Non-invasive screening of breast cancer from fingertip smears-a proof of concept study.

Breast cancer is a global health issue affecting 2.3 million women per year, causing death in over 600,000. Mammography (and biopsy) is the gold standard for screening and diagnosis. Whilst effective, this test exposes individuals to radiation, has limitations to its sensitivity and specificity and may cause moderate to severe discomfort. Some women may also find this test culturally unacceptable. This proof-of-concept study, combining bottom-up proteomics with Matrix Assisted Laser Desorption Ionisation Mass Spectrometry (MALDI MS) detection, explores the potential for a non-invasive technique for the early detection of breast cancer from fingertip smears. A cohort of 15 women with either benign breast disease (n = 5), early breast cancer (n = 5) or metastatic breast cancer (n = 5) were recruited from a single UK breast unit. Fingertips smears were taken from each patient and from each of the ten digits, either at the time of diagnosis or, for metastatic patients, during active treatment. A number of statistical analyses and machine learning approaches were investigated and applied to the resulting mass spectral dataset. The highest performing predictive method, a 3-class Multilayer Perceptron neural network, yielded an accuracy score of 97.8% when categorising unseen MALDI MS spectra as either the benign, early or metastatic cancer classes. These findings support the need for further research into the use of sweat deposits (in the form of fingertip smears or fingerprints) for non-invasive screening of breast cancer.

Exploring the problem of determining human age from fingermarks using MALDI MS-machine learning combined approaches.

For over a century fingerprints have been predominantly used as a means of biometric identification. Notwithstanding, the unique pattern of lines that can contribute to identifying a suspect is made up of molecules originating from touch chemistry (contaminants) as well as from within the body. It is the latter class of molecules that could provide additional information about a suspect, such as lifestyle, as well as physiological, pharmacological and pathological states. An example of the physiological state (and semi-biometric information) is the sex of an individual; recent investigations have demonstrated the opportunity to determine the sex of an individual with an 86% accuracy of prediction based on the peptidic/protein profile of their fingerprints. In the study presented here, the first of its kind, a range of supervised learning predictive methods have been evaluated to explore the depth of the issue connected to human age determination from fingermarks exploiting again the differential presence of peptides and small proteins. A number of observations could be made providing (i) an understanding of the more appropriate study design for this kind of investigation, (ii) the most promising prediction model to test within future work and (iii) the deeper issues relating to this type of determination and concerning a mismatch between chronological and biological ages. Particularly resolving point (iii) is crucial to the success in determining the age of an individual from the molecular composition of their fingermark.

Submandibular Gland Transfer: A Potential Imaging Pitfall.

BACKGROUND AND PURPOSE: The Seikaly and Jha submandibular gland transfer surgery is performed to facilitate gland shielding during radiation therapy for head and neck tumors to circumvent radiation-induced xerostomia. It results in an asymmetric postsurgical appearance of the submandibular and submental spaces. Our purpose was to characterize the morphologic and enhancement characteristics of the transferred submandibular gland and identify potential pitfalls in postoperative radiologic interpretation. MATERIALS AND METHODS: This retrospective study identified patients with head and neck cancer who had undergone the submandibular gland transfer procedure at our institution. Chart reviews were performed to identify relevant oncologic histories and therapies. CT and MR neck imaging was reviewed to characterize morphologic and enhancement characteristics of the pre- and postoperative submandibular glands, as well as interpretive accuracy. RESULTS: Eleven patients with oropharyngeal and nasopharyngeal squamous cell carcinomas who underwent submandibular gland transfer were identified. The transferred glands were significantly lengthened in the anteroposterior dimension compared with contralateral glands (P < .001) and displaced anteriorly and inferiorly within the submandibular and submental spaces. Enhancement patterns of the transferred submandibular glands varied, depending on the time of imaging relative to the operation and radiation therapy. Submandibular gland transfer was acknowledged in the postoperative report in 7/11 cases. Errors in interpretation were present in 2/11 reports. CONCLUSIONS: After the submandibular gland transfer procedure, the submandibular and submental spaces lose their symmetric appearances as the transferred submandibular glands become lengthened and located more anteriorly and inferiorly, with variable enhancement characteristics. Familiarity with the postsurgical appearance of the transferred submandibular glands is key to accurate imaging interpretation.

STAT3 Expression and Activity are Up-Regulated in Diffuse Large B Cell Lymphoma of Dogs.

