Head and neck squamous cell carcinomas (HNSCCs) are an aggressive, genetically complex and difficult to treat group of cancers. In lieu of truly effective targeted therapies, surgery and radiotherapy ...represent the primary treatment options for most patients. But these treatments are associated with significant morbidity and a reduction in quality of life. Resistance to both radiotherapy and the only available targeted therapy, and subsequent relapse are common. Research has therefore focussed on identifying biomarkers to stratify patients into clinically meaningful groups and to develop more effective targeted therapies. However, as we are now discovering, the poor response to therapy and aggressive nature of HNSCCs is not only affected by the complex alterations in intracellular signalling pathways but is also heavily influenced by the behaviour of the extracellular microenvironment. The HNSCC tumour landscape is an environment permissive of these tumours' aggressive nature, fostered by the actions of the immune system, the response to tumour hypoxia and the influence of the microbiome. Solving these challenges now rests on expanding our knowledge of these areas, in parallel with a greater understanding of the molecular biology of HNSCC subtypes. This update aims to build on our earlier 2014 review by bringing up to date our understanding of the molecular biology of HNSCCs and provide insights into areas of ongoing research and perspectives for the future.
Systemic approaches to the study of a biological cell or tissue rely increasingly on the use of context-specific metabolic network models. The reconstruction of such a model from high-throughput data ...can routinely involve large numbers of tests under different conditions and extensive parameter tuning, which calls for fast algorithms. We present fastcore, a generic algorithm for reconstructing context-specific metabolic network models from global genome-wide metabolic network models such as Recon X. fastcore takes as input a core set of reactions that are known to be active in the context of interest (e.g., cell or tissue), and it searches for a flux consistent subnetwork of the global network that contains all reactions from the core set and a minimal set of additional reactions. Our key observation is that a minimal consistent reconstruction can be defined via a set of sparse modes of the global network, and fastcore iteratively computes such a set via a series of linear programs. Experiments on liver data demonstrate speedups of several orders of magnitude, and significantly more compact reconstructions, over a rival method. Given its simplicity and its excellent performance, fastcore can form the backbone of many future metabolic network reconstruction algorithms.
Abstract
Drug repositioning has received increased attention since the past decade as several blockbuster drugs have come out of repositioning. Computational approaches are significantly contributing ...to these efforts, of which, network-based methods play a key role. Various structural (topological) network measures have thereby contributed to uncovering unintuitive functional relationships and repositioning candidates in drug-disease and other networks. This review gives a broad overview of the topic, and offers perspectives on the application of topological measures for network analysis. It also discusses unexplored measures, and draws attention to a wider scope of application efforts, especially in drug repositioning.
Failure of fixation suppression of spontaneous nystagmus is sometimes seen in patients with vestibular strokes involving the cerebellum or brainstem; however, the accuracy of this test for the ...discrimination between peripheral and central causes in patients with an acute vestibular syndrome (AVS) is unknown.
Patients with AVS were screened and recruited (convenience sample) as part of a prospective cross-sectional study in the emergency department between 2015 and 2020. All patients received neuroimaging, which served as a reference standard. We recorded fixation suppression with video-oculography (VOG) for forward, right, and left gaze. The ocular fixation index (OFI) and the spontaneous nystagmus slow velocity reduction was calculated.
We screened 1,646 patients reporting dizziness in the emergency department and tested for spontaneous nystagmus in 148 patients with AVS. We analyzed 56 patients with a diagnosed acute unilateral vestibulopathy (vestibular neuritis) and 28 patients with a confirmed stroke. There was a complete nystagmus fixation suppression in 49.5% of patients with AVS, in 40% of patients with vestibular neuritis, and in 62.5% of patients with vestibular strokes. OFI scores had no predictive value for detecting strokes; however, a nystagmus reduction of less than 2 °/s showed a high accuracy of 76.9% (confidence interval 0.59-0.89) with a sensitivity of 62.2% and specificity of 84.8% in detecting strokes.
The presence of fixation suppression does not rule out a central lesion. The magnitude of suppression was lower compared to patients with vestibular neuritis. The nystagmus suppression test predicts vestibular strokes accurately provided that eye movements are recorded with VOG.
This study provides Class II evidence that in patients with an AVS, decreased fixation suppression recorded with VOG occurred more often in stroke (76.9%) than in vestibular neuritis (37.8%).
