Targeting BRCA1-BER deficient breast cancer by ATM or DNA-PKcs blockade either alone or in combination with cisplatin for personalized therapy

BRCA1, a key factor in homologous recombination repair may also regulate base excision repair (BER). Targeting BRCA1-BER deficient cells by blockade of ATM and DNA-PKcs could be a promising strategy in breast cancer. We investigated BRCA1, XRCC1 and pol β protein expression in two cohorts (n=1602 sporadic and n=50 germ-line BRCA1 mutated) and mRNA expression in two cohorts (n=1952 and n=249). Artificial neural network analysis for BRCA1-DNA repair interacting genes was conducted in 249 tumours. Pre-clinically, BRCA1 proficient and deficient cells were DNA repair expression profiled and evaluated for synthetic lethality using ATM and DNA-PKcs inhibitors either alone or in combination with cisplatin. In human tumours, BRCA1 negativity was strongly associated with low XRCC1, and low pol β at mRNA and protein levels (p<0.0001). In patients with BRCA1 negative tumours, low XRCC1 or low pol β expression was significantly associated with poor survival in univariate and multivariate analysis compared to high XRCC1 or high pol β expressing BRCA1 negative tumours (ps<0.05). Pre-clinically, BRCA1 negative cancer cells exhibit low mRNA and low protein expression of XRCC1 and pol β. BRCA1-BER deficient cells were sensitive to ATM and DNA-PKcs inhibitor treatment either alone or in combination with cisplatin and synthetic lethality was evidenced by DNA double strand breaks accumulation, cell cycle arrest and apoptosis. We conclude that XRCC1 and pol β expression status in BRCA1 negative tumours may have prognostic significance. BRCA1-BER deficient cells could be targeted by ATM or DNA-PKcs inhibitors for personalized therapy

Preferential transcription of the mutated allele in NPM1 mutated acute myeloid leukaemia

Nucleophosmin is commonly both over-expressed and mutated in acute myeloid leukemia (AML). NPM1 mutations are always heterozygous. In addition, NPM1 has a number of different splice variants with the major variant encoded by exons 1–9 and 11–12 (NPM1.1). Further variants include NPM1.2 which lacks exons 8 and 10 and NPM1.3 which comprises exons 1–10 (and so lacks the region of sequence mutated in AML). In this study we quantified the expression of these three variants in 108 AML patient samples with and without NPM1 mutations and also assessed the level of expression from the wild-type and mutant alleles in variants NPM1.1 and NPM1.2. The results show that NPM1.1 is the most commonly expressed variant, however transcripts from wild-type and mutated alleles do not occur at equal levels, with a significant bias toward the mutated allele. Considering the involvement of mutant nucleophosmin in the progression and maintenance of AML, a bias towards mutated transcripts could have a significant impact on disease maintenance

Can the Revised UK Code Direct Practice?

The Nursing and Midwifery Council, the United Kingdom regulator of nursing and midwifery has recently revised its professional code of practice. This paper begins by arguing that a professional code must be capable of sustaining close reading and of action guidance. Using four exemplar clauses it is argued that the new revised code does not met this purpose. First, I show that in setting out requirements for consent and documentation, the meaning of the relevant clause has changed significantly during the editing process so that a literal reading of the final document bears little relation to established professional practice. Second, I argue that the clause concerning the nature of professional relationships has also been altered during the editing process so that it is inconsistent with other professional groups and established accounts of the professional nurse-patient relationship. Third, I argue that the clause concerning disclosure of confidential information, which survived revision and editing with its meaning intact is nevertheless factually incorrect and inconsistent with UK law and authoritative guidance. Finally, fourth, I argue that use of the word ‘inappropriate’ is inappropriate as it amounts to meaningless circularity, discussed in relation to a clause on expressing personal beliefs. Taken together, these examples demonstrate that the Code is seriously flawed and does not fulfil its purpose. One way that simple prescriptive clauses in the Code can be usefully understood is through the provision of detailed guidance. I argue that the NMC has changed its position on its view of the value of guidance and has significantly reduced the amount of written guidance and advice is provides. The paper concludes by arguing that in order to meet its action directing function, further clarifying revision and the provision of detailed guidance is required

Facilitative effects of learner-directed codeswitching : Evidence from Chinese learners of English

This study examines the interaction between learner-oriented codeswitching (CS) practices and the degree to which intermediate Chinese L2 learners of English engage in classroom interaction. The guiding questions are whether the teacher's CS use facilitates classroom interaction at moderate L2 proficiency, and if so, at which specific stages of the lesson, and to what extent. A systematic comparison of two classroom types was carried out in the same Chinese secondary school, with English-only instruction versus with English–Chinese CS. A combination of quantitative and qualitative analyses was based on class observations (two classes per type) and subsequent teacher interviews. CS behaviour was analysed in relation to the particular teaching focus of the task at hand. Interviews included a stimulated recall technique using selected CS extracts to enrich insights from the teachers' perspective. The results showed a higher student response frequency as well as a longer mean utterance length in CS classes. Overall, codeswitches were systematically distributed across lesson stages and were closely related to changes in the teaching focus. These findings call for an optimal use of CS in instructed environments so as to maximise its benefits via a sensitive adjustment to specific pedagogic aims

Identities at odds: embedded and implicit language policing in the internationalized workplace

