HDAC inhibitors increase NRF2-signaling in tumour cells and blunt the efficacy of co-adminstered cytotoxic agents

The NRF2 signalling cascade provides a primary response against electrophilic chemicals and oxidative stress. The activation of NRF2-signaling is anticipated to have adverse clinical consequences; NRF2 is activated in a number of cancers and, additionally, its pharmacological activation by one compound can reduce the toxicity or efficiency of a second agent administered concomitantly. In this work, we have analysed systematically the ability of 152 research, pre-clinical or clinically used drugs to induce an NRF2 response using the MCF7-AREc32 NRF2 reporter. Ten percent of the tested drugs induced an NRF2 response. The NRF2 activators were not restricted to classical cytotoxic alkylating agents but also included a number of emerging anticancer drugs, including an IGF1-R inhibitor (NVP-AEW541), a PIM-1 kinase inhibitor (Pim1 inhibitor 2), a PLK1 inhibitor (BI 2536) and most strikingly seven of nine tested HDAC inhibitors. These findings were further confirmed by demonstrating NRF2-dependent induction of endogenous AKR genes, biomarkers of NRF2 activity. The ability of HDAC inhibitors to stimulate NRF2-signalling did not diminish their own potency as antitumour agents. However, when used to pre-treat cells, they did reduce the efficacy of acrolein. Taken together, our data suggest that the ability of drugs to stimulate NRF2 activity is common and should be investigated as part of the drug-development process

Expressing dual concern in criticism for wrongdoing: The persuasive power of criticizing with care

To call attention to and motivate action on ethical issues in business or society, messengers often criticize groups for wrongdoing and ask these groups to change their behavior. When criticizing target groups, messengers frequently identify and express concern about harm caused to a victim group, and in the process address a target group by criticizing them for causing this harm and imploring them to change. However, we find that when messengers criticize a target group for causing harm to a victim group in this way—expressing singular concern for the victim group—members of the target group infer, often incorrectly, that the messenger views the target group as less moral and unworthy of concern. This inferred lack of moral concern reduces criticism acceptance and prompts backlash from the target group. To address this problem, we introduce dual concern messaging—messages that simultaneously communicate that a target group causes harm to a victim group and express concern for the target group. A series of several experiments demonstrate that dual concern messages reduce inferences that a critical messenger lacks moral concern for the criticized target group, increase the persuasiveness of the criticism among members of the target group, and reduce backlash from consumers against a corporate messenger. When pursuing justice for victims of a target group, dual concern messages that communicate concern for the victim group as well as the target group are more effective in fostering openness toward criticism, rather than defensiveness, in a target group, thus setting the stage for change

Synergy Between Licensed Rehabilitation Professionals and Clinical Exercise Physiologists: Optimizing Patient Care for Cancer Rehabilitation

Objectives: To differentiate between rehabilitation and exercise training and propose how rehabilitation professionals and exercise physiologists can collaborate to optimize cancer survivor care.Data Source: Professional organizations and peer-reviewed manuscripts.Conclusion: Both professions offer complementary skillsets that, when integrated, optimize the ability of the cancer care team to implement more effective survivorship care plans. Future models of care must incorporate efficient communications between the cancer rehabilitation program and oncology team, include various reimbursement/payment/funding options, and continuously assess program efficacy.Implications for Nursing Practice: Nurses must be cognizant of physical needs (ie, functional and conditioning status) and cancer-related comorbidities when referring cancer survivors for exercise reconditioning

What would happen if?: A comparison of fathers’ and mothers’ questions to children during a science activity

Parents’ questions are an effective strategy for fostering the development of young children’s science understanding and discourse. However, this work has not yet distinguished whether the frequency of questions about scientific content differs between mothers and fathers, despite some evidence from other contexts (i.e., book reading) showing that fathers ask more questions than mothers. The current study compared fathers’ and mothers’ questions to their four- to six-year-old children (N = 49) while interacting with scientific stimuli at a museum research exhibit. Results indicated that fathers asked significantly more questions than mothers, and fathers’ questions were more strongly related to children’s scientific discourse. Results are discussed in terms of the importance of adult questions for the development of children’s scientific understanding as well as broadening research to include interlocutors other than mothers

Revisiting benzene cluster cations for the chemical ionization of dimethyl sulfide and select volatile organic compounds

Benzene cluster cations were revisited as a sensitive and selective reagent ion for the chemical ionization of dimethyl sulfide (DMS) and a select group of volatile organic compounds (VOCs). Laboratory characterization was performed using both a new set of compounds (i.e., DMS, β-caryophyllene) as well as previously studied VOCs (i.e., isoprene, α-pinene). Using a field deployable chemical-ionization time-of-flight mass spectrometer (CI-ToFMS), benzene cluster cations demonstrated high sensitivity (> 1 ncps ppt^(−1)) to DMS, isoprene, and α-pinene standards. Parallel measurements conducted using a chemical-ionization quadrupole mass spectrometer, with a much weaker electric field, demonstrated that ion–molecule reactions likely proceed through a combination of ligand-switching and direct charge transfer mechanisms. Laboratory tests suggest that benzene cluster cations may be suitable for the selective ionization of sesquiterpenes, where minimal fragmentation ( 0.95, 10 s averages) over a wide range of sampling conditions

Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials

Objectives. To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination. Design. There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naı¨ve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime–MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG. Results. MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination. Conclusions. The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here. Trial Registration. ClinicalTrials.Oxford University was the sponsor for all the clinical trials reported here

Are there ethnic and religious variations in uptake of bowel cancer screening?:A retrospective cohort study among 1.7 million people in Scotland

This work was supported by the Chief Scientist’s Office (grant number CZH/4/878), Cancer Research UK (grant number C3743/A16594), and supplementary funding from NHS Health Scotland. ISD and National Records of Scotland both made ‘in-house’ contributions to the work.Objective Cancer screening should be equitably accessed by all populations. Uptake of colorectal cancer screening was examined using the Scottish Health and Ethnicity Linkage Study that links the Scottish Census 2001 to health data by individual-level self-reported ethnicity and religion. Setting Data on 1.7 million individuals in two rounds of the Scottish Bowel Cancer Screening Programme (2007–2013) were linked to the 2001 Census using the Scottish Community Health Index number. Main outcome measure Uptake of colorectal cancer screening, reported as age-adjusted risk ratios (RRs) by ethnic group and religion were calculated for men and women with 95% CI. Results In the first, incidence screening round, compared with white Scottish men, Other White British (RR 109.6, 95% CI 108.8 to 110.3) and Chinese (107.2, 95% CI 102.8 to 111.8) men had higher uptake. In contrast, men of all South Asian groups had lower uptake (Indian RR 80.5, 95% CI 76.1 to 85.1; Pakistani RR 65.9, 95% CI 62.7 to 69.3; Bangladeshi RR 76.6, 95% CI 63.9 to 91.9; Other South Asian RR 88.6, 95% CI 81.8 to 96.1). Comparable patterns were seen among women in all ethnic groups, for example, Pakistani (RR 55.5, 95% CI 52.5 to 58.8). Variation in uptake was also observed by religion, with lower rates among Hindu (RR (95%CI): 78.4 (71.8 to 85.6)), Muslim (69.5 (66.7 to 72.3)) and Sikh (73.4 (67.1 to 80.3)) men compared with the reference population (Church of Scotland), with similar variation among women: lower rates were also seen among those who reported being Jewish, Roman Catholic or with no religion. Conclusions There are important variations in uptake of bowel cancer screening by ethnic group and religion in Scotland, for both sexes, that require further research and targeted interventions.Publisher PDFPeer reviewe

Exercise recommendations for people with bone metastases: Expert consensus for healthcare providers and clinical exercise professionals

Purpose: Exercise has been underutilized in people with advanced or incurable cancer despite the potential to improve physical function and reduce psychosocial morbidity, especially for people with bone metastases because of concerns over skeletal complications. The International Bone Metastases Exercise Working Group (IBMEWG) was formed to develop best practice recommendations for exercise programming for people with bone metastases on the basis of published research, clinical experience, and expert opinion. Methods: The IBMEWG undertook sequential steps to inform the recommendations: (1) modified Delphi survey, (2) systematic review, (3) cross-sectional survey to physicians and nurse practitioners, (4) in-person meeting of IBMEWG to review evidence from steps 1-3 to develop draft recommendations, and (5) stakeholder engagement. Results: Recommendations emerged from the contributing evidence and IBMEWG discussion for pre-exercise screening, exercise testing, exercise prescription, and monitoring of exercise response. Identification of individuals who are potentially at higher risk of exercise-related skeletal complication is a complex interplay of these factors: (1) lesion-related, (2) cancer and cancer treatment–related, and (3) the person-related. Exercise assessment and prescription requires consideration of the location and presentation of bone lesion(s) and should be delivered by qualified exercise professionals with oncology education and exercise prescription experience. Emphasis on postural alignment, controlled movement, and proper technique is essential. Conclusion: Ultimately, the perceived risk of skeletal complications should be weighed against potential health benefits on the basis of consultation between the person, health care team, and exercise professionals. These recommendations provide an initial framework to improve the integration of exercise programming into clinical care for people with bone metastases

Multiple Cytokines Are Released When Blood from Patients with Tuberculosis Is Stimulated with Mycobacterium tuberculosis Antigens

