Post-Radiotherapy Dysphagia in Head and Neck Cancer: Current Management by Speech-Language Pathologists.

OPINION STATEMENT: Dysphagia, difficulty in eating and drinking, remains the most common side effect of radiotherapy treatment for head and neck cancer (HNC) with devastating consequences for function and quality of life (QOL). Over the past decade, 5-year survival has improved due to multiple factors including treatment advances, reduction in smoking, introduction of the human papillomavirus (HPV) vaccine and more favourable prognosis of HPV-related cancers. Increased prevalence of HPV-positive disease, which tends to affect younger individuals, has led to an elevated number of people living for longer with the sequelae of cancer and its treatment. Symptoms are compounded by late effects of radiotherapy which may lead to worsening of dysphagia for some long-term survivors or new-onset dysphagia for others. Speech-language pathology (SLP) input remains core to the assessment and management of dysphagia following HNC treatment. In this article, we present current SLP management of dysphagia post-radiotherapy. We discuss conventional treatment approaches, the emergence of therapy adjuncts and current service delivery models. The impact of adherence on therapy outcomes is highlighted. Despite treatment advancements, patients continue to present with dysphagia which is resistant to existing intervention approaches. There is wide variation in treatment programmes, with a paucity of evidence to support optimal type, timing and intensity of treatment. We discuss the need for further research, including exploration of the impact of radiotherapy on the central nervous system (CNS), the link between sarcopenia and radiotherapy-induced dysphagia and the benefits of visual biofeedback in rehabilitation.

Inducible gene modification in the gastric epithelium of Tff1-CreERT2, Tff2-rtTA, Tff3-luc mice.

Temporal and spatial regulation of genes mediated by tissue-specific promoters and conditional gene expression systems provide a powerful tool to study gene function in health, disease, and during development. Although transgenic mice expressing the Cre recombinase in the gastric epithelium have been reported, there is a lack of models that allow inducible and reversible gene modification in the stomach. Here, we exploited the gastrointestinal epithelium-specific expression pattern of the three trefoil factor (Tff) genes and bacterial artificial chromosome transgenesis to generate a novel mouse strain that expresses the CreERT2 recombinase and the reverse tetracycline transactivator (rtTA). The Tg(Tff1-CreERT2;Tff2-rtTA;Tff3-Luc) strain confers tamoxifen-inducible irreversible somatic recombination and allows simultaneous doxycycline-dependent reversible gene activation in the gastric epithelium of developing and adult mice. This strain also confers luciferase activity to the intestinal epithelium to enable in vivo bioluminescence imaging. Using fluorescent reporters as conditional alleles, we show Tff1-CreERT2 and Tff2-rtTA transgene activity in a partially overlapping subset of long-term regenerating gastric stem/progenitor cells. Therefore, the Tg(Tff1-CreERT2;Tff2-rtTA;Tff3-Luc) strain can confer intermittent transgene expression to gastric epithelial cells that have undergone previous gene modification, and may be suitable to genetically model therapeutic intervention during development, tumorigenesis, and other genetically tractable diseases. Birth Defects Research (Part A) 106:626-635, 2016. © 2016 Wiley Periodicals, Inc.

Electrochemical studies of silver nanoparticles: a guide for experimentalists and a perspective.

This perspective summarises four different electrochemical techniques that have been established and frequently used to characterize various properties of silver nanoparticles. These are based on drop casting (I), in situ nanoparticle sticking and stripping (II), transfer sticking and stripping (III) or nanoparticle impacts (IV). The specific characteristics of the different methodologies are explained and contrasted with each other with the focus being on the respective benefits and limitations together with essential insights for experimentalists.

Sustained year-round oceanographic measurements from Rothera Research Station, Antarctica, 1997-2017.

Oceanographic changes adjacent to Antarctica have global climatic and ecological impacts. However, this is the most challenging place in the world to obtain marine data due to its remoteness and inhospitable nature, especially in winter. Here, we present more than 2000 Conductivity-Temperature-Depth (CTD) profiles and associated water sample data collected with (almost uniquely) full year-round coverage from the British Antarctic Survey Rothera Research Station at the west Antarctic Peninsula. Sampling is conducted from a small boat or a sled, depending on the sea ice conditions. When conditions allow, sampling is twice weekly in summer and weekly in winter, with profiling to nominally 500 m and with discrete water samples taken at 15 m water depth. Daily observations are made of the sea ice conditions in the area. This paper presents the first 20 years of data collection, 1997-2017. This time series represents a unique and valuable resource for investigations of the high-latitude ocean's role in climate change, ocean/ice interactions, and marine biogeochemistry and carbon drawdown.

