Abstract
Background
Although elderly population is generally frail, it is important to closely monitor their health deterioration to improve the care and support in residential aged care homes ...(RACs). Currently, the best identification approach is through time-consuming regular geriatric assessments. This study aimed to develop and validate a retrospective electronic frailty index (reFI) to track the health status of people staying at RACs using the daily routine operational data records.
Methods
We have access to patient records from the Royal Freemasons Benevolent Institution RACs (Australia) over the age of 65, spanning 2010 to 2021. The reFI was developed using the cumulative deficit frailty model whose value was calculated as the ratio of number of present frailty deficits to the total possible frailty indicators (32). Frailty categories were defined using population quartiles. 1, 3 and 5-year mortality were used for validation. Survival analysis was performed using Kaplan-Meier estimate. Hazard ratios (HRs) were estimated using Cox regression analyses and the association was assessed using receiver operating characteristic (ROC) curves.
Results
Two thousand five hundred eighty-eight residents were assessed, with an average length of stay of 1.2 ± 2.2 years. The RAC cohort was generally frail with an average reFI of 0.21 ± 0.11. According to the Kaplan-Meier estimate, survival varied significantly across different frailty categories (
p
< 0.01). The estimated hazard ratios (HRs) were 1.12 (95% CI 1.09–1.15), 1.11 (95% CI 1.07–1.14), and 1.1 (95% CI 1.04–1.17) at 1, 3 and 5 years. The ROC analysis of the reFI for mortality outcome showed an area under the curve (AUC) of ≥0.60 for 1, 3 and 5-year mortality.
Conclusion
A novel reFI was developed using the routine data recorded at RACs. reFI can identify changes in the frailty index over time for elderly people, that could potentially help in creating personalised care plans for addressing their health deterioration.
Abstract
Cancer research has long been hampered by the limitations of the current model systems. Both cultured cells and mouse xenografts grow in an environment highly dissimilar to that of their ...originating tumor, frequently resulting in promising treatments that are ultimately clinically ineffective. The development of highly immunodeficient mouse strains into which human immune systems can be engrafted can help bridge this gap. The need for more representative tools to investigate the human tumor microenvironment (TME) has led to the development of humanized mouse (HM) models. HM allow researchers to examine xenograft growth in the context of a human immune system and resultant tumor microenvironment, and recent studies have highlighted the increased similarities in attendant tumor structure, metastasis, and signaling to those features in cancer patients. This setting also facilitates the examination of investigational cancer therapies, including new immunotherapies.
We have developed an improved method for generating mismatched humanized mice (mHM), using a dual infusion of human hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stem cells (MSCs), isolated from cord blood and expanded in vitro. Engraftment with both HSPCs and MSCs produces mice with almost twice the percentage of human immune cells in their bone marrow, compared to mice engrafted with HSPCs alone, and yields 9- to 38-fold higher levels of mature peripheral human immune cells. When head and neck squamous cell carcinoma (HNSCC) tumors are implanted on the flanks of HSPC-MSC engrafted mice, human T cells, B cells, and macrophages infiltrate the stroma of these tumors at 2- to 8-fold higher ratios. In dually HSPC-MSC engrafted mice we also more frequently observed additional types of immune cells, including regulatory T cells, cytotoxic T cells, and MDSCs. Higher humanization was associated with in vivo response to immune-directed therapy. The complex immune environment arising in tumors from dually HSPC-MSC engrafted mice better resembles that of the originating patient’s tumor, suggesting an enhanced capability to accurately recapitulate a human TME.
This review presentation also discusses other recent advancements in the generation and application of HM models, such as engineering mouse strains expressing human cytokines or HLA proteins, and implanting human bone, liver, and thymus tissue to facilitate immune cell maturation and trafficking. Finally, we discuss how these improvements may help direct future HM model cancer studies, and their potential in generating clinically relevant treatments.
Citation Format: Antonio Jimeno. Novel approaches to study the tumor-stroma interaction and translate immune-directed therapies abstract. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA04.
