Proteomic profile of KSR1-regulated signalling in response to genotoxic agents in breast cancer

Kinase suppressor of Ras 1 (KSR1) has been implicated in tumorigenesis in multiple cancers, including skin, pancreatic and lung carcinomas. However, our recent study revealed a role of KSR1 as a tumour suppressor in breast cancer, the expression of which is potentially correlated with chemotherapy response. Here, we aimed to further elucidate the KSR1-regulated signalling in response to genotoxic agents in breast cancer. Stable isotope labelling by amino acids in cell culture (SILAC) coupled to high-resolution mass spectrometry (MS) was implemented to globally characterise cellular protein levels induced by KSR1 in the presence of doxorubicin or etoposide. The acquired proteomic signature was compared and GO-STRING analysis was subsequently performed to illustrate the activated functional signalling networks. Furthermore, the clinical associations of KSR1 with identified targets and their relevance in chemotherapy response were examined in breast cancer patients. We reveal a comprehensive repertoire of thousands of proteins identified in each dataset and compare the unique proteomic profiles as well as functional connections modulated by KSR1 after doxorubicin (Doxo-KSR1) or etoposide (Etop-KSR1) stimulus. From the up-regulated top hits, several proteins, including STAT1, ISG15 and TAP1 are also found to be positively associated with KSR1 expression in patient samples. Moreover, high KSR1 expression, as well as high abundance of these proteins, is correlated with better survival in breast cancer patients who underwent chemotherapy. In aggregate, our data exemplify a broad functional network conferred by KSR1 with genotoxic agents and highlight its implication in predicting chemotherapy response in breast cancer

Controlling plasma properties under differing degrees of electronegativity using odd harmonic dual frequency excitation

International audienceThe charged particle dynamics in low-pressure oxygen plasmas excited by odd harmonic dual frequency waveforms (low frequency of 13.56 MHz and high frequency of 40.68 MHz) are investigated using a one-dimensional numerical simulation in regimes of both low and high electronegativity. In the low electronegativity regime, the time and space averaged electron and negative ion densities are approximately equal and plasma sustainment is dominated by ionisation at the sheath expansion for all combinations of low and high frequency and the phase shift between them. In the high electronegativity regime, the negative ion density is a factor of 15--20 greater than the low electronegativity cases. In these cases, plasma sustainment is dominated by ionisation inside the bulk plasma and at the collapsing sheath edge when the contribution of the high frequency to the overall voltage waveform is low. As the high frequency component contribution to the waveform increases, sheath expansion ionisation begins to dominate. It is found that the control of the average voltage drop across the plasma sheath and the average ion flux to the powered electrode are similar in both regimes of electronegativity, despite the differing electron dynamics using the considered dual frequency approach. This offers potential for similar control of ion dynamics under a range of process conditions, independent of the electronegativity. This is in contrast to ion control offered by electrically asymmetric waveforms where the relationship between the ion flux and ion bombardment energy is dependent upon the electronegativity

Experimental benchmark of kinetic simulations of capacitively coupled plasmas in molecular gases

International audienceWe discuss the origin of uncertainties in the results of numerical simulations of low-temperature plasma sources, focusing on capacitively coupled plasmas. These sources can be operated in various gases/gas mixtures, over a wide domain of excitation frequency, voltage, and gas pressure. At low pressures, the non-equilibrium character of the charged particle transport prevails and particle-based simulations become the primary tools for their numerical description. The particle-in-cell method, complemented with Monte Carlo type description of collision processes, is a well-established approach for this purpose. Codes based on this technique have been developed by several authors/groups, and have been benchmarked with each other in some cases. Such benchmarking demonstrates the correctness of the codes, but the underlying physical model remains unvalidated. This is a key point, as this model should ideally account for all important plasma chemical reactions as well as for the plasma-surface interaction via including specific surface reaction coefficients (electron yields, sticking coefficients, etc). In order to test the models rigorously, comparison with experimental ?benchmark data? is necessary. Examples will be given regarding the studies of electron power absorption modes in O 2 , and CF 4 ?Ar discharges, as well as on the effect of modifications of the parameters of certain elementary processes on the computed discharge characteristics in O 2 capacitively coupled plasmas

