Predictive Value of EGFR-PI3K-AKT-mTOR-Pathway Inhibitor Biomarkers for Head and Neck Squamous Cell Carcinoma:A Systematic Review

BACKGROUND: Understanding molecular pathogenesis of head and neck squamous cell carcinomas (HNSCC) has considerably improved in the last decades. As a result, novel therapeutic strategies have evolved, amongst which are epidermal growth factor receptor (EGFR)-targeted therapies. With the exception of cetuximab, targeted therapies for HNSCC have not yet been introduced into clinical practice. One important aspect of new treatment regimes in clinical practice is presence of robust biomarkers predictive for therapy response.METHODS: We performed a systematic search in PubMed, Embase and the Cochrane library. Articles were included if they investigated a biomarker for targeted therapy in the EGFR-PI3K-AKT-mTOR-pathway.RESULTS: Of 83 included articles, 52 were preclinical and 33 were clinical studies (two studies contained both a preclinical and a clinical part). We classified EGFR pathway inhibitor types and investigated the type of biomarker (biomarker on epigenetic, DNA, mRNA or protein level).CONCLUSION: Several EGFR-PI3K-AKT-mTOR-pathway inhibitor biomarkers have been researched for HNSCC but few of the investigated biomarkers have been adequately confirmed in clinical trials. A more systematic approach is needed to discover proper biomarkers as stratifying patients is essential to prevent unnecessary costs and side effects.</p

Parsing and reflective printing, bidirectionally

Language designers usually need to implement parsers and printers. Despite being two intimately related programs, in practice they are often designed separately, and then need to be revised and kept consistent as the language evolves. It will be more convenient if the parser and printer can be unified and developed in one single program, with their consistency guaranteed automatically.Furthermore, in certain scenarios (like showing compiler optimisation results to the programmer), it is desirable to have a more powerful reflective printer that, when an abstract syntax tree corresponding to a piece of program text is modified, can reflect the modification to the program text while preserving layouts, comments, and syntactic sugar.To address these needs, we propose a domain-specific language BIYACC, whose programs denote both a parser and a reflective printer for an unambiguous context-free grammar. BIYACC is based on the theory of bidirectional transformations, which helps to guarantee by construction that the pairs of parsers and reflective printers generated by BIYACC are consistent. We show that BIYACC is capable of facilitating many tasks such as Pombrio and Krishnamurthi's "resugaring", simple refactoring, and language evolution.We would like to thank reviewers for their valuable comments. This work was partially supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (A) No. 25240009

Mental healthcare goes online:Practitioners' experiences of providing mental healthcare during the COVID-19 pandemic

The outbreak of the COVID-19 pandemic has necessitated sudden and radical changes in mental health care delivery, as strict social distancing and lockdown measures were imposed in the early phases of the pandemic. Almost overnight, practitioners were forced to transfer their face-to-face care practice to online means. To understand the implications of this drastic change for mental health care, and to improve the online care offerings, an online qualitative survey was held among mental health care professionals in Netherlands (n = 51). Our findings indicate that technological and usability problems pose a significant challenge, as do difficulties to establish rapport with clients. Moreover, not all mental health issues and treatment forms are equally amenable to online interaction. In contrast, in many instances, practitioners were positive about the effectiveness of treatment, and reported flexibility, a lower threshold for contact, and lack of travel time as advantages. Their most prominent needs concern better technological, organizational, and logistical support. It is critical that these needs are acted upon by institutions and governments. In addition, current results inform future research on the improvement of e-mental health technologies

Light, alertness, and alerting effects of white light:A literature overview

Light is known to elicit non-image-forming responses, such as effects on alertness. This has been reported especially during light exposure at night. Nighttime results might not be translatable to the day. This article aims to provide an overview of (1) neural mechanisms regulating alertness, (2) ways of measuring and quantifying alertness, and (3) the current literature specifically regarding effects of different intensities of white light on various measures and correlates of alertness during the daytime. In general, the present literature provides inconclusive results on alerting effects of the intensity of white light during daytime, particularly for objective measures and correlates of alertness. However, the various research paradigms employed in earlier studies differed substantially, and most studies tested only a limited set of lighting conditions. Therefore, the alerting potential of exposure to more intense white light should be investigated in a systematic, dose-dependent manner with multiple correlates of alertness and within one experimental paradigm over the course of day

p-mTOR, p-ERK and PTEN Expression in Tumor Biopsies and Organoids as Predictive Biomarkers for Patients with HPV Negative Head and Neck Cancer

Background: Survival rates of head and neck squamous cell carcinoma (HNSCC) have only marginally improved in the last decades. Hence there is a need for predictive biomarkers for long-time survival that can help to guide treatment decisions and might lead to the development of new therapies. The phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathway is the most frequently altered pathway in HNSCC, genes are often mutated, amplificated and overexpressed causing aberrant signaling affecting cell growth and differentiation. Numerous genetic alterations of upstream and downstream factors have currently been clarified. However, their predictive value has yet to be established. Therefore we assess the predictive value of p-mTOR, p-ERK and PTEN expression. Methods: Tissue microarrays (TMA’s) of HPV-negative patients with oropharyngeal (n = 48), hypopharyngeal (n = 16) or laryngeal (n = 13) SCC, treated with primary chemoradiation (cisplatin/carboplatin/cetuximab and radiotherapy), were histologically stained for p-mTOR, PTEN and p-ERK. Expression was correlated to overall survival (OS), disease free survival (DFS) and locoregional control (LRC). Also p-mTOR was histologically stained in a separate cohort of HNSCC organoids (n = 8) and correlated to mTOR-inhibitor everolimus response. Results: High p-mTOR expression correlated significantly with worse OS in multivariate analysis in the whole patient cohort [Hazar Ratio (HR) 1.06, 95%CI 1.01–1.11, p = 0.03] and in the cisplatin/carboplatin group with both worse OS (HR 1.09, 95%CI 1.02–1.16, p = 0.02) and DFS (HR 1.06, 95%CI 1.00–1.12, p = 0,04). p-ERK expression correlated significantly with DFS in univariate analysis in the whole patient cohort (HR 1.03, 95%CI 1.00–1.05, p = 0.04) and cisplatin/carboplatin group (HR 1.03, 95%CI 1.00–1.07, p = 0.04). PTEN-expression did not correlate with OS/DFS/LRC. Better organoid response to everolimus correlated significantly to higher p-mTOR expression (Rs = − 0.731, p = 0.04). Conclusions: High p-mTOR expression predicts and high p-ERK expression tends to predict worse treatment outcome in HPV negative HNSCC patients treated with chemoradiation, providing additional evidence that these markers are candidate prognostic biomarkers for survival in this patient population. Also this study shows that the use of HNSCC organoids for biomarker research has potential. The role of PTEN expression as prognostic biomarker remains unclear, as consistent evidence on its prognostic and predictive value is lacking.</p

