An overview of gene therapy in head and neck cancer

Gene therapy is a new treatment modality in which new gene is introduced or existing gene is manipulated to cause cancer cell death or slow the growth of the tumor. In this review, we have discussed the different treatment approaches for cancer gene therapy; gene addition therapy, immunotherapy, gene therapy using oncolytic viruses, antisense ribonucleic acid (RNA) and RNA interference-based gene therapy. Clinical trials to date in head and neck cancer have shown evidence of gene transduction and expression, mediation of apoptosis and clinical response including pathological complete responses. The objective of this article is to provide an overview of the current available gene therapies for head and neck cancer.     

Development of peptide inhibitor as a therapeutic agent against head and neck squamous cell carcinoma (HNSCC) targeting p38α MAP kinase

Background

The p38α MAP kinase pathway is involved in inflammation, cell differentiation, growth, apoptosis and production of pro-inflammatory cytokines TNF-α and IL-1β. The overproduction of these cytokines plays an important role in cancer. The aim of this work was to design a peptide inhibitor on the basis of structural information of the active site of p38α.

Methods

A tetrapeptide, VWCS as p38α inhibitor was designed on the basis of structural information of the ATP binding site by molecular modeling. The inhibition study of peptide with p38α was performed by ELISA, binding study by Surface Plasmon Resonance and anti-proliferative assays by MTT and flow cytometry.

Results

The percentage inhibition of designed VWCS against pure p38α protein and serum of HNSCC patients was 70.30 and 71.5%, respectively. The biochemical assay demonstrated the K_D and IC₅₀ of the selective peptide as 7.22 × 10^− 9 M and 20.08 nM, respectively. The VWCS as inhibitor significantly reduced viability of oral cancer KB cell line with an IC₅₀ value of 10 μM and induced apoptosis by activating Caspase 3 and 7.

Conclusions

VWCS efficiently interacted at the ATP binding pocket of p38α with high potency and can be used as a potent inhibitor in case of HNSCC.

General significance

VWCS can act as an anticancer agent as it potentially inhibits the cell growth and induces apoptosis in oral cancer cell-line in a dose as well as time dependent manner. Hence, p38α MAP kinase inhibitor can be a potential therapeutic agent for human oral cancer.     

A modified human head model for the study of impact head injury

A recently published finite element (FE) head model is modified to consider the viscoelasticity of the meninges, the spongy and compact bone in the skull. The cerebrospinal fluid (CSF) is simulated explicitly as a hydrostatic fluid by using a surface-based fluid modelling method, which allows fluid and structure interaction. It is found that the modified model yields smoother pressure responses in a head impact simulation. The baseline model underestimated the peak von Mises stress in the brain by 15% and the peak principal stress in the skull by 33%. The increase in the maximum principal stress in the skull is mainly caused by the updation of the material's viscoelasticity, and the change in the maximum von Mises stress in the brain is mainly caused by the improvement of the CSF simulation. The study shows that the viscoelasticity of the head tissue should be considered, and that the CSF should be modelled as a fluid, when using FE analysis to study head injury due to impact.     

Helmet liner evaluation to mitigate head response from primary blast exposure

Head injury resulting from blast loading, including mild traumatic brain injury, has been identified as an important blast-related injury in modern conflict zones. A study was undertaken to investigate potential protective ballistic helmet liner materials to mitigate primary blast injury using a detailed sagittal plane head finite element model, developed and validated against previous studies of head kinematics resulting from blast exposure. Five measures reflecting the potential for brain injury that were investigated included intracranial pressure, brain tissue strain, head acceleration (linear and rotational) and the head injury criterion. In simulations, these measures provided consistent predictions for typical blast loading scenarios. Considering mitigation, various characteristics of foam material response were investigated and a factor analysis was performed which showed that the four most significant were the interaction effects between modulus and hysteretic response, stress–strain response, damping factor and density. Candidate materials were then identified using the predicted optimal material values. Polymeric foam was found to meet the density and modulus requirements; however, for all significant parameters, higher strength foams, such as aluminum foam, were found to provide the highest reduction in the potential for injury when compared against the unprotected head.     

Numerical model (switchable/dual model) of the human head for rigid body and finite elements applications

In this paper, a methodology for the development and validation of a numerical model of the human head using generic procedures is presented. All steps required, starting with the model generation, model validation and applications will be discussed. The proposed model may be considered as a dual one due to its capabilities to switch from deformable to a rigid body according to the application's requirements. The first step is to generate the numerical model of the human head using geometry files or medical images. The required stiffness and damping for the elastic connection used for the rigid body model are identified by performing a natural frequency analysis. The presented applications for model validation are related to impact analysis. The first case is related to Nahum's (Nahum and Smith 1970) experiments pressure data being evaluated and a pressure map generated using the results from discrete elements. For the second case, the relative displacement between the brain and the skull is evaluated according to Hardy's (Hardy WH, Foster CD, Mason, MJ, Yang KH, King A, Tashman S. 2001.Investigation of head injury mechanisms using neutral density technology and high-speed biplanar X-ray. Stapp Car Crash J. 45:337–368, SAE Paper 2001-22-0016) experiments. The main objective is to validate the rigid model as a quick and versatile tool for acquiring the input data for specific brain analyses.     