BACKGROUND: The Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathways play important roles in the pathogenesis of diffuse large B cell lymphoma (DLBCL) in humans, and up-regulated STAT3 expression and activity are associated with worse clinical outcome in humans. No studies have evaluated the JAK-STAT signaling pathway in DLBCL of dogs. HYPOTHESIS: STAT3 pathway is deregulated in DLBCL in dogs. We aim to assess the expression, activation, and cellular localization of STAT3 and mitogen-activated protein kinase ERK1/2 in DLBCL of dogs. ANIMALS: Forty-three client-owned dogs diagnosed with DLBCL by histopathology METHODS: Retrospective analysis of DLBCL in dogs, including patient characteristics and treatment, immunohistochemistry, and protein expressions by Western blot. RESULTS: A higher percentage of STAT3 and p-STAT3 immunolabelled cells were observed in DLBCL of dogs when compared to normal canine lymph nodes. In STAT3 immunolabelled cells, STAT3 has higher nuclear expression in lymphoma samples than in normal or reactive lymph nodes. In addition to up-regulated STAT3 expression and activation, mitogen-activated kinase ERK1/2 activation is up-regulated in DLBCL of dogs. CONCLUSION AND CLINICAL IMPORTANCE: Compared with the normal canine lymph node, DLBCL of dogs has up-regulated STAT3 pathway. Our results support future investigation of JAK inhibitors in the treatment of DLBCL in dogs.

Prognostic significance of hyoid bone invasion in advanced base of tongue carcinoma treated by chemoradiation.

OBJECTIVES: To examine the prognostic influence of hyoid bone invasion in advanced base of tongue squamous cell carcinoma treated with chemoradiation. METHODS: We retrospectively reviewed pre-treatment imaging (CT/MRI) for the presence or absence of hyoid bone invasion in patients with advanced (clinical T3 or T4a stage) base of tongue squamous cell carcinoma treated with chemoradiation from January 2001 to January 2011. We compared patients with hyoid bone invasion to those without based on the following metrics: 1-, 2- and 5-year locoregional recurrence-free survival, disease-free survival, disease-specific survival and overall survival. RESULTS: Eleven of thirty-seven patients had hyoid invasion present on pre-treatment imaging. Average follow-up was 45 months. Patients with hyoid bone invasion were found to have lower percentages in all survival metrics measured compared to patients without, respectively, with statistical significance achieved in the following: 2-year locoregional recurrence-free survival: 36.4% versus 86.4% (P = 0.006), 5-year locoregional recurrence-free survival: 12.5% versus 63.6% (P = 0.05), 2-year disease-free survival: 36.4% versus 77.3% (P = 0.05), 5-year disease-free survival: 12.5% versus 63.3% (P = 0.05) and the Kaplan-Meier curve for locoregional recurrence-free survival (P = 0.0075). CONCLUSIONS: Hyoid bone invasion by base of tongue squamous cell carcinoma may indicate a poorer prognosis despite treatment. Hyoid bone invasion may be a possible indication for intensification of treatment and/or may indicate a necessity for increasing the degree of post-treatment surveillance monitoring and imaging.

Association of the NPAS3 gene and five other loci with response to the antipsychotic iloperidone identified in a whole genome association study.

A whole genome association study was performed in a phase 3 clinical trial conducted to evaluate a novel antipsychotic, iloperidone, administered to treat patients with schizophrenia. Genotypes of 407 patients were analyzed for 334,563 single nucleotide polymorphisms (SNPs). SNPs associated with iloperidone efficacy were identified within the neuronal PAS domain protein 3 gene (NPAS3), close to a translocation breakpoint site previously observed in a family with schizophrenia. Five other loci were identified that include the XK, Kell blood group complex subunit-related family, member 4 gene (XKR4), the tenascin-R gene (TNR), the glutamate receptor, inotropic, AMPA 4 gene (GRIA4), the glial cell line-derived neurotrophic factor receptor-alpha2 gene (GFRA2), and the NUDT9P1 pseudogene located in the chromosomal region of the serotonin receptor 7 gene (HTR7). The study of these polymorphisms and genes may lead to a better understanding of the etiology of schizophrenia and of its treatment. These results provide new insight into response to iloperidone, developed with the ultimate goal of directing therapy to patients with the highest benefit-to-risk ratio.

Whole genome association study identifies polymorphisms associated with QT prolongation during iloperidone treatment of schizophrenia.