Mycobacterium tuberculosis (Mtb) infection may cause overt disease or remain latent. Interferon gamma release assays (IGRAs) detect Mtb infection, both latent infection and infection manifesting as overt disease, by measuring whole-blood interferon gamma (IFN-γ) responses to Mtb antigens such as early secreted antigenic target-6 (ESAT-6), culture filtrate protein 10 (CFP-10), and TB7.7. Due to a lack of adequate diagnostic standards for confirming latent Mtb infection, IGRA sensitivity for detecting Mtb infection has been estimated using patients with culture-confirmed tuberculosis (CCTB) for whom recovery of Mtb confirms the infection. In this study, cytokines in addition to IFN-γ were assessed for potential to provide robust measures of Mtb infection.Cytokine responses to ESAT-6, CFP-10, TB7.7, or combinations of these Mtb antigens, for patients with CCTB were compared with responses for subjects at low risk for Mtb infection (controls). Three different multiplexed immunoassays were used to measure concentrations of 9 to 20 different cytokines. Responses were calculated by subtracting background cytokine concentrations from cytokine concentrations in plasma from blood stimulated with Mtb antigens.Two assays demonstrated that ESAT-6, CFP-10, ESAT-6+CFP-10, and ESAT-6+CFP-10+TB7.7 stimulated the release of significantly greater amounts of IFN-γ, IL-2, IL-8, MCP-1 and MIP-1β for CCTB patients than for controls. Responses to combination antigens were, or tended to be, greater than responses to individual antigens. A third assay, using whole blood stimulation with ESAT-6+CFP-10+TB7.7, revealed significantly greater IFN-γ, IL-2, IL-6, IL-8, IP-10, MCP-1, MIP-1β, and TNF-α responses among patients compared with controls. One CCTB patient with a falsely negative IFN-γ response had elevated responses with other cytokines.Multiple cytokines are released when whole blood from patients with CCTB is stimulated with Mtb antigens. Measurement of multiple cytokine responses may improve diagnostic sensitivity for Mtb infection compared with assessment of IFN-γ alone

Selective decontamination of the digestive tract in critically ill patients treated in intensive care units: a mixed-methods feasibility study (the SuDDICU study)

Background: Hospital-acquired infections (HAIs) are a major cause of morbidity and mortality. Critically ill patients in intensive care units (ICUs) are particularly susceptible to these infections. One intervention that has gained much attention in reducing HAIs is selective decontamination of the digestive tract (SDD). SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of intravenous (i.v.) antibiotics. SDD may reduce infections and improve mortality, but has not been widely adopted in the UK or internationally. Hence, there is a need to identify the reasons for low uptake and whether or not further clinical research is needed before wider implementation would be considered appropriate. Objectives: The project objectives were to (1) identify and describe the SDD intervention, (2) identify views about the evidence base, (3) identify acceptability of further research and (4) identify feasibility of further randomised controlled trials (RCTs). Design : A four-stage approach involving (1) case studies of two ICUs in which SDD is delivered including observations, interviews and documentary analysis, (2) a three-round Delphi study for in-depth investigation of clinicians' views, including semi-structured interviews and two iterations of questionnaires with structured feedback, (3) a nationwide online survey of consultants in intensive care medicine and clinical microbiology and (4) semistructured interviews with international clinical triallists to identify the feasibility of further research. Setting : Case studies were set in two UK ICUs. Other stages of this research were conducted by telephone and online with NHS staff working in ICUs. Participants : (1) Staff involved in SDD adoption or delivery in two UK ICUs, (2) ICU experts (intensive care consultants, clinical microbiologists, hospital pharmacists and ICU clinical leads), (3) all intensive care consultants and clinical microbiologists in the UK with responsibility for patients in ICUs were invited and (4) international triallists, selected from their research profiles in intensive care, clinical trials and/or implementation trials. Interventions : SDD involves the application of topical non-absorbable antibiotics to the oropharynx and stomach and a short course of i.v. antibiotics. Main outcome measures: Levels of support for, or opposition to, SDD in UK ICUs; views about the SDD evidence base and about barriers to implementation; and feasibility of further SDD research (e.g. likely participation rates). Results : (1) The two case studies identified complexity in the interplay of clinical and behavioural components of SDD, involving multiple staff. However, from the perspective of individual staff, delivery of SDD was regarded as simple and straightforward. (2) The Delphi study (n = 42) identified (a) specific barriers to SDD implementation, (b) uncertainty about the evidence base and (c) bimodal distributions for key variables, e.g. support for, or opposition to, SDD. (3) The national survey (n = 468) identified uncertainty about the effect of SDD on antimicrobial resistance, infection rates, mortality and cost-effectiveness. Most participants would participate in further SDD research. (4) The triallist interviews (n = 10) focused largely on the substantial challenges of conducting a large, multinational clinical effectiveness trial. Conclusions : There was considerable uncertainty about possible benefits and harms of SDD. Further large-scale clinical effectiveness trials of SDD in ICUs may be required to address these uncertainties, especially relating to antimicrobial resistance. There was a general willingness to participate in a future effectiveness RCT of SDD. However, support was not unanimous. Future research should address the barriers to acceptance and participation in any trial. There was some, but a low level of, interest in adoption of SDD, or studies to encourage implementation of SDD into practice