A Study of preconditioned Krylov subspace methods with reordering for linear systems from a biphasic v–p finite element formulation

A study was conducted on combinations of preconditioned iterative methods with matrix reordering to solve the linear systems arising from a biphasic velocity–pressure (v–p) finite element formulation used to simulate soft hydrated tissues in the human musculoskeletal system. Krylov subspace methods were tested due to the symmetric indefiniteness of our systems, specifically the generalized minimal residual (GMRES), transpose-free quasi-minimal residual (TFQMR), and biconjugate gradient stabilized (BiCGSTAB) methods. Standard graph reordering techniques were used with incomplete LU (ILU) preconditioning. Performance of the methods was compared on the basis of convergence rate, computing time, and memory requirements. Our results indicate that performance is affected more significantly by the choice of reordering scheme than by the choice of Krylov method. Overall, BiCGSTAB with one-way dissection (OWD) reordering performed best for a test problem representative of a physiological tissue layer. The preferred methods were then used to simulate the contact of the humeral head and glenoid tissue layers in glenohumeral joint of the shoulder, using a penetration-based method to approximate contact. The distribution of pressure and stress fields within the tissues shows significant through-thickness effects and demonstrates the importance of simulating soft hydrated tissues with a biphasic model.     

Azadirachtin affects the circadian rhythm of locomotion in Leucophaea maderae

Abstract

Azadirachtin shortens the period length of the locomotor activity rhythm in the circadian rhythm of Leucophaea maderae and induces splitting of this rhythm in two components in about 40% of the animals. The phase relationship between the two components is 180°. Both shortening of period and splitting are more pronounced in animals possessing longer periods before the injection of azadirachtin.     

Minor Differences in Anther Extrusion Affect Resistance to Fusarium Head Blight in Wheat

Fusarium head blight (FHB) remains a serious problem due to yield loss and mycotoxin accumulation in wheat production worldwide. We previously reported that the closed‐flowering (no anther extrusion) characteristic was effective for increasing resistance to FHB infection. In this study, we investigated the relationships between the degree of anther extrusion (AE) and FHB damage using double haploid lines (DHLs), derived from F₁ plants from crosses between closed‐flowering and opened‐flowering varieties. These DHLs exhibited various degrees of AE, and the degree of AE was significantly different among DHLs, regardless of the year and environment (pot‐ or field‐grown). FHB severity was the lowest in closed‐flowering DHLs, and DHLs with partially extruded anthers showed significantly higher FHB symptoms than those with closed‐flowering phenotypes. In general, DHLs with partially extruded anthers also had relatively severe FHB symptoms compared with those exhibiting full anther extrusion. FHB severity was significantly correlated with Fusarium‐damaged kernels and deoxynivalenol concentration. The results of this study showed that partially extruded anthers were considered to be a source of FHB infection. The closed‐flowering phenotype improved resistance to FHB infection. Meanwhile, phenotypes with rapid anther extrusion and ejection also could contribute to the avoidance of FHB infection.     

Tentorial mobility in centipedes (Chilopoda) revisited: 3D reconstruction of the mandibulo-tentorial musculature of Geophilomorpha

Mandibular mechanisms in Geophilomorpha are revised based on three-dimensional reconstructions of the mandibulo-tentorial complex and its muscular equipment in Dicellophilus carniolensis (Placodesmata) and Hydroschendyla submarina (Adesmata). Tentorial structure compares closely in the two species and homologies can be proposed for the 14/17 muscles that attach to the tentorium. Both species retain homologues of muscles that in other Pleurostigmophora are traditionally thought to cause swinging movements of the tentorium that complement the mobility of the mandibles. Although the original set of tentorial muscles is simplified in Geophilomorpha, the arrangement of the preserved homologues conforms to a system of six degrees of freedom of movement, as in non-geophilomorph Pleurostigmophora. A simplification of the mandibular muscles is confirmed for Geophilomorpha, but our results reject absence of muscles that in other Pleurostigmophora primarily support see-saw movements of the mandibles. In the construction of the tentorium, paralabial sclerites seem to be involved in neither Placodesmata nor Adesmata, and we propose their loss in Geophilomorpha as a whole. Current insights on the tentorial skeleton and its musculature permit two alternative conclusions on their transformation in Geophilomorpha: either tentorial mobility is primarily maintained in both Placodesmata and Adesmata (contrary to Manton’s arguments for immobility), or the traditional assumption of the tentorium as being mobile is a misinterpretation for Pleurostigmophora as a whole.