigated potential prognostic factors in patients treated with whole-brain irradiation (WBI) alone for brain metastases from relatively radioresistant tumors such as malignant melanoma, renal cell carcinoma, and colorectal cancer. Additionally, a potential benefit from escalating the radiation dose was investigated.</p> <p>Methods</p> <p>Data from 220 patients were retrospectively analyzed for overall survival and local control. Nine potential prognostic factors were evaluated: tumor type, WBI schedule, age, gender, Karnofsky performance score, number of brain metastases, extracerebral metastases, interval from diagnosis of cancer to WBI, and recursive partitioning analysis (RPA) class.</p> <p>Results</p> <p>Survival rates at 6 and 12 months were 32% and 19%, respectively. In the multivariate analysis, WBI doses >30 Gy (p = 0.038), KPS ≥70 (p < 0.001), only 1-3 brain metastases (p = 0.007), no extracerebral metastases (p < 0.001), and RPA class 1 (p < 0.001) were associated with improved survival. Local control rates at 6 and 12 months were 37% and 15%, respectively. In the multivariate analyses, KPS ≥70 (p < 0.001), only 1-3 brain metastases (p < 0.001), and RPA class 1 (p < 0.001) were associated with improved local control. In RPA class 3 patients, survival rates at 6 months were 10% (35 of 39 patients) after 10 × 3 Gy and 9% (2 of 23 patients) after greater doses, respectively (p = 0.98).</p> <p>Conclusions</p> <p>Improved outcomes were associated with WBI doses >30 Gy, better performance status, fewer brain metastases, lack of extracerebral metastases, and lower RPA class. Patients receiving WBI alone appear to benefit from WBI doses >30 Gy. However, such a benefit is limited to RPA class 1 or 2 patients.</p

Comparison and interpretability of machine learning models to predict severity of chest injury

Objective: Trauma quality improvement programs and registries improve care and outcomes for injured patients. Designated trauma centers calculate injury scores using dedicated trauma registrars; however, many injuries arrive at nontrauma centers, leaving a substantial amount of data uncaptured. We propose automated methods to identify severe chest injury using machine learning (ML) and natural language processing (NLP) methods from the electronic health record (EHR) for quality reporting. Materials and Methods: A level I trauma center was queried for patients presenting after injury between 2014 and 2018. Prediction modeling was performed to classify severe chest injury using a reference dataset labeled by certified registrars. Clinical documents from trauma encounters were processed into concept unique identifiers for inputs to ML models: logistic regression with elastic net (EN) regularization, extreme gradient boosted (XGB) machines, and convolutional neural networks (CNN). The optimal model was identified by examining predictive and face validity metrics using global explanations. Results: Of 8952 encounters, 542 (6.1%) had a severe chest injury. CNN and EN had the highest discrimination, with an area under the receiver operating characteristic curve of 0.93 and calibration slopes between 0.88 and 0.97. CNN had better performance across risk thresholds with fewer discordant cases. Examination of global explanations demonstrated the CNN model had better face validity, with top features including “contusion of lung” and “hemopneumothorax.” Discussion: The CNN model featured optimal discrimination, calibration, and clinically relevant features selected. Conclusion: NLP and ML methods to populate trauma registries for quality analyses are feasible

Estrogen/progesterone Receptor and HER2 Discordance Between Primary Tumor and Brain Metastases in Breast Cancer and Its Effect on Treatment and Survival

BACKGROUND: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM). METHODS: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM. RESULTS: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08). CONCLUSIONS: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly. KEY POINTS: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment

A Neutralizing RNA Aptamer against EGFR Causes Selective Apoptotic Cell Death

Nucleic acid aptamers have been developed as high-affinity ligands that may act as antagonists of disease-associated proteins. Aptamers are non immunogenic and characterised by high specificity and low toxicity thus representing a valid alternative to antibodies or soluble ligand receptor traps/decoys to target specific cancer cell surface proteins in clinical diagnosis and therapy. The epidermal growth factor receptor (EGFR) has been implicated in the development of a wide range of human cancers including breast, glioma and lung. The observation that its inhibition can interfere with the growth of such tumors has led to the design of new drugs including monoclonal antibodies and tyrosine kinase inhibitors currently used in clinic. However, some of these molecules can result in toxicity and acquired resistance, hence the need to develop novel kinds of EGFR-targeting drugs with high specificity and low toxicity. Here we generated, by a cell-Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach, a nuclease resistant RNA-aptamer that specifically binds to EGFR with a binding constant of 10 nM. When applied to EGFR-expressing cancer cells the aptamer inhibits EGFR-mediated signal pathways causing selective cell death. Furthermore, at low doses it induces apoptosis even of cells that are resistant to the most frequently used EGFR-inhibitors, such as gefitinib and cetuximab, and inhibits tumor growth in a mouse xenograft model of human non-small-cell lung cancer (NSCLC). Interestingly, combined treatment with cetuximab and the aptamer shows clear synergy in inducing apoptosis in vitro and in vivo. In conclusion, we demonstrate that this neutralizing RNA-aptamer is a promising bio-molecule that can be developed as a more effective alternative to the repertoire of already existing EGFR-inhibitors