Proteomics in chronic wound research : potentials in healing and health

Chronic wounds, such as venous and diabetic leg ulcers, represent a significant health and financial burden to individuals and healthcare systems. In worst case scenarios this condition may require the amputation of an affected limb, with significant impact on patient quality of life and health. Presently there are no clinical biochemical analyses used in the diagnosis and management of this condition; moreover few biochemical therapies are accessible to patients. This presents a significant challenge in the efficient and efficacious treatment of chronic wounds by medical practitioners. A number of protein-centric investigations have analysed the wound environment and implicated a suite of molecular species predicted to be involved in the initiation or perpetuation of the condition. However, comprehensive proteomic investigation is yet to be engaged in the analysis of chronic wounds for the identification of molecular diagnostic/prognostic markers of healing or therapeutic targets. This review examines clinical chronic wound research and recommends a path towards proteomic investigation for the discovery of medically significant targets. Additionally, the supplementary documents associated with this review provide the first comprehensive summary of protein-centric, small molecule and elemental analyses in clinical chronic wound research.

Co-occurring anger in young people with Asperger's syndrome

Objectives: The co-occurrence of anger in young people with Asperger's syndrome (AS) has received little attention despite aggression, agitation, and tantrums frequently being identified as issues of concern in this population. The present study investigated the occurrence of anger in young people with AS and explores its relationship with anxiety and depression. Method: Sixty-two young people (12-23 years old) diagnosed with AS were assessed using the Beck Anger Inventory for Youth, Spence Children's Anxiety Scale, and Reynolds Adolescent Depression Scale. Results: Among young people with AS who participated in this study, 41% of participants reported clinically significant levels of anger (17%), anxiety (25.8%) and/or depression (11.5%). Anger, anxiety, and depression were positively correlated with each other. Depression, however, was the only significant predictor of anger. Conclusion: Anger is commonly experienced by young people with AS and is correlated with anxiety and depression. These findings suggest that the emotional and behavioral presentation of anger could serve as a cue for further assessment, and facilitate earlier identification and intervention for anger, as well as other mental health problems.

Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia

We show that imatinib, nilotinib, and dasatinib possess weak off-target activity against RAF and, therefore, drive paradoxical activation of BRAF and CRAF in a RAS-dependent manner. Critically, because RAS is activated by BCR-ABL, in drug-resistant chronic myeloid leukemia (CML) cells, RAS activity persists in the presence of these drugs, driving paradoxical activation of BRAF, CRAF, MEK, and ERK, and leading to an unexpected dependency on the pathway. Consequently, nilotinib synergizes with MEK inhibitors to kill drug-resistant CML cells and block tumor growth in mice. Thus, we show that imatinib, nilotinib, and dasatinib drive paradoxical RAF/MEK/ERK pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug-resistant CML cells in vitro and in vivo.

Unswitch-ABL drugs overcome resistance in chronic myeloid leukemia

ABL inhibitors have revolutionized the clinical management of chronic myeloid leukemia, but the BCR-ABLT315I mutation confers resistance to currently approved drugs. Chan et al. show, in this issue of Cancer Cell, that " switch-control" inhibitors block BCR-ABLT315I activity by preventing ABL from switching from the inactive to active conformation.

Mismatch negativity in recent-onset and chronic schizophrenia : a current source density analysis

Mismatch negativity (MMN) is a component of the event-related potential elicited by deviant auditory stimuli. It is presumed to index pre-attentive monitoring of changes in the auditory environment. MMN amplitude is smaller in groups of individuals with schizophrenia compared to healthy controls. We compared duration-deviant MMN in 16 recent-onset and 19 chronic schizophrenia patients versus age- and sex-matched controls. Reduced frontal MMN was found in both patient groups, involved reduced hemispheric asymmetry, and was correlated with Global Assessment of Functioning (GAF) and negative symptom ratings. A cortically-constrained LORETA analysis, incorporating anatomical data from each individual's MRI, was performed to generate a current source density model of the MMN response over time. This model suggested MMN generation within a temporal, parietal and frontal network, which was right hemisphere dominant only in controls. An exploratory analysis revealed reduced CSD in patients in superior and middle temporal cortex, inferior and superior parietal cortex, precuneus, anterior cingulate, and superior and middle frontal cortex. A region of interest (ROI) analysis was performed. For the early phase of the MMN, patients had reduced bilateral temporal and parietal response and no lateralisation in frontal ROIs. For late MMN, patients had reduced bilateral parietal response and no lateralisation in temporal ROIs. In patients, correlations revealed a link between GAF and the MMN response in parietal cortex. In controls, the frontal response onset was 17 ms later than the temporal and parietal response. In patients, onset latency of the MMN response was delayed in secondary, but not primary, auditory cortex. However amplitude reductions were observed in both primary and secondary auditory cortex. These latency delays may indicate relatively intact information processing upstream of the primary auditory cortex, but impaired primary auditory cortex or cortico-cortical or thalamo-cortical communication with higher auditory cortices as a core deficit in schizophrenia.