Genomic and expression analyses define MUC17 and PCNX1 as predictors of chemotherapy response in breast cancer

Poor prognosis breast cancers are treated with cytotoxic chemotherapy, but often without any guidance from therapy predictive markers since universally-accepted markers are not currently available. Treatment failure, in the form of recurrences, is relatively common. We aimed to identify chemotherapy predictive markers and resistance pathways in breast cancer. Our hypothesis was that tumour cells remaining after neoadjuvant chemotherapy (NAC) contain somatic variants causing therapy resistance, while variants present pre-NAC but lost post-NAC cause sensitivity. Whole exome sequencing was performed on matched pre- and post-NAC cancer cells, which were isolated by laser microdissection, from 6 cancer cases, and somatic variants selected for or against by NAC were identified. Somatic variant diversity was significantly reduced after therapy (p<0.05). MUC17 variants were identified in 3 tumours and were selected against by NAC in each case, while PCNX1 variants were identified in 2 tumours and were selected for in both cases, implicating the function of these genes in defining chemoresponse. In vitro knock-down of MUC17 or PCNX1 was associated with significantly increased or decreased chemotherapy sensitivity respectively (p<0.05), further supporting their roles in chemotherapy response. Expression was tested for predictive value in two independent cohorts of chemotherapy-treated breast cancers (n=53, n=303). Kaplan-Meier analyses revealed that low MUC17 expression was significantly associated with longer survival after chemotherapy, while low PCNX1 was significantly associated with reduced survival. We concluded that therapy-driven selection of somatic variants allows identification of chemotherapy response genes. With respect to MUC17 and PCNX1, therapy-driven selection acting on somatic variants, in vitro knock-down data concerning drug sensitivity, and survival analysis of expression levels in patient cohorts all define the genes as mediators of and predictive markers for chemotherapy response in breast cancer

Addiction to the nicotine gum in never smokers

Abstract Background Addiction to nicotine gum has never been described in never smokers or in never users of tobacco. Methods Internet questionnaire in 2004–2006 in a self-selected sample of 434 daily users of nicotine gum. To assess dependence on nicotine gum, we used modified versions of the Nicotine Dependence Syndrome Scale (NDSS), the Fagerström Test for Nicotine Dependence and the Cigarette Dependence Scale. Results Five never smokers used the nicotine gum daily. They had been using the nicotine gum for longer than the 429 ever smokers (median = 6 years vs 0.8 years, p = 0.004), and they had higher NDSS-gum Tolerance scores (median = 0.73 vs = -1.0, p = 0.03), a difference of 1.5 standard deviation units. Two never smokers had never used smokeless tobacco, both answered "extremely true" to: "I use nicotine gums because I am addicted to them", both "fully agreed" with: "after a few hours without chewing a nicotine gum, I feel an irresistible urge to chew one" and: "I am a prisoner of nicotine gum". Conclusion This is to our knowledge the first report of addiction to nicotine gum in never users of tobacco. However, this phenomenon is rare, and although the long-term effect of nicotine gum is unknown, this product is significantly less harmful than tobacco.</p

The Ergogenic Potential of Arginine

Arginine is a conditionally essential amino acid that is involved in protein synthesis, the detoxification of ammonia, and its conversion to glucose as well as being catabolized to produce energy. In addition to these physiological functions, arginine has been purported to have ergogenic potential. Athletes have taken arginine for three main reasons: 1) its role in the secretion of endogenous growth hormone; 2) its involvement in the synthesis of creatine; 3) its role in augmenting nitric oxide. These aspects of arginine supplementation will be discussed as well as a review of clinical investigations involving exercise performance and arginine ingestion

Alterations of brain and cerebellar proteomes linked to Aβ and tau pathology in a female triple-transgenic murine model of Alzheimer's disease

The triple-transgenic Alzheimer (3 × Tg-AD) mouse expresses mutant PS1M146V, APPswe, and tauP301L transgenes and progressively develops plaques and neurofibrillary tangles with a temporal- and region-specific profile that resembles the neuropathological progression of Alzheimer's disease (AD). In this study, we used proteomic approaches such as two-dimensional gel electrophoresis and mass spectrometry to investigate the alterations in protein expression occurring in the brain and cerebellum of 3 × Tg-AD and presenilin-1 (PS1) knock-in mice (animals that do not develop Aβ- or tau-dependent pathology nor cognitive decline and were used as control). Finally, using the Ingenuity Pathway Analysis we evaluated novel networks and molecular pathways involved in this AD model. We identified several differentially expressed spots and analysis of 3 × Tg-AD brains showed a significant downregulation of synaptic proteins that are involved in neurotransmitter synthesis, storage and release, as well as a set of proteins that are associated with cytoskeleton assembly and energy metabolism. Interestingly, in the cerebellum, a structure not affected by AD, we found an upregulation of proteins involved in carbohydrate metabolism and protein catabolism. Our findings help to unravel the pathogenic brain mechanisms set in motion by mutant amyloid precursor protein (APP) and hyperphosphorylated tau. These data also reveal cerebellar pathways that may be important to counteract the pathogenic actions of Aβ and tau, and ultimately offer novel targets for therapeutic intervention