Oncogenic kinase fusions of
,
,
, and
act as drivers in human lung and other cancers. Residual tumor burden following treatment of ALK or ROS1
lung cancer patients with oncogene-targeted therapy ...ultimately enables the emergence of drug-resistant clones, limiting the long-term effectiveness of these therapies. To determine the signaling mechanisms underlying incomplete tumor cell killing in oncogene-addicted cancer cells, we investigated the role of EGFR signaling in drug-naïve cancer cells harboring these oncogene fusions. We defined three distinct roles for EGFR in the response to oncogene-specific therapies. First, EGF-mediated activation of EGFR blunted fusion kinase inhibitor binding and restored fusion kinase signaling complexes. Second, fusion kinase inhibition shifted adaptor protein binding from the fusion oncoprotein to EGFR. Third, EGFR enabled bypass signaling to critical downstream pathways such as MAPK. While evidence of EGFR-mediated bypass signaling has been reported after ALK and ROS1 blockade, our results extended this effect to RET and NTRK1 blockade and uncovered the other additional mechanisms in gene fusion-positive lung cancer cells, mouse models, and human clinical specimens before the onset of acquired drug resistance. Collectively, our findings show how EGFR signaling can provide a critical adaptive survival mechanism that allows cancer cells to evade oncogene-specific inhibitors, providing a rationale to cotarget EGFR to reduce the risks of developing drug resistance.
.
Abstract
Motivation
A biochemical reaction, bio-event, depicts the relationships between participating entities. Current text mining research has been focusing on identifying bio-events from ...scientific literature. However, rare efforts have been dedicated to normalize bio-events extracted from scientific literature with the entries in the curated reaction databases, which could disambiguate the events and further support interconnecting events into biologically meaningful and complete networks.
Results
In this paper, we propose BioNorm, a novel method of normalizing bio-events extracted from scientific literature to entries in the bio-molecular reaction database, e.g. IntAct. BioNorm considers event normalization as a paraphrase identification problem. It represents an entry as a natural language statement by combining multiple types of information contained in it. Then, it predicts the semantic similarity between the natural language statement and the statements mentioning events in scientific literature using a long short-term memory recurrent neural network (LSTM). An event will be normalized to the entry if the two statements are paraphrase. To the best of our knowledge, this is the first attempt of event normalization in the biomedical text mining. The experiments have been conducted using the molecular interaction data from IntAct. The results demonstrate that the method could achieve F-score of 0.87 in normalizing event-containing statements.
Availability and implementation
The source code is available at the gitlab repository https://gitlab.com/BioAI/leen and BioASQvec Plus is available on figshare https://figshare.com/s/45896c31d10c3f6d857a.
Highlights • Multimodality treatment improves OS in HPV-positive stage III–IVB disease. • AJCC stage was poorly associated with survival in HPV-positive cancers. • Positive margins and/or ECE ...predicts OS in HPV negative but not positive disease. • Traditional high-risk features may be less impactful in HPV-positive disease.
This trial evaluated the efficacy of maintenance erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, after first-line chemotherapy.
Eligible patients had high-risk ...International Federation of Gynecology and Obstetrics stage I or stage II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer and were not selected for EGFR expression. All patients underwent first-line platinum-based chemotherapy (CT) and showed no signs of progression at the end of CT. Patients were randomly assigned to maintenance erlotinib 150 mg orally daily for 2 years or to observation. EGFR immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and mutation analyses were performed in 318 patients.
Between October 2005 and February 2008, 835 patients were randomly assigned (median follow-up, 51 months). Twenty-six percent of the patients stopped erlotinib as a result of adverse effects (of these, 67% were due to rash). For erlotinib and observation, respectively, the median progression-free survival was 12.7 and 12.4 months (hazard ratio HR, 1.05; 95% CI, 0.90 to 1.23), and the median overall survival was 50.8 and 59.1 months (HR, 0.99; 95% CI, 0.81 to 1.20 months), respectively. No subgroup could be identified with improved effect of erlotinib, based on IHC or FISH for EGFR, or mutations in genes related to the EGFR pathway, or on rash during erlotinib therapy. However, patients with a positive FISH EGFR score had a worse overall survival (46.1 months) than those with a negative score (67.0 months; HR, 1.56; 95% CI, 1.01 to 2.40; P = .044). Global health/quality-of-life scores showed a significant difference during the first year (P = .0102) in favor of the observation arm.
Maintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival.
Deep learning is a powerful technique for the analysis of remote sensing imagery. For applications that require real-time processing on mobile platforms, a low power consumption processing unit is ...advantageous. The human brain is remarkably powerful at image recognition tasks while operating at very low power consumption levels. Neuromorphic computing designs aim to achieve energy efficiency through the use of spiking neurons and low-precision synapses to perform data processing. We demonstrate here the classification of red, green, blue and depth and hyperspectral data sets using a neuromorphic processing unit (IBM TrueNorth Neurosynaptic System). The convolutional neural-network architecture of the classifier network has been adapted to fit the neuromorphic architecture. The results on overhead imagery and hyperspectral imagery data show that neuromorphic platforms can achieve the state-of-the-art performance in semantic labeling with significantly (<inline-formula> <tex-math notation="LaTeX">\approx 1000\times </tex-math></inline-formula>) lower power consumption than traditional GPU-based solutions.