Signal transducers and enzyme cofactors are susceptible to oxidation by nanographite impurities in carbon nanotube materials.

Carbon nanotubes (CNTs) are often employed in biofuel cells, artificial photosystems and bioelectronics in order to enhance electron transfer and to efficiently shuttle electrons between redox active molecules and the electrode surface. However, it should be noted that typical CNTs are highly heterogeneous materials, containing large amounts of impurities. Herein, we report the influence of nanographite impurities contained within CNTs upon the redox properties of signal transducers and enzyme cofactors that are vital for the functioning of biofuel cells, artificial leaves and bioelectronics as well as for the survival of living organisms. We investigate the susceptibility of tyrosine and tryptophan, amino acids involved in electron transfer and biorecognition reactions as well in the synthesis of neurotransmitters, in addition we also consider the susceptibility of the principal electron carrier ß-nicotinamide adenine dinucleotide. We conclude that nanographite impurities within CNTs are responsible for the "electrocatalytic" oxidation of NADH and two amino acids involved in signal transduction, tyrosine and tryptophan. Our findings are of high importance for both industrial and biomedical applications.

Impurities within carbon nanotubes govern the electrochemical oxidation of substituted hydrazines.

Electrochemistry and electrocatalysis on carbon nanomaterials is at the forefront of research. The presence of carbonaceous and metallic impurities within carbon nanotubes (CNTs) is a persistent problem. Here we show that the electrochemistry of the entire group of hydrazine compounds is governed by impurities within single-walled, double-walled and few-walled CNTs. The oxidation of organic substituted hydrazines at CNTs is driven by nanographitic impurities, in contrast to unsubstituted hydrazine, for which the electrochemistry is driven by metallic impurities within CNTs. This finding is unexpected, as one would assume that a whole group of compounds would be susceptible to "electrocatalysis" by only one type of impurity. This discovery should be taken into account when predicting the susceptibility of whole groups of compounds to electrocatalysis by metallic or nanographitic impurities. Our findings have strong implications on the electrochemical sensing of hydrazines and on the use of hydrazines as fuels for nanomotors.

Enhanced diffusion of pollutants by self-propulsion.

Current environmental models mostly account for the passive participation of pollutants in their environmental propagation. Here we demonstrate the paradigm-changing concept that pollutants can propagate themselves with a rate that is greater than the rate for standard molecular diffusion by five orders of magnitude.

Is useful research data usually shared? An investigation of genome-wide association study summary statistics.

Primary data collected during a research study is often shared and may be reused for new studies. To assess the extent of data sharing in favourable circumstances and whether data sharing checks can be automated, this article investigates summary statistics from primary human genome-wide association studies (GWAS). This type of data is highly suitable for sharing because it is a standard research output, is straightforward to use in future studies (e.g., for secondary analysis), and may be already stored in a standard format for internal sharing within multi-site research projects. Manual checks of 1799 articles from 2010 and 2017 matching a simple PubMed query for molecular epidemiology GWAS were used to identify 314 primary human GWAS papers. Of these, only 13% reported the location of a complete set of GWAS summary data, increasing from 3% in 2010 to 23% in 2017. Whilst information about whether data was shared was typically located clearly within a data availability statement, the exact nature of the shared data was usually unspecified. Thus, data sharing is the exception even in suitable research fields with relatively strong data sharing norms. Moreover, the lack of clear data descriptions within data sharing statements greatly complicates the task of automatically characterising shared data sets.

The combination of epigallocatechin gallate and curcumin suppresses ER alpha-breast cancer cell growth in vitro and in vivo.

Both epigallocatechin gallate (EGCG) and curcumin have shown efficacy in various in vivo and in vitro models of cancer. This study was designed to determine the efficacy of these naturally derived polyphenolic compounds in vitro and in vivo, when given in combination. Studies in MDA-MB-231 cells demonstrated that EGCG + curcumin was synergistically cytotoxic and that this correlated with G(2)/M-phase cell cycle arrest. After 12 hr, EGCG (25 microM) + curcumin (3 microM) increased the proportion of cells in G(2)/M-phase to 263 +/- 16% of control and this correlated with a 50 +/- 4% decrease in cell number compared to control. To determine if this in vitro result would translate in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with curcumin (200 mg/kg/day, po), EGCG (25 mg/kg/day, ip), EGCG + curcumin, or vehicle control (5 ml/kg/day, po) for 10 weeks. Tumor volume in the EGCG + curcumin treated mice decreased 49% compared to vehicle control mice (p < 0.05), which correlated with a 78 +/- 6% decrease in levels of VEGFR-1 protein expression in the tumors. Curcumin treatment significantly decreased tumor protein levels of EGFR and Akt, however the expression of these proteins was not further decreased following combination treatment. Therefore, these results demonstrate that the combination of EGCG and curcumin is efficacious in both in vitro and in vivo models of ER alpha-breast cancer and that regulation of VEGFR-1 may play a key role in this effect.