Clinician acquisition and retention of Motivational Interviewing skills: a two-and-a-half-year exploratory study

<p>Abstract</p> <p>Background</p> <p>Motivational interviewing (MI) is a collaborative, client-centred counselling style aimed at eliciting and strengthening clients' intrinsic motivation to change. There is strong research evidence supporting the efficacy of MI, notably in its application among alcohol and drug abuse populations. MI interventions in smoking cessation may yield modest but significant increases in quitting. The present study sought to assess the acquisition and retention of MI skills in counsellors at the Swedish National Tobacco Quitline.</p> <p>Methods</p> <p>Three audio-recorded sessions from each of three counsellors were assessed using the Motivational Interviewing Treatment Integrity (MITI) Code Version 3.0 over 11 assessment periods at fixed intervals in a two-and-a-half year period during which counsellors received ongoing supervision.</p> <p>Results</p> <p>The mean skill for all counsellors improved throughout the study period in most MITI variables. However, great variations in MI skill between counsellors were observed, as well as fluctuations in performance in counsellors over time.</p> <p>Conclusion</p> <p>The present exploratory study covers a longer time period than most evaluations of MI training, and has several advantages with regard to study design. It may provide a basis for (larger sample) replication to test MI skill (as measured by the MITI) in relation to behaviour change in clients, to evaluate MI training, and to assess the acquisition and retention of MI skill over time. Difficulties in acquiring and retaining MI skill may raise the issue of a selection policy for MI training. Moreover, fluctuations in MI skill over time emphasise the greater importance of continuous feedback and supervision over initial MI training, and the need for the use of validated treatment integrity assessment instruments in ordinary clinical implementations of MI.</p

Health Education through Analogies: Preparation of a Community for Clinical Trials of a Vaccine against Hookworm in an Endemic Area of Brazil

Conducting clinical trials of new vaccines in rural, resource-limited areas can be challenging since the people living in these areas often have high levels of illiteracy, little experience with clinical research, and limited access to routine health care. Especially difficult is obtaining informed consent for participation in this type of research and ensuring that potential participants adequately understand the potential risks and benefits of participation. The researchers have been preparing a remote field site in the northeastern part of the state of Minas Gerais, Brazil, for clinical trials of experimental hookworm vaccines. A special educational video was designed based on the method of analogies to introduce new scientific concepts related to the researchers' work and to improve knowledge of hookworm, a disease that is highly prevalent in their community. A questionnaire was administered both before and after the video was shown to a group of adults at the field site, which demonstrated the effectiveness of the video in disseminating knowledge about hookworm infection and about the vaccine being developed. Therefore, even in a rural, resource-limited area, educational tools can be specially designed that significantly improve understanding and therefore the likelihood of obtaining truly informed consent for participation in clinical research

Genome Scan of M. tuberculosis Infection and Disease in Ugandans

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is an enduring public health problem globally, particularly in sub-Saharan Africa. Several studies have suggested a role for host genetic susceptibility in increased risk for TB but results across studies have been equivocal. As part of a household contact study of Mtb infection and disease in Kampala, Uganda, we have taken a unique approach to the study of genetic susceptibility to TB, by studying three phenotypes. First, we analyzed culture confirmed TB disease compared to latent Mtb infection (LTBI) or lack of Mtb infection. Second, we analyzed resistance to Mtb infection in the face of continuous exposure, defined by a persistently negative tuberculin skin test (PTST-); this outcome was contrasted to LTBI. Third, we analyzed an intermediate phenotype, tumor necrosis factor-alpha (TNFα) expression in response to soluble Mtb ligands enriched with molecules secreted from Mtb (culture filtrate). We conducted a full microsatellite genome scan, using genotypes generated by the Center for Medical Genetics at Marshfield. Multipoint model-free linkage analysis was conducted using an extension of the Haseman-Elston regression model that includes half sibling pairs, and HIV status was included as a covariate in the model. The analysis included 803 individuals from 193 pedigrees, comprising 258 full sibling pairs and 175 half sibling pairs. Suggestive linkage (p<10−3) was observed on chromosomes 2q21-2q24 and 5p13-5q22 for PTST-, and on chromosome 7p22-7p21 for TB; these findings for PTST- are novel and the chromosome 7 region contains the IL6 gene. In addition, we replicated recent linkage findings on chromosome 20q13 for TB (p = 0.002). We also observed linkage at the nominal α = 0.05 threshold to a number of promising candidate genes, SLC11A1 (PTST- p = 0.02), IL-1 complex (TB p = 0.01), IL12BR2 (TNFα p = 0.006), IL12A (TB p = 0.02) and IFNGR2 (TNFα p = 0.002). These results confirm not only that genetic factors influence the interaction between humans and Mtb but more importantly that they differ according to the outcome of that interaction: exposure but no infection, infection without progression to disease, or progression of infection to disease. Many of the genetic factors for each of these stages are part of the innate immune system

Attention Enhances the Retrieval and Stability of Visuospatial and Olfactory Representations in the Dorsal Hippocampus

Attention enhances the encoding and retrieval of olfactory and visuospatial representations by modulating place field stability, firing rate, and neuronal synchronization of pyramidal cells in the hippocampus