Local control and overall survival in patients with advanced head and neck squamous cell cancer (HNSCC) remains dismal. Signaling through the Hedgehog (Hh) pathway is associated with ...epithelial-to-mesenchymal transition, and activation of the Hh effector transcription factor Gli1 is a poor prognostic factor in this disease setting. Here, we report that increased GLI1 expression in the leading edge of HNSCC tumors is further increased by irradiation, where it contributes to therapeutic inhibition. Hh pathway blockade with cyclopamine suppressed GLI1 activation and enhanced tumor sensitivity to radiotherapy. Furthermore, radiotherapy-induced GLI1 expression was mediated in part by the mTOR/S6K1 pathway. Stroma exposed to radiotherapy promoted rapid tumor repopulation, and this effect was suppressed by Hh inhibition. Our results demonstrate that Gli1 that is upregulated at the tumor-stroma intersection in HNSCC is elevated by radiotherapy, where it contributes to stromal-mediated resistance, and that Hh inhibitors offer a rational strategy to reverse this process to sensitize HNSCC to radiotherapy.
A Gene Reference Into Function (GeneRIF) describes novel functionality of genes. GeneRIFs are available from the National Center for Biotechnology Information (NCBI) Gene database. GeneRIF indexing ...is performed manually, and the intention of our work is to provide methods to support creating the GeneRIF entries. The creation of GeneRIF entries involves the identification of the genes mentioned in MEDLINE®; citations and the sentences describing a novel function.
We have compared several learning algorithms and several features extracted or derived from MEDLINE sentences to determine if a sentence should be selected for GeneRIF indexing. Features are derived from the sentences or using mechanisms to augment the information provided by them: assigning a discourse label using a previously trained model, for example. We show that machine learning approaches with specific feature combinations achieve results close to one of the annotators. We have evaluated different feature sets and learning algorithms. In particular, Naïve Bayes achieves better performance with a selection of features similar to one used in related work, which considers the location of the sentence, the discourse of the sentence and the functional terminology in it.
The current performance is at a level similar to human annotation and it shows that machine learning can be used to automate the task of sentence selection for GeneRIF annotation. The current experiments are limited to the human species. We would like to see how the methodology can be extended to other species, specifically the normalization of gene mentions in other species.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The novel dual-action humanized IgG1 antibody MEHD7945A targeting HER3 and EGFR inhibits ligand-dependent HER dimer signaling. This phase I study evaluated the safety, pharmacokinetics, ...pharmacodynamics, and antitumor activity of MEHD7945A.
Patients with locally advanced or metastatic epithelial tumors received escalating doses of MEHD7945A (1-30 mg/kg) every 2 weeks (q2w) until disease progression or intolerable toxicity. An expansion cohort was enrolled at the recommended phase II dose (14 mg/kg, q2w). Plasma samples, tumor biopsies, FDG-PET were obtained for assessment of pharmacokinetics, and pharmacodynamic modulation downstream of EGFR and HER3.
No dose-limiting toxicities or MEHD7945A-related grade ≥ 4 adverse events (AE) were reported in dose-escalation (n = 30) or expansion (n = 36) cohorts. Related grade 3 AEs were limited to diarrhea and nausea in the same patient (30 mg/kg). Related AEs in ≥20% of patients ≤24 hours after the first infusion included grade 1/2 headache, fever, and chills, which were managed with premedication and/or symptomatic treatment. Pharmacodynamic data indicated target inhibition in 25% of evaluable patients. Best response by RECIST included 2 confirmed partial responses in squamous cell carcinomas of head and neck (SCCHN) patients with high tumor tissue levels of the HER3 ligand heregulin; 14 patients had stable disease ≥8 weeks, including SCCHN (n = 3), colorectal cancer (n = 6), and non-small cell lung cancer (n = 3).
MEHD7945A was well-tolerated as single agent with evidence of tumor pharmacodynamic modulation and antitumor activity in SCCHN. Phase II studies were initiated with flat (nonweight-based) dosing at 1,100 mg q2w in SCCHN and colorectal cancer.
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