Emergency Department (ED) visits and health care costs are increasing globally, but little is known about contributing factors of ED resource consumption. This study aims to analyse and to predict ...the total ED resource consumption out of the patient and consultation characteristics in order to execute performance analysis and evaluate quality improvements.
Characteristics of ED visits of a large Swiss university hospital were summarized according to acute patient condition factors (e.g. chief complaint, resuscitation bay use, vital parameter deviations), chronic patient conditions (e.g. age, comorbidities, drug intake), and contextual factors (e.g. night-time admission). Univariable and multivariable linear regression analyses were conducted with the total ED resource consumption as the dependent variable.
In total, 164,729 visits were included in the analysis. Physician resources accounted for the largest proportion (54.8%), followed by radiology (19.2%), and laboratory work-up (16.2%). In the multivariable final model, chief complaint had the highest impact on the total ED resource consumption, followed by resuscitation bay use and admission by ambulance. The impact of age group was small. The multivariable final model was validated (R2 of 0.54) and a scoring system was derived out of the predictors.
More than half of the variation in total ED resource consumption can be predicted by our suggested model in the internal validation, but further studies are needed for external validation. The score developed can be used to calculate benchmarks of an ED and provides leaders in emergency care with a tool that allows them to evaluate resource decisions and to estimate effects of organizational changes.
While COVID-19 significantly overburdens emergency rooms (ERs) and hospitals in affected areas, ERs elsewhere report a marked decrease in patient numbers. This study aimed to investigate the ...assumption that patients with urgent problems currently avoid the ER.
Electronic health records from the ER of a large Swiss university hospital were extracted for three periods: first, the awareness phase (ap) from the publication of the national government's initiative "How to protect ourselves" on 1 March 2020 to the lockdown of the country on 16 March; second, the mitigation phase (mp) from 16-30 March; finally, patients presenting in March 2019 were used as a control group. We compared parameters including a critical illness as the discharge diagnosis (e.g., myocardial infarction, stroke, sepsis and ER death) using logistic and linear regression, as well as 15-day bootstrapped means and 95% confidence intervals for the control group.
In the three periods, a total of 7143 patients were treated. We found a 24.9% (42.5%) significant decline in the number of patients presenting during the ap (mp). Patients presenting during the mp were more likely to be critically ill. There was an increase of 233% and 367% (ap and mp, respectively) of ER deaths (none related to COVID-19) compared with the control period. Apart from polytrauma (increase of 5% in the mp), all other critical illnesses as discharge diagnosis showed a lower incidence in descriptive analysis. Significantly more patients died in the ER in both the ap and mp.
Barriers to seeking emergency care during COVID-19 pandemic may lead to higher morbidity and mortality. Healthcare authorities and hospitals must ensure low barriers to treatment and business as usual for all patients.
Health systems face major challenges during the COVID-19 pandemic with new information and challenges emerging daily and frequently changing guidelines. Online forward triage tools (OFTTs) provide ...useful information, direct patients and free physician resources.We implemented an OFTT targeted at the current pandemic, adapted the content and goals and assessed its effects. The OFTT was implemented on 2 March 2020 and modified regularly based on the revised testing criteria issued by the Swiss Federal Office of Public Health. After testing criteria liberalised, a chatbot tool was set up on 9 April 2020 to assess urgency of testing, referral to available testing sites and need for emergency care.In the first 40 days of the OFTT, there were more than 17 300 visitors and 69.8% indicated they would have contacted the healthcare system if the online test had not been available. During the initial week of operation, using the conservative testing strategy, 9.1% of visitors received recommendations to be tested, which increased to 36.0% of visitors after a change in testing criteria on 9 March 2020. Overall, since the implementation of the tool, 26.27% of all users of the site have been directed to obtain testing. The Chatbot tool has had approximately 50 consults/day.Setting up an OFTT should be considered as part of local strategies to cope with the COVID-19 pandemic. It may ease the burden on the healthcare system, reassure patients and inform authorities. To account for the dynamic development of the pandemic, frequent adaptation of the tool is of great importance. Further research on clinical outcomes of OFTT is urgently needed.