Comorbid mental disorders in substance users from a single catchment area - a clinical study

<p>Abstract</p> <p>Background</p> <p>The optimal treatment of patients with substance use disorders (SUDs) requires an awareness of their comorbid mental disorders and vice versa. The prevalence of comorbidity in first-time-admitted SUD patients has been insufficiently studied. Diagnosing comorbidity in substance users is complicated by symptom overlap, symptom fluctuations, and the limitations of the assessment methods. The aim of this study was to diagnose all mental disorders in substance users living in a single catchment area, without any history of treatment for addiction or psychiatric disorders, admitted consecutively to the specialist health services. The prevalence of substance-induced versus substance-independent disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), in SUD patients will be described.</p> <p>Methods</p> <p>First-time consecutively admitted patients from a single catchment area, aged 16 years or older, admitted to addiction clinics or departments of psychiatry as outpatients or inpatients will be screened for substance-related problems using the Alcohol Use Disorder Identification Test and the Drug Use Disorder Identification Test. All patients with scores above the cutoff value will be asked to participate in the study. The patients included will be diagnosed for SUD and other axis I disorders by a psychiatrist using the Psychiatric Research Interview for Substance and Mental Disorders. This interview was designed for the diagnosis of primary and substance-induced disorders in substance users. Personality disorders will be assessed according to the Structured Clinical Interview for DSM-IV axis II disorders. The Symptom Checklist-90-Revised, the Inventory of Depressive Symptoms, the Montgomery Asberg Depression Rating Scale, the Young Mania Rating Scale, and the Angst Hypomania Check List will be used for additional diagnostic assessments. The sociodemographic data will be recorded with the Stanley Foundation's Network Entry Questionnaire. Biochemical assessments will reveal somatic diseases that may contribute to the patient's symptoms.</p> <p>Discussion</p> <p>This study is unique because the material represents a complete sample of first-time-admitted treatment seekers with SUD from a single catchment area. Earlier studies have not focused on first-time-admitted patients, so chronically ill patients, may have been overrepresented in those samples. This study will contribute new knowledge about mental disorders in first-time-admitted SUD patients.</p

Primary and secondary anosognosia for memory impairment in patients with Alzheimer's disease

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldThe neuropsychology of anosognosia for memory impairment in Alzheimer's disease (AD) was examined in 92 AD patients and 92 case matched individuals for comparison, using three quantitative methods of assessment: Experimenter Rating Scale (ERS), Objective Judgement Discrepancy (OJD) and Subjective-Rating Discrepancy (SRD). The OJD showed significant domain specific correlations with memory functioning as well as a significant correlation with susceptibility to intrusional errors. Memory or executive dysfunction may affect the immediate ability to judge cognitive performance in a domain specific manner (secondary anosognosia). Longer-term awareness of cognitive deficit appears less influenced by impaired basic cognitive functions, than by the decline of metacognitive function (primary anosognosia)

The ambivalence towards neuropsychology in dementia research, diagnosis, and drug development: Myths and misconceptions.

Clinical assessments remain the gold standard for diagnosing neurodegenerative dementia and monitoring disease progression and treatment effects as well research. However, rapid soluble biomarker developments hold promise for increasingly targeted therapeutic approaches, targeted selection of participants in clinical trials, and more direct physiological efficacy readouts. Unfortunately, the anchoring of biomarker research to clinical symptomatology and disease progression is often based on brief and uninformative cognitive tests or screening tools that lack sensitivity to the early stages of cognitive decline. The use of these tools has given the impression that cognitive symptoms occur relatively late in the disease and that disease progression in the early stages of disease is slow. This can hinder advancements in the field and may lead to treatment interventions occurring too late. Poor cognitive test selection has likely been a factor in the failure record of dementia drug development over the last two decades. A thorough cognitive assessment is a powerful tool in the hands of an expert neuropsychologist and continues to play a key role in the accurate and early diagnosis of neurodegenerative disease. This clinical assessment is very different from the cognitive testing we traditionally see in dementia biomarker research and drug development. Yet the distinction between the two approaches is unclear to many. This paper aims to elucidate some of the myths and misconceptions around cognitive research in dementia and suggests a way forward to facilitate biomarker and drug development through the improved utility of cognitive assessment tools