Independent regulation of P53 stabilisation and activation after Rb deletion in primary epithelial cells

We have previously reported that deletion of the retinoblastoma gene Rb leads to rapid but transient p53 stabilisation. We investigated here the pathways involved. We show that upon Rb-deletion dysregulated E2F activates p19(ARF) expression that localises in the nucleoli. There it interacts with MDM2, leading to P53 stabilisation. At the same time, ATR is activated, activating CHK1 that may phosphorylate P53 but also contribute to inhibition of MnSOD expression leading to accumulation of ROS (reactive oxygen species) and subsequent DNA injury, which in turn maintains ATR/CHK1 activated. However, from 72 h after Rb deletion, NPM interacts with P19ARF and concomitantly the interaction between p19(ARF) and MDM2 decreases leading to a return to P53 degradation. This occurs despite the persistence of the DNA damage response pathways. We therefore observe in primary cells not subjected to exogenous gene expression or exogenous DNA damaging treatment, activation of 2 concomitant pathways of activation of P53 that are dealt with in independent manner: an oncogenic pathway with rapid activation of ARF which is 'switched off' downstream of p19(ARF) activation after 72 h of induction and a DNA damage response pathway keeping a low level of transcriptionally active P53 sufficient to deal with a physiological elevation of oxidative DNA injury. A possible connection between the two pathways is discussed.Publisher PDFPeer reviewe

Digital pathology in clinical use: where are we now and what is holding us back?

Whole slide imaging is being used increasingly in research applications and in frozen section, consultation and external quality assurance practice. Digital pathology, when integrated with other digital tools such as barcoding, specimen tracking and digital dictation, can be integrated into the histopathology workflow, from specimen accession to report sign-out. These elements can bring about improvements in the safety, quality and efficiency of a histopathology department. The present paper reviews the evidence for these benefits. We then discuss the challenges of implementing a fully digital pathology workflow, including the regulatory environment, validation of whole slide imaging and the evidence for the design of a digital pathology workstation

Study of vibrational excitation mechanisms of CO2 at high temperatures

Calculating vibrational excitation of CO2 for anharmonic coupling and normal mode at high temperatur

Study of vibrational excitation mechanisms of carbon dioxide at high temperatures

Vibrational relaxation models of carbon dioxide at high temperature

Cognitive impairment among prostate cancer patients: an overview of reviews

To identify and clarify definitions and methods of measuring cancer-related cognitive impairment among prostate cancer patients treated with Androgen Deprivation Therapy (ADT) and to assess the incidence and prevalence of cognitive impairment. A systematic review of Medline, EMBASE, PubMed, PsycINFO and CINAHL up to December 2015 was undertaken to identify English-language reviews. A total of twenty-eight reviews were identified describing twenty primary studies. There were no studies of incidence. Reported prevalence rates varied between 10 and 69%. Cognitive domains impaired by ADT included: verbal memory, visuospatial ability and executive functions. Cognitive impairment was infrequently defined and four definitions were reported. A variety of measures and methods were used to assess cognitive function including neuropsychological tests, self-report measures and clinical assessments. The finding that, often, one measure was used to assess more than one aspect of cognition is likely to have contributed to imprecise estimates. There is a need to agree a definition of cognitive impairment in the clinical epidemiology of cancer and to standardise the selection of measures in order to aid accurate assessment and fair comparisons across studies regarding the prevalence of cognitive impairment among prostate cancer patient

Integrating ecology with management to control wildlife brucellosis

Summary Bison (Bison bison) and elk (Cervus elaphus) in the greater Yellowstone ecosystem have long been infected with Brucella abortus. The continued culling of large numbers of Yellowstone bison to reduce the risk of brucellosis transmission to cattle could negatively affect long-term conservation. A desirable management objective is to reduce the level of B. abortus infection while conserving wildlife populations. Identifying the ecological factors that infl uence immune suppression and vulnerability to infection will help initiate effective control measures. Seasonal food restriction during pregnancy has the potential to limit resources available for immune defence and may be an important factor sustaining brucellosis in wild ungulate populations. Consequently, effective management practices will need to include a diverse range of integrated methods, which include maintaining separation of livestock and wildlife, managing habitat to reduce brucellosis transmission, and reducing disease prevalence in wildlife. The long-term success of these management practices will depend on sound science and support of the stakeholders involved

Acceptability of Computerized Cognitive Behavioral Therapy for Adults : Umbrella Review

Background: Mental ill-health presents a major public health problem. A potential part solution that is receiving increasing attention is computer-delivered psychological therapy, particularly during the COVID-19 pandemic as health care systems moved to remote service delivery. However, computerized cognitive behavioral therapy (cCBT) requires active engagement by service users, and low adherence may minimize treatment effectiveness. Therefore, it is important to investigate the acceptability of cCBT to understand implementation issues and maximize potential benefits. Objective: This study aimed to produce a critical appraisal of published reviews about the acceptability of cCBT for adults. Methods: An umbrella review informed by the Joanna Briggs Institute (JBI) methodology identified systematic reviews about the acceptability of cCBT for common adult mental disorders. Acceptability was operationalized in terms of uptake of, dropping out from, or completion of cCBT treatment; factors that facilitated or impeded adherence; and reports about user, carer, and health care professional experience and satisfaction with cCBT. Databases were searched using search terms informed by relevant published research. Review selection and quality appraisal were guided by the JBI methodology and the AMSTAR tool and undertaken independently by 2 reviewers. Results: The systematic searches of databases identified 234 titles, and 9 reviews (covering 151 unique studies) met the criteria. Most studies were comprised of service users with depression, anxiety, or specifically, panic disorder or phobia. Operationalization of acceptability varied across reviews, thereby making it difficult to synthesize results. There was a similar number of guided and unguided cCBT programs; 34% of guided and 36% of unguided users dropped out; and guidance included email, telephone, face-to-face, and discussion forum support. Guided cCBT was completed in full by 8%-74% of the participants, while 94% completed one module and 67%-84% completed some modules. Unguided cCBT was completed in full by 16%-66% of participants, while 95% completed one module and 54%-93% completed some modules. Guided cCBT appeared to be associated with adherence (sustained via telephone). A preference for face-to-face CBT compared to cCBT (particularly for users who reported feeling isolated), internet or computerized delivery problems, negative perceptions about cCBT, low motivation, too busy or not having enough time, and personal circumstances were stated as reasons for dropping out. Yet, some users favored the anonymous nature of cCBT, and the capacity to undertake cCBT in one's own time was deemed beneficial but also led to avoidance of cCBT. There was inconclusive evidence for an association between sociodemographic variables, mental health status, and cCBT adherence or dropping out. Users tended to be satisfied with cCBT, reported improvements in mental health, and recommended cCBT. Overall, the results indicated that service users' preferences were important considerations regarding the use of cCBT. Conclusions: The review indicated that "one size did not fit all" regarding the acceptability of cCBT and that individual tailoring of cCBT is required in order to increase population reach, uptake, and adherence and therefore, deliver treatment benefits and improve mental health.Peer reviewe