Under-sampling and compressed sensing of 3D spatially-resolved displacement propagators in porous media using APGSTE-RARE MRI.

A method for under-sampling and compressed sensing of 3D spatially-resolved propagators is presented and demonstrated for flow in a packed bed and a heterogeneous carbonate rock. By sampling only 12.5% of q,k-space, the experimental acquisition time was reduced by almost an order of magnitude. In particular, for both systems studied, a 3D image was acquired at 1 mm isotropic spatial resolution such that 134,400 local propagators were obtained. Data were acquired in ~1 h and ~11 h for the packed bed and rock, respectively. It is shown that spatial resolution and under-sampling using this implementation retains the quantitative nature of the propagator measurement, and differences between implementation of this measurement in two and three dimensions are identified. The potential for 3D spatially-resolved propagators to provide new insights into transport processes in porous media by characterisation of the statistical moments of the propagators is discussed

Image method in the calculation of the van der Waals force between an atom and a conducting surface

Initially, we make a detailed historical survey of van der Waals forces, collecting the main references on the subject. Then, we review a method recently proposed by Eberlein and Zietal to compute the dispersion van der Waals interaction between a neutral but polarizable atom and a perfectly conducting surface of arbitrary shape. This method has the advantage of relating the quantum problem to a corresponding classical one in electrostatics so that all one needs is to compute an appropriate Green function. We show how the image method of electrostatics can be conveniently used together with the Eberlein and Zietal mehtod (when the problem admits an image solution). We then illustrate this method in a couple of simple but important cases, including the atom-sphere system. Particularly, in our last example, we present an original result, namely, the van der Waals force between an atom and a boss hat made of a grounded conducting material.Comment: This is a pedagogical and introductory paper on van der Waals forces between an atom and a conducting surfac

Assessing professionals' adoption readiness for eMental health:Development and validation of the eMental health adoption readiness scale

BACKGROUND: The last few decades have witnessed significant advances in the development of digital tools and applications for mental health care. Despite growing evidence for their effectiveness, acceptance and use of these tools in clinical practice remain low. Hence, a validated and easy-to-use instrument for assessing professionals’ readiness to adopt eMental health (EMH) is necessary to gain further insights into the process of EMH adoption and facilitate future research on this topic. OBJECTIVE: The aim of this study is to develop and validate an instrument for assessing mental health care professionals’ readiness to adopt EMH. METHODS: Item generation was guided by literature and inputs from mental health care professionals and experts in survey development. Exploratory factor analyses were conducted on an initial set of 29 items completed by a sample of mental health care professionals (N=432); thereafter, the scale was reduced to 15 items in an iterative process. The factor structure thus obtained was subsequently tested using a confirmatory factor analysis with a second sample of mental health care professionals (N=363). The internal consistency, convergent validity, and predictive validity of the eMental Health Adoption Readiness (eMHAR) Scale were assessed. RESULTS: Exploratory factor analysis resulted in a 3-factor solution with 15 items. The factors were analyzed and labeled as perceived benefits and applicability of EMH, EMH proactive innovation, and EMH self-efficacy. These factors were confirmed through a confirmatory factor analysis. The total scale and subscales showed a good internal consistency (Cronbach α=.73-.88) along with acceptable convergent and predictive relationships with related constructs. CONCLUSIONS: The constructed eMHAR Scale showed a conceptually interpretable 3-factor structure having satisfactory characteristics and relationships with relevant concepts. Its ease of use allows for quick acquisition of data that can contribute to understanding and facilitating the process of adoption of EMH by clinical professionals

Serum Iron Parameters, HFE C282Y Genotype, and Cognitive Performance in Older Adults: Results From the FACIT Study

Although iron homeostasis is essential for brain functioning, the effects of iron levels on cognitive performance in older individuals have scarcely been investigated. In the present study, serum iron parameters and hemochromatosis (HFE) C282Y genotype were determined in 818 older individuals who participated in a 3-year randomized, placebo-controlled double-blind trial examining the effects of folic acid on carotid intima-media thickness. All participants had slightly elevated homocysteine levels and were vitamin B12 replete. Cognitive functioning was assessed at baseline and after 3 years by means of a neuropsychological test battery. At baseline, increased serum ferritin was associated with decreased sensorimotor speed, complex speed, and information-processing speed and increased serum iron was associated with decreased sensorimotor speed. Cognitive performance over 3 years was not associated with HFE C282Y genotype or iron parameters. In conclusion, serum iron parameters do not show a straightforward relationship with cognitive functioning, although elevated iron levels may decrease cognitive speed in older individuals susceptible to cognitive impairmen