The combination of raloxifene and epigallocatechin gallate suppresses growth and induces apoptosis in MDA-MB-231 cells.

Previous studies have demonstrated that raloxifene induces apoptosis in a variety of cancer cell lines. We aimed to determine if this effect was enhanced by combining raloxifene with epigallocatechin gallate (EGCG). Results demonstrated that EGCG (25 microM) and raloxifene (1-5 microM) produced enhanced cytotoxicity toward MDA-MB-231 breast cancer cells compared to either drug alone following 7 days of treatment. The combination of 5 microM raloxifene and EGCG was the most effective as it decreased cell number by 96% of control, and time-course studies demonstrated that significant cytotoxicity began 36 h after treatment. Potential mechanisms for this effect were then investigated. Flow cytometry experiments demonstrated that apoptosis was significantly increased following 12 h of combination treatment compared to all other treatment groups. A maximal increase in the proportion of cells in the G(1)-phase of the cell cycle (116% of control) occurred following 24 h of combination treatment, 12 h after the significant increase in apoptosis, and thus was not considered to be a viable mechanism for the enhancement of apoptosis. While raloxifene was a competitive inhibitor of microsomal UDP-glucuronosyltransferase activity (K(i) of 24 microM), it did not decrease the metabolism of EGCG as the rate of disappearance of EGCG from the media was the same for cells treated with either EGCG or EGCG+raloxifene. Finally, the combination treatment reduced the phosphorylation of EGFR and AKT proteins by 21.2+/-3.3% and 31.5+/-1.7% from control, respectively. In conclusion, the synergistic cytotoxicity elicited by the combination of EGCG and raloxifene results from an earlier and greater induction of apoptosis. This is likely to be a result of reduced phosphorylation of EGFR and AKT signaling proteins.

Sex-specific differences in CYP450 isoforms in humans.

BACKGROUND: The activity of various CYP isoforms is critical for maintaining the clinical effectiveness of many medications. Therefore, determining the sex-dependent activity of clinically relevant CYP families is highly important for optimal therapeutic effectiveness. OBJECTIVE: This review examined the sex-dependent activity of CYP3A, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP2E1. METHODS: This review searched for studies performed in humans and hormonal status was not a limiting factor. RESULTS/CONCLUSIONS: The current evidence suggests that CYP2E1 and CYP1A2 activity is higher in males than females, while CYP3A, one of the most clinically relevant CYP isoforms, appears to have greater activity in females. Overall, more studies are needed to fully support these conclusions as there are many factors that influence drug metabolism and thus it is very difficult to isolate gender as a sole modulator of CYP activity.

Potential mechanisms for the synergistic cytotoxicity elicited by 4-hydroxytamoxifen and epigallocatechin gallate in MDA-MB-231 cells.

Potential mechanisms for the synergistic cytotoxicity elicited by epigallocatechin gallate (EGCG) (25 microM) and 4-hydroxytamoxifen (4-OHT) (1 microM) in MDA-MB-231 human breast cancer cells were investigated. The role of apoptosis was determined using chromatin condensation and Annexin-V staining. Condensed chromatin was visible following 24 h of combination treatment while flow cytometry experiments demonstrated that apoptosis was 2-fold greater following 36 h of combination treatment compared to EGCG. The temporal appearance of cells in G1-arrest did not correlate with apoptosis and thus was not considered to be a viable mechanism for the enhancement of apoptosis. While 4-OHT was a weak competitive inhibitor of microsomal UGT activity (Ki 95 microM), it did not alter the metabolism of EGCG as the rate of disappearance of EGCG from the media was the same for cells treated with either EGCG or EGCG + 4-OHT. Additionally, the metabolism of EGCG was not shifted toward the production of active methylated metabolites, as neither 4''-MeEGCG nor 4',4''-diMeEGCG (2.5-25 microM) were cytotoxic toward MDA-MB-231 cells. In conclusion, the synergistic cytotoxicity elicited by the combination of EGCG and 4-OHT results from an earlier induction of apoptosis but this was not caused by an increase in G1-arrest or 4-OHT-mediated changes in the metabolism of EGCG.

The proteolytic profile of prelabour ruptured amnion at term: a case-control study.