EGFR upregulation is an established biomarker of treatment resistance and aggressiveness in head and neck cancers (HNSCC). EGFR-targeted therapies have shown benefits for HPV-negative HNSCC; ...surprisingly, inhibiting EGFR in HPV-associated HNSCC led to inferior therapeutic outcomes suggesting opposing roles for EGFR in the two HNSCC subtypes. The current study aimed to understand the link between EGFR and HPV-infected HNSCC particularly the regulation of HPV oncoproteins E6 and E7. We demonstrate that EGFR overexpression suppresses cellular proliferation and increases radiosensitivity of HPV-positive HNSCC cell lines. EGFR overexpression inhibited protein expression of BRD4, a known cellular transcriptional regulator of HPV E6/E7 expression and DNA damage repair facilitator. Inhibition of EGFR by cetuximab restored the expression of BRD4 leading to increased HPV E6 and E7 transcription. Concordantly, pharmacological inhibition of BRD4 led to suppression of HPV E6 and E7 transcription, delayed cellular proliferation and sensitised HPV-positive HNSCC cells to ionising radiation. This effect was shown to be mediated through EGFR-induced upregulation of microRNA-9-5p and consequent silencing of its target BRD4 at protein translational level, repressing HPV E6 and E7 transcription and restoring p53 tumour suppressor functions. These results suggest a novel mechanism for EGFR inhibition of HPV E6/E7 oncoprotein expression through an epigenetic pathway, independent of MAPK, but mediated through microRNA-9-5p/BRD4 regulation. Therefore, targeting EGFR may not be the best course of therapy for certain cancer types including HPV-positive HNSCC, while targeting specific signalling pathways such as BRD4 could provide a better and potentially new treatment to improve HNSCC therapeutic outcome.
Multi-substance use is accompanied by increased morbidity and mortality and responsible for a large number of emergency department (ED) consultations. To improve the treatment for this vulnerable ...group of patients, it is important to quantify and break down in detail the ED resources used during the ED treatment of multi-substance users.
This retrospective single centre case-control study included all ED consultations of multi-substance users over a three-year study period at a university hospital in Switzerland. Resource consumption of these patients was compared to an age-matched control group of non-multi-substance users.
The analysis includes 867 ED consultations of multi-substance users compared to 4,335 age-matched controls (5:1). Multi-substance users needed more total resources (median tax points medical currency (IQR): 762 (459-1226) vs. 462 (196-833), p<0.001), especially physician, radiology, and laboratory resources. This difference persisted in multivariable analysis (geometric mean ratio (GMR) 1.2, 95% CI: 1.1-1.3, p = 0.001) adjusted for sociodemographic parameters, consultation characteristics, and patient comorbidity; the GMR was highest in ED laboratory and radiology resource consumption. Among multi-substance user, indirect and non-drug-related consultations had higher ED resource consumption compared to drug-related consultations. Furthermore, leading discipline as well as urgency were predictors of ED resource consumption. Moreover, multi-substance users had more revisits (55.2% vs. 24.9%, p<0.001) as well as longer ED and in-hospital stays (both: GMR 1.2, 95% CI: 1.1-1.3, p<0.001).
ED consultations of multi-substance users are expensive and resource intensive. Multi-substance users visited the ED more often and stayed longer at the ED and in-hospital. The findings of our study underline the importance of this patient group. Additional efforts should be made to improve their ED care. Special interventions should target this patient group in order to decrease the high frequency and costs of emergency consultations caused by multi-substance users.
This book is an introduction to the language of systems biology, which is spoken among many disciplines, from biology to engineering. Authors Thomas Sauter and Marco Albrecht draw on a ...multidisciplinary background and evidence-based learning to facilitate the understanding of biochemical networks, metabolic modeling and system dynamics. Their pedagogic approach briefly highlights core ideas of concepts in a broader interdisciplinary framework to guide a more effective deep dive thereafter. The learning journey starts with the purity of mathematical concepts, reveals its power to connect biological entities in structure and time, and finally introduces physics concepts to tightly align abstraction with reality. This workbook is all about self-paced learning, supports the flipped-classroom concept, and kick-starts with scientific evidence on studying. Each chapter comes with links to external YouTube videos, learning checklists, and Integrated real-world examples to gain confidence in thinking across scientific perspectives. The result is an integrated approach that opens a line of communication between theory and application, enabling readers to actively learn as they read. This overview of capturing and analyzing the behavior of biological systems will interest adherers of systems biology and network analysis, as well as related fields such as bioinformatics, biology, cybernetics, and data science.
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