Administration of certain drugs (for example, antiarrhythmics, antihistamines, antibiotics, antipsychotics) may occasionally affect myocardial repolarization and cause prolongation of the QT interval. We performed a whole genome association study of drug-induced QT prolongation after 14 days of treatment in a phase 3 clinical trial evaluating the efficacy, safety and tolerability of a novel atypical antipsychotic, iloperidone, in patients with schizophrenia. We identified DNA polymorphisms associated with QT prolongation in six loci, including the CERKL and SLCO3A1 genes. Each single nucleotide polymorphism (SNP) defined two genotype groups associated with a low mean QT change (ranging from -0.69 to 5.67 ms depending on the SNP) or a higher mean QT prolongation (ranging from 14.16 to 17.81 ms). The CERKL protein is thought to be part of the ceramide pathway, which regulates currents conducted by various potassium channels, including the hERG channel. It is well established that inhibition of the hERG channel can prolong the QT interval. SLCO3A1 is thought to play a role in the translocation of prostaglandins, which have known cardioprotective properties, including the prevention of torsades de pointes. Our findings also point to genes involved in myocardial infarction (PALLD), cardiac structure and function (BRUNOL4) and cardiac development (NRG3). Results of this pharmacogenomic study provide new insight into the clinical response to iloperidone, developed with the goal of directing therapy to those patients with the optimal benefit/risk ratio.

Re-engineering the target specificity of Clostridial neurotoxins - a route to novel therapeutics.

The ability to chemically couple proteins to LH(N)-fragments of clostridial neurotoxins and create novel molecules with selectivity for cells other than the natural target cell of the native neurotoxin is well established. Such molecules are able to inhibit exocytosis in the target cell and have the potential to be therapeutically beneficial where secretion from a particular cell plays a causative role in a disease or medical condition. To date, these molecules have been produced by chemical coupling of the LH(N)-fragment and the targeting ligand. This is, however, not a suitable basis for producing pharmaceutical agents as the products are ill defined, difficult to control and heterogeneous. Also, the molecules described to date have targeted neuroendocrine cells that are susceptible to native neurotoxins, and therefore the benefit of creating a molecule with a novel targeting domain has been limited. In this paper, the production of a fully recombinant fusion protein from a recombinant gene encoding both the LH(N)-domain of a clostridial neurotoxin and a specific targeting domain is described, together with the ability of such recombinant fusion proteins to inhibit secretion from non-neuronal target cells. Specifically, a novel protein consisting of the LH(N)-domains of botulinum neurotoxin type C and epidermal growth factor (EGF) that is able to inhibit secretion of mucus from epithelial cells is reported. Such a molecule has the potential to prevent mucus hypersecretion in asthma and chronic obstructive pulmonary disease.

Snacking patterns influence energy and nutrient intakes but not body mass index.

OBJECTIVE: To study dietary intake and body mass index (BMI) patterns among US adults, stratified by snacking patterns. DESIGN: The 1994-1996 Continuing Survey of Food Intakes by Individuals (CSFII) provided the study sample. Snacking episodes were defined as a 'food and/or beverage break', and subjects were classified as morning, afternoon, evening, multiple or never snackers. SUBJECTS/SETTING: Our study included data from 1756 men and 1511 women who provided two nonconsecutive, multiple-pass 24-h dietary recalls. STATISTICAL ANALYSES: Mean values of each subject's two 24-h recalls were used for analyses, and data were analysed using the Statistical Package for the Social Sciences (SPSS) for Windows and SUDAAN. RESULTS: Compared with women, men were more likely to be evening, multiple or never snackers. Male multiple snackers had significantly higher energy intakes than did afternoon and never snackers, whereas female multiple snackers had higher energy intakes than did morning, evening and never snackers. At the same time, male and female multiple snackers had more prudent energy-adjusted intakes of protein, cholesterol, calcium and sodium. Coffee, cola, milk, ice cream and fruits were among the most frequently consumed snacks by men and women. The BMI did not differ significantly across snacker categories. CONCLUSIONS: These data indicate that snacking patterns have some effects on energy and nutrient intakes but not on BMI. Snack food choices remain a concern, especially beverages, including those that are sweetened. Vegetables and fruits as snacks should be encouraged.

External peer review in Europe: an overview from the ExPeRT Project. External Peer Review Techniques.

