Zein-Based Nanoparticles Improve the Oral Bioavailability of Resveratrol and Its Anti-inflammatory Effects in a Mouse Model of Endotoxic Shock

Resveratrol offers pleiotropic health benefits including a reported ability to inhibit lipopolysaccharide (LPS)-induced cytokine production. The aim of this work was to prepare, characterize and evaluate a resveratrol nanoparticulate formulation based on zein. For this purpose, the oral bioavailability of the encapsulated polyphenol as well as its anti-inflammatory effects in a mouse model of endotoxic shock was studied. The resveratrol-loaded nanoparticles displayed a mean size of 307±3 nm, with a negative zeta potential (-51.1±1.55 mV), and a polyphenol loading of 80.2±3.26 μg/mg. In vitro, the release of resveratrol from the nanoparticles was found to be pH independent and adjusted well to the Peppas-Sahlin kinetic model, suggesting a mechanism based on the combination of diffusion and erosion of the nanoparticle matrix. Pharmacokinetic studies demonstrated that zein-based nanoparticles provided high and prolonged plasma levels of the polyphenol for at least 48 h. The oral bioavailability of resveratrol when administered in these nanoparticles increased up to 50% (19.2-fold higher than for the control solution of the polyphenol). Furthermore, nanoparticles administered daily for 7 days at 15 mg/kg, were able to diminish the endotoxic symptoms induced in mice by the intraperitoneal administration of LPS (i.e., hypothermia, piloerection and stillness). In addition, serum TNF-α levels were slightly lower (approximately 15%) than those observed in the control.

Post-diagnostic oral bisphosphonate use and colorectal cancer mortality: a population-based cohort study within the UK Clinical Practice Research Datalink

Background:We conducted the first study to investigate post-diagnostic oral bisphosphonates use and colorectal cancer-specific mortality.

Methods:Colorectal cancer patients were identified from the National Cancer Data Repository (1998–2007) and linked to the UK Clinical Practice Research Datalink, providing prescription records, and Office of National Statistics mortality data. Time-dependent Cox regression models investigated colorectal cancer-specific mortality in post-diagnostic bisphosphonate users.

Results:Overall, in 4791 colorectal cancer patients, there was no evidence of an association between bisphosphonate use and colorectal cancer-specific mortality (adjusted hazard ratio=1.11; 95% confidence interval 0.80, 1.54) or with drug frequency or type.

Conclusions:In this novel population-based cohort study, post-diagnostic bisphosphonate use was not associated with longer rates of colorectal cancer survival.

Relationships between Oral Health and Nutritional Status of Older Adults

Objectives: The World Health Organisation has highlighted the paucity of research into the oral health needs of older adults. In particular, the relationships between oral health and nutritional status require further investigation and analysis. This study aimed to describe some of the relationships between the number of remaining occluding tooth contacts, oral health related quality of life and nutritional status of partially dentate older adults.

Methods: 45 partially dentate patients aged 65 years and older were recruited to the study after visiting a university dental hospital. An initial dental examination charted the remaining teeth including the number of occluding contacts. Oral health related quality of life was recorded using the 14 item Oral Health Impact Profile. Nutritional status was measured using the Mini Nutritional Assessment (MNA) in addition to biochemical analysis of a haematological sample. Correlation between data values was measured using a Pearson's correlation coefficient (r).

Results: The patient sample was made up of 44% males and 56% females with a mean age of 72.4 years (range 65-84 years). With increasing age the patients' oral health related quality of life scores improved. (r=-0.25) Within the sample the number of occluding tooth contacts ranged from 6 to 11. It was found that as the number of occluding contacts increased, better oral health related quality of life scores were recorded. (r=-0.30) Generally mini nutritional assessment scores improved with increasing numbers of tooth contacts. (r=0.14) In addition, as the number of occluding teeth contacts increased total lymphocyte count (r=0.35), vitamin B12 (r=0.22) and serum folate (r=0.06) all increased.

Conclusions: In older patients increased numbers of tooth contacts are associated with better oral health related quality of life. Increasing numbers of occluding contacts are also associated with better MNA scores and some haematological indicators of nutritional status.