This study offers an interaction analytic account of how linguistic identities in internationalized workplaces in Denmark are indexed against members' institutional positions in particular interactional contexts. Where language policy may not be explicitly articulated between members, it is still embedded in how participants micro-manage their interactions and implicit in how members display orientations to deviance, in the case of encountering others in the workplace whose language repertoires or preferences do not meet with expectation pertaining to the institutional position they hold. The study uses recordings of naturally occurring interaction in different international workplace settings and argues for greater attention to be paid to the actual language-policy practices in international workplace settings, as an entry point into developing a more nuanced understanding of the practices through which professional identities are brought about, affirmed or contested, and the linguistic considerations that are implicated in this

Protein kinase C epsilon overexpression is associated with poor patient outcomes in AML and promotes daunorubicin resistance through p-glycoprotein-mediated drug efflux

The protein kinase C (PKC) family of serine/threonine kinases are pleiotropic signaling regulators and are implicated in hematopoietic signaling and development. Only one isoform however, PKCϵ, has oncogenic properties in solid cancers where it is associated with poor outcomes. Here we show that PKCϵ protein is significantly overexpressed in acute myeloid leukemia (AML; 37% of patients). In addition, PKCϵ expression in AML was associated with a significant reduction in complete remission induction and disease-free survival. Examination of the functional consequences of PKCϵ overexpression in normal human hematopoiesis, showed that PKCϵ promotes myeloid differentiation, particularly of the monocytic lineage, and decreased colony formation, suggesting that PKCϵ does not act as an oncogene in hematopoietic cells. Rather, in AML cell lines, PKCϵ overexpression selectively conferred resistance to the chemotherapeutic agent, daunorubicin, by reducing intracellular concentrations of this agent. Mechanistic analysis showed that PKCϵ promoted the expression of the efflux pump, P-GP (ABCB1), and that drug efflux mediated by this transporter fully accounted for the daunorubicin resistance associated with PKCϵ overexpression. Analysis of AML patient samples also showed a link between PKCϵ and P-GP protein expression suggesting that PKCϵ expression drives treatment resistance in AML by upregulating P-GP expression

Designing a consequentially based study into the online support of pre-service teachers in the UK

This paper reports on the design of a pilot doctoral study into the online support of pre-service teachers. It highlights the significance of a consequential, rather than deontological, perspective in guiding the development of a study's design. The study initially aimed to explore pre-service teachers’ perceptions and use of social media on their school placements by setting up groups on Facebook and Twitter. However, several problems occurred in relation to the recruitment of participants. It became increasingly clear that there was significance in the positionality of the researcher as an “outsider” to the research context and the potential role for gatekeepers in understanding remote research sites. An ethical framework was used to make a more comprehensive analysis of the issues at play, which helped identify ways of proceeding. A redesign of the study followed with a stronger rationale for the way consequential considerations can help address deontological concerns

Acute myeloid leukemia of donor origin after allogeneic stem cell transplantation from a sibling who harbors germline XPD and XRCC3 homozygous polymorphisms

A 54-year-old woman was diagnosed with infiltrative ductal breast carcinoma. Two years after treatment, the patient developed an acute myeloid leukemia (AML) which harbored del(11q23) in 8% of the blast cells. The patient was submitted for allogeneic stem cell transplantation (aSCT) from her HLA-compatible sister. Ten months after transplantation, she relapsed with an AML with basophilic maturation characterized by CD45low CD33high, CD117+, CD13-/+, HLA Drhigh, CD123high, and CD203c+ blast cells lacking expression of CD7, CD10, CD34, CD15, CD14, CD56, CD36, CD64, and cytoplasmic tryptase. Karyotype analysis showed the emergence of a new clone with t(2;14) and FISH analysis indicated the presence of MLL gene rearrangement consistent with del(11q23). Interestingly, AML blast cell DNA tested with microsatellite markers showed the same pattern as the donor's, suggesting that this AML emerged from donor cells. Additionally, polymorphisms of the XPA, XPD, XRCC1, XRCC3 and RAD51 DNA repair genes revealed three unfavorable alleles with low DNA repair capacity

What facilitates the delivery of dignified care to older people? A survey of health care professionals Geriatrics

Background: Whilst the past decade has seen a growing emphasis placed upon ensuring dignity in the care of older people this policy objective is not being consistently achieved and there appears a gap between policy and practice. We need to understand how dignified care for older people is understood and delivered by the health and social care workforce and how organisational structures and policies can promote and facilitate, or hinder, the delivery of such care. Methods: To achieve our objective of understanding the facilitators and to the delivery of dignified care we undertook a survey with health and social care professionals across four NHS Trusts in England. Participants were asked provide free text answers identifying any facilitators/barriers to the provision of dignified care. Survey data was entered into SPSSv15 and analysed using descriptive statistics. These data provided the overall context describing staff attitudes and beliefs about dignity and the provision of dignified care. Qualitative data from the survey were transcribed verbatim and categorised into themes using thematic analysis. Results: 192 respondents were included in the analysis. 79 % of respondents identified factors within their working environment that helped them provide dignified care and 68 % identified barriers to achieving this policy objective. Facilitators and barriers to delivering dignified care were categorised into three domains: 'organisational level'; 'ward level' and 'individual level'. Within the these levels, respondents reported factors that both supported and hindered dignity in care including 'time', 'staffing levels', training',' 'ward environment', 'staff attitudes', 'support', 'involving family/carers', and 'reflection'. Conclusion: Facilitators and barriers to the delivery of dignity as perceived by health and social care professionals are multi-faceted and range from practical issues to interpersonal and training needs. Thus interventions to support health and social care professionals in delivering dignified care, need to take a range of issues into account to ensure that older people receive a high standard of care in NHS Trusts.Professor David Oliver, Professor Andree le May, Dr. Sally Richards, Dr Wendy Marti