OBJECTIVES: The aim of this study was to investigate whether prelabour ruptured membranes at term display increased proteolytic activity and to determine whether regional structural alterations within membranes are reflective of regional variations in proteolytic activity. STUDY DESIGN: Multiple amnion samples were collected from 37 women with prelabour membrane rupture and 37 women whose membranes ruptured spontaneously during labour. In all cases the gestation was greater than 37 weeks. Substrate zymography was used to qualitatively assess gelatinase and serine protease involvement. General protease activity (metallo, serine, acid and sulfhydryl) was measured quantitatively by fluorescent substrate cleavage. RESULTS: Substrate zymography revealed no active gelatinases or serine proteases. Fluorescent studies of general protease activity showed no significant difference between the groups and no significant regional variation. CONCLUSIONS: Gelatinase and serine protease activity do not play a major role in the formation of a membrane rupture initiation site or in prelabour membrane rupture at term.

Role of epigallocatechin gallate (EGCG) in the treatment of breast and prostate cancer.

Green tea and its major constituent epigallocatechin gallate (EGCG) have been extensively studied as a potential treatment for a variety of diseases, including cancer. Epidemiological data have suggested that EGCG may provide protective effects against hormone related cancers, namely breast or prostate cancer. Extensive in vitro investigations using both hormone responsive and non-responsive cell lines have shown that EGCG induces apoptosis and alters the expression of cell cycle regulatory proteins that are critical for cell survival and apoptosis. This review will highlight the important in vitro mechanistic actions elicited by EGCG in various breast and prostate cancer cell lines. Additionally, the actions of green tea/EGCG in in vivo models for these cancers as well as in clinical trials will be discussed.

Differential macrophage function in Brown Swiss and Holstein Friesian cattle.

There is strong evidence that high yielding dairy cows are extremely susceptible to infectious diseases, and that this has severe economic consequences for the dairy industry and welfare implications. Here we present preliminary functional evidence showing that the innate immune response differs between cow breeds. The ability of macrophages (MØ) to kill pathogens depends in part on oxygen-dependent and independent mechanisms. The oxygen-dependent mechanisms rely on the generation of reactive oxygen and nitrogen species (ROS/RNS, respectively). ROS production has been shown to activate the inflammasome complex in MØ leading to increased production of the pro-inflammatory cytokine Interleukin-1ß (IL-1ß). Conversely RNS inhibits inflammasome mediated IL-1ß activation, indicating a division between inflammasome activation and RNS production. In the present study MØ from Brown Swiss (BS) cattle produce significantly more RNS and less IL-1ß when compared to cells from Holstein Friesian (HF) cattle in response to bacterial or fungal stimuli. Furthermore, BS MØ killed ingested Salmonella typhimurium more efficiently, supporting anecdotal evidence of increased disease resistance of the breed. Inhibition of autophagy by 3-methyladenine (3-MA) stimulated IL-1ß secretion in cells from both breeds, but was more pronounced in HF MØ. Blocking RNS production by l-arginase completely abolished RNS production but increased IL-1ß secretion in BS MØ. Collectively these preliminary data suggest that the dichotomy of inflammasome activation and RNS production exists in cattle and differs between these two breeds. As pattern recognition receptors and signaling pathways are involved in the assessed functional differences presented herein, our data potentially aid the identification of in vitro predictors of appropriate innate immune response. Finally, these predictors may assist in the discovery of candidate genes conferring increased disease resistance for future use in combination with known production traits.

Electrochemical observation of single collision events: fullerene nanoparticles.

Individual fullerene nanoparticles are detected and sized in a non-aqueous solution via cathodic particle coulometry where the direct, quantitative reduction of single nanoparticles is achieved upon collision with a potentiostated gold electrode. This is the first time that the nanoparticle impact technique has been shown to work in a non-aqueous electrolyte and utilized to coulometrically size carbonaceous nanoparticles. Contrast is drawn between single-nanoparticle electrochemistry and that seen using nanoparticle ensembles via modified electrodes.

Therapeutic inhibition of Jak activity inhibits progression of gastrointestinal tumors in mice.