Current treatments for renal cell carcinoma

Renal cell carcinoma (RCC), also known as kidney cancer, renal adenocarcinoma or hypernephroma, and metastatic renal cell carcinoma is a global burden. This article aims to provide a brief overview of RCC. It outlines epidemiology and presentation; invesitgation and staging; treatments and prognosis. The article also includes a focus on currently available drug treatments, and serves as an introduction to the topic.

Protein expression differences between lung adenocarcinoma and squamous cell carcinoma with brain metastasis

AIM: We investigated tissue biomarkers in non-small cell lung cancer (NSCLC) to find indicators of brain metastasis and peritumoral brain edema.

PATIENTS AND METHODS: Fifty-two cases were studied out of which 26 had corresponding brain metastatic tissue. Clinicopathological characteristics of tumors were correlated with biomarkers of cell adhesion, cell growth, cell cycle and apoptosis regulation that were previously immunohistochemically studied but never analyzed separately according to histological subgroups, gender and smoking history.

RESULTS: Increased collagen XVII in adenocarcinoma (ADC) and increased caspase-9, CD44v6, and decreased cellular apoptosis susceptibility protein (CAS) and Ki-67 in squamous cell carcinoma (SCC) correlated significantly with brain metastasis. Increased β-catenin, E-cadherin and decreased caspase-9 expression in primary SCC, and decreased CD44v6 expression in brain metastatic SCC tissues showed a significant correlation with the extent of peritumoral brain edema. Positive correlation between smoking and biomarker expression could be observed in metastatic ADCs with p16 and caspase-8, while-negative correlation was found in SCC without brain metastasis with caspase-3, and in SCC with brain metastasis with p27.

CONCLUSION: Our results highlight the importance of separate analysis of biomarker expression in histological subtypes of NSCLC.

Tumor necrosis factor receptor expression and signaling in renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC), a tubular epithelial cell (TEC) malignancy, frequently secretes tumor necrosis factor (TNF). TNF signals via two distinct receptors (TNFRs). TNFR1, expressed in normal kidney primarily on endothelial cells, activates apoptotic signaling kinase 1 and nuclear factor-kappaB (NF-kappaB) and induces cell death, whereas TNFR2, inducibly expressed on endothelial cells and on TECs by injury, activates endothelial/epithelial tyrosine kinase (Etk), which trans-activates vascular endothelial growth factor receptor 2 (VEGFR2) to promote cell proliferation. We investigated TNFR expression in clinical samples and function in short-term organ cultures of ccRCC tissue treated with wild-type TNF or specific muteins selective for TNFR1 (R1-TNF) or TNFR2 (R2-TNF). There is a significant increase in TNFR2 but not TNFR1 expression on malignant TECs that correlates with increasing malignant grade. In ccRCC organ cultures, R1-TNF increases TNFR1, activates apoptotic signaling kinase and NF-kappaB, and promotes apoptosis in malignant TECs. R2-TNF increases TNFR2, activates NF-kappaB, Etk, and VEGFR2 and increases entry into the cell cycle. Wild-type TNF induces both sets of responses. R2-TNF actions are blocked by pretreatment with a VEGFR2 kinase inhibitor. We conclude that TNF, acting through TNFR2, is an autocrine growth factor for ccRCC acting via Etk-VEGFR2 cross-talk, insights that may provide a more effective therapeutic approach to this disease.

AURKA overexpression accompanies dysregulation of DNA-damage response genes in invasive urothelial cell carcinoma

Invasive urothelial cell carcinoma (UCC) is characterized by increased chromosomal instability and follows an aggressive clinical course in contrast to non-invasive disease. To identify molecular processes that confer and maintain an aggressive malignant phenotype, we used a high-throughput genome-wide approach to interrogate a cohort of high and low clinical risk UCC tumors. Differential expression analyses highlighted cohesive dysregulation of critical genes involved in the G(2)/M checkpoint in aggressive UCC. Hierarchical clustering based on DNA Damage Response (DDR) genes separated tumors according to a pre-defined clinical risk phenotype. Using array-comparative genomic hybridization, we confirmed that the DDR was disrupted in tumors displaying high genomic instability. We identified DNA copy number gains at 20q13.2-q13.3 (AURKA locus) and determined that overexpression of AURKA accompanied dysregulation of DDR genes in high risk tumors. We postulated that DDR-deficient UCC tumors are advantaged by a selective pressure for AURKA associated override of M phase barriers and confirmed this in an independent tissue microarray series. This mechanism that enables cancer cells to maintain an aggressive phenotype forms a rationale for targeting AURKA as a therapeutic strategy in advanced stage UCC.

Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma

The matrix metalloproteinases (MMPs) are endopeptidases which break down the extracellular matrix and regulate cytokine and growth factor activity. Several MMPs have been implicated in the promotion of invasion and metastasis in a broad range of tumours including urothelial carcinoma. In this study, RNA from 132 normal bladder and urothelial carcinoma specimens was profiled for each of the 24 human MMPs, the four endogenous tissue inhibitors of MMPs (TIMPs) and several key growth factors and their receptors using quantitative real time RT-PCR. Laser capture microdissection (LCM) of RNA from 22 tumour and 11 normal frozen sections was performed allowing accurate RNA extraction from either stromal or epithelial compartments. This study confirms the over expression in bladder tumour tissue of well-documented MMPs and highlights a range of MMPs which have not previously been implicated in the development of urothelial cancer. In summary, MMP-2, MT1-MMP and the previously unreported MMP-28 were very highly expressed in tumour samples while MMPs 1, 7, 9, 11, 15, 19 and 23 were highly expressed. There was a significant positive correlation between transcript expression and tumour grade for MMPs 1, 2, 8, 10, 11, 12, 13, 14, 15 and 28 (P < 0.001). At the same confidence interval, TIMP-1 and TIMP-3 also correlated with increasing tumour grade. LCM revealed that most highly expressed MMPs are located primarily within the stromal compartment except MMP-13 which localised to the epithelial compartment. This work forms the basis for further functional studies, which will help to confirm the MMPs as potential diagnostic and therapeutic targets in early bladder cancer.

Oral rehabilitation for partially dentate elders: a qualitative analysis

Aims: This study aimed to gain insight into patient’s perceptions of natural tooth loss and explored their experiences of oral rehabilitation according to a functionally orientated approach (SDA) and Removable Partial Dentures (RPD).
Study Design: For this qualitative study, a purposive sample of 15 partially dentate older patients
were recruited from Cork Dental School and Hospital. These patients had previously participated in a randomised controlled clinical trial (RCT) where they were provided with either SDA treatment using adhesive bridgework or provided with Cobalt Chromium framework RPDs. In- depth interviews were undertaken and thematic analysis was utilised to interpret the data.
Results: The findings of this study indicated strong satisfaction with SDA treatment. Patients referred to the ease in which they adapted to the adhesive prostheses as they were “lightweight”, “neat” and “fixed”. Irrespective of treatment option, patients indicated that they felt
their new prostheses were durable and an improvement on previous treatments. Most patients indicated that, previous to the RCT, they had not attended a general dentist for a number of years and only then for acute issues. They had concerns that treatment which was provided to them as part of the RCT would not be available to them in primary care. Interestingly, although they do not want their condition to dis-improve, if their prostheses failed they stated that they would not seek alternative treatment but would revert back
to adopting previous coping mechanisms.
Conclusion: This study illustrates that partially dentate older patients were very satisfied with oral rehabilitation according to a functionally orientated approach. Unfortunately they did not believe that this treatment would currently be made available to them in a primary care setting.

Oral Health Status of Patients Undergoing Treatment for Head and Neck Oncology in Northern Ireland

This study aimed to collect data on the oral health status of patients undergoing treatment for head and neck oncology across Northern Ireland. Data were collected on all patients referred to the Northern Ireland Multidisciplinary Head and Neck Oncology Team for discussion and treatment planning. Each patient underwent pre-treatment dental assessment in the Centre for Dentistry, Queen’s University Belfast, between June 2013 and November 2014. Data were collected from clinical oral examinations supplemented with intra-oral radiographs. During the course of the study 96 patients were assessed and the levels of dental disease observed in this cohort were high. On clinical examination
43% were diagnosed with caries and 46% with periodontal disease. Ten patients were completely edentate. The disease profile of this patient group presents significant challenges to dental services tasked with rendering patients dentally fit prior to undergoing oncology treatment.