OBJECTIVE: This paper aims to evaluate the use and development of external peer review models and to identify where the main models are used in European Union member states and countries with reciprocal research agreements with the European Union. DESIGN: The ExPeRT (external peer review techniques) project research team conducted a series of fact-finding missions to all participating European nations. Study participants. I. Blomberg, Sweden; L. Bohigas, Spain; S. Cucic, The Netherlands; P. Morosini, Italy. The Project is led by C. Shaw, UK and is managed by C. Heaton, CASPE Research. RESULTS: We identified four main external peer review models aimed at measuring the quality of service management and delivery: health care accreditation, the International Organization for Standardization ISO 9000 standards, the European Foundation for Quality Management Excellence Model and visitatie, which is Dutch for 'visitation' or peer review-based schemes. DISCUSSION: ExPeRT has demonstrated that in principle, convergence of the four main models in order to gain from each model's key strengths is feasible. Whether convergence is practical, depends upon the willingness of governments, health service providers, health care quality professionals and organizations to come together and adopt the recommendations of the ExPeRT project.

Interpretations and variations of ISO 9000 in acute health care. International Organization for Standardization.

OBJECTIVE: This paper aims to address two questions related to the implementation of the ISO 9000 Quality Management System standard in the acute health care sector: which countries have developed specific nationwide guidelines/interpretations? and what variances exist between the different interpretations of the ISO 9002 standard? DESIGN: The study was carried out via an assessment of the available guideline documents for the use of ISO 9000 in the acute health care sector. The interpretation of each document was examined for common elements and deviations from the commonly agreed terms. SETTING: Worldwide in the acute health care sector (excluding that of laboratories). STUDY PARTICIPANTS: Eighty-two international ISO members and/or quality health care organizations. RESULTS: The results showed variation in the interpretations of the ISO 9000 standard. In total, 16 of the clauses/subclauses note distinct variations, between one or more of the documents, which could alter the perception of the system. CONCLUSION: From examination of the six identified guideline documents, the claim that ISO 9000 introduces quality systems which are comparable from one country to another is unfounded in the acute health care sector.

Methods for external evaluation of health care institutions.

OBJECTIVE: To compare the methods used by external evaluators of health care institutions in Europe. METHODS: A common framework for analysis was designed by the authors and shared among the members of the ExPeRT Project. Each member prepared a description of a model and the results were compared in two workshops. RESULTS: Programmes share similarities in the methods used, but they differ in the focus and purpose of the evaluation. Differences in focus included whether a part or the whole of the institution is analysed and whether the review is patient or system centred. Different purposes of the programmes are reflected in the emphasis and use of the methodological tools: for instance, the appeal system is used only in the programmes that provide a certificate to the institution audited.

Fax/modem board communications decrease preceptor communication costs.

BACKGROUND: Mail and the telephone are common communication links between departments of family medicine and their community-based preceptors. The availability of low-cost fax/modem boards offers the potential for new communication methods. This study compares the cost of personal computer-based fax/modem board communications with traditional mail and telephone linkages. METHODS: The department's community preceptor faculty served as the study population. Sixty-eight physicians (54%) had fax machines; these physicians received faxes instead of mailed communications. The remaining 59 physicians (46%) received mailed communications. All preceptors received standard telephone calls. Costs for telephone, mail, and fax/modem board communications were tracked over a 4-month period. RESULTS: Faxes were significantly less expensive and more efficient than either telephone or mail communications. Telephone communications were the most expensive. CONCLUSIONS: The study suggests that fax/modem boards offer a communication linkage with preceptors that is more economical than either mail or telephone.

The revival of nitric acid for the treatment of anogenital warts.

The destruction of small lesions by tissue denaturation (fixation) rather than erosion (acid hydrolysis) is accomplished by nitric acid of moderate strength in which nitric acid reduction products are generated by nitric acid oxidation of added organic acids. Such solutions show a temperature-dependent increase or loss of nitrite during storage, with loss of therapeutic activity when nitrite levels decrease after storage at cooler temperatures. Use of a preparation technique that completely consumes all the oxidizable organic components added to generate nitrite results in a stable preparation that is effective, well tolerated, and convenient in the treatment of anogenital warts (condylomata acuminata). Of 50 patients monitored after treatment with a 6.6 mol/L nitric acid preparation with no residual oxidizable organic agents, results were good in 39 patients, satisfactory in four patients, and unsatisfactory in seven patients. These observations lead to a simplified stable preparation of modest nitric acid concentration with adequate nitrate reduction products for efficacy in the topical ablation of small skin lesions such as condylomata acuminata.