Aberrant activation of the latent transcription factor STAT3 and its downstream targets is a common feature of epithelial-derived human cancers, including those of the gastrointestinal tract. Mouse models of gastrointestinal malignancy implicate Stat3 as a key mediator of inflammatory-driven tumorigenesis, in which its cytokine/gp130/Janus kinase (Jak)-dependent activation provides a functional link through which the microenvironment sustains tumor promotion. Although therapeutic targeting of STAT3 is highly desirable, such molecules are not available for immediate clinical assessment. Here, we investigated whether the small-molecule Jak1/2 inhibitor AZD1480 confers therapeutic benefits in two mouse models of inflammation-associated gastrointestinal cancer, which are strictly dependent of excessive Stat3 activation. We confirm genetically that Cre-mediated, tumor cell-specific reduction of Stat3 expression arrests the growth of intestinal-type gastric tumors in gp130(F/F) mice. We find that systemic administration of AZD1480 readily replicates this effect, which is associated with reduced Stat3 activation and correlates with diminished tumor cell proliferation and increased apoptosis. Likewise, AZD1480 therapy also conferred a cytostatic effect on established tumors in a colitis-associated colon cancer model in wild-type mice. As predicted from our genetic observations in gp130(F/F) mice, the therapeutic effect of AZD1480 remains fully reversible upon cessation of compound administration. Collectively, our results provide the first evidence that pharmacologic targeting of excessively activated wild-type Jak kinases affords therapeutic suppression of inflammation-associated gastrointestinal cancers progression in vivo.

Partial inhibition of gp130-Jak-Stat3 signaling prevents Wnt-ß-catenin-mediated intestinal tumor growth and regeneration.

Most colon cancers arise from somatic mutations in the tumor suppressor gene APC (adenomatous polyposis coli), and these mutations cause constitutive activation of the Wnt-to-ß-catenin pathway in the intestinal epithelium. Because Wnt-ß-catenin signaling is required for homeostasis and regeneration of the adult intestinal epithelium, therapeutic targeting of this pathway is challenging. We found that genetic activation of the cytokine-stimulated pathway mediated by the receptor gp130, the associated Jak (Janus kinase) kinases, and the transcription factor Stat3 (signal transducer and activator of transcription 3) was required for intestinal regeneration in response to irradiation-induced damage in wild-type mice and for tumorigenesis in Apc-mutant mice. Systemic pharmacological or partial genetic inhibition of gp130-Jak-Stat3 signaling suppressed intestinal regeneration, the growth of tumors in Apc-mutant mice, and the growth of colon cancer xenografts. The growth of Apc-mutant tumors depended on gp130-Jak-Stat3 signaling for induction of the polycomb repressor Bmi-1, and the associated repression of genes encoding the cell cycle inhibitors p16 and p21. However, suppression of gp130-Jak-Stat3 signaling did not affect Wnt-ß-catenin signaling or homeostasis in the intestine. Thus, these data not only suggest a molecular mechanism for how the gp130-Jak-Stat3 pathway can promote cancer but also provide a rationale for therapeutic inhibition of Jak in colon cancer.

Get more out of your data: a new approach to agglomeration and aggregation studies using nanoparticle impact experiments.

Anodic particle coloumetry is used to size silver nanoparticles impacting a carbon microelectrode in a potassium chloride/citrate solution. Besides their size, their agglomeration state in solution is also investigated solely by electrochemical means and subsequent data analysis. Validation of this new approach to nanoparticle agglomeration studies is performed by comparison with the results of a commercially available nanoparticle tracking analysis system, which shows excellent agreement. Moreover, it is demonstrated that the electrochemical technique has the advantage of directly yielding the number of atoms per impacting nanoparticle irrespective of its shape. This is not true for the optical nanoparticle tracking system, which requires a correction for the nonspherical shape of agglomerated nanoparticles to derive reasonable information on the agglomeration state.

In vitro mechanism of action for the cytotoxicity elicited by the combination of epigallocatechin gallate and raloxifene in MDA-MB-231 cells.

The anticancer effects elicited by epigallocatechin gallate (EGCG) are well established in various models of cancer, while raloxifene is as an established selective estrogen receptor modulator (SERM), which is not yet clinically utilized for the treatment of breast cancer. Previous study from this laboratory has demonstrated that the combination of EGCG (25 microM) and raloxifene (4 microM) elicits a strong cytotoxic response in MDA-MB-231 human breast cancer cells, which lack the estrogen receptor (ER) and erbB-2/ Her-2 receptor. This study was therefore designed to probe the mechanism underlying this cytotoxic response, with an emphasis on determining how the combination treatment influenced the total expression and phosphorylation of key signaling proteins. Specifically, following 12 and 18 h of the combination treatment, we observed significant decreases in the phosphorylation of the epidermal growth factor receptor (EGFR), AKT, mammalian target of rapamycin (mTOR) and S-6-kinase (S6K), and significant increases in the phosphorylation of stress activated protein kinases (SAPKs). Furthermore, these changes were associated with a reduction in the nuclear localization of p65, a major subunit of NF-kappaB. These results demonstrate that the combination of EGCG and raloxifene effectively reduced the mitogenic and survival signaling in MDA-MB-231 cells. Thus, this combination warrants further experimentation as a potential treatment for ER-negative breast cancer.