Role of endonucleases XPF and XPG in nucleotide excision repair of platinated DNA and cisplatin/oxaliplatin cytotoxicity

Resistance of tumor cells to platinum anticancer agents poses a major problem in cancer chemotherapy. One of the mechanisms associated with platinum-based drug resistance is the enhanced capacity of the cell to carry out nucleotide excision repair (NER) on platinum-damaged DNA. Endonucleases XPF and XPG are critical components of NER, responsible for excising the damaged DNA strand to remove the DNA lesion. Here, we investigated possible consequences of down-regulation of XPF and XPG gene expression in osteosarcoma cancer cells (U2OS) and the impact on cellular transcription and DNA repair. We further evaluated the sensitivity of such cells toward the platinum anticancer drugs cisplatin and oxaliplatin.National Cancer Institute (U.S.) (Grant Number CA034992.)National University of Singapore.German Academic Exchange Service (DAAD

Consumers of natural health products: natural-born pharmacovigilantes?

<p>Abstract</p> <p>Background</p> <p>Natural health products (NHPs), such as herbal medicines and vitamins, are widely available over-the-counter and are often purchased by consumers without advice from a healthcare provider. This study examined how consumers respond when they believe they have experienced NHP-related adverse drug reactions (ADRs) in order to determine how to improve current safety monitoring strategies.</p> <p>Methods</p> <p>Qualitative semi-structured interviews were conducted with twelve consumers who had experienced a self-identified NHP-related ADR. Key emergent themes were identified and coded using content analysis techniques.</p> <p>Results</p> <p>Consumers were generally not comfortable enough with their conventional health care providers to discuss their NHP-related ADRs. Consumers reported being more comfortable discussing NHP-related ADRs with personnel from health food stores, friends or family with whom they had developed trusted relationships. No one reported their suspected ADR to Health Canada and most did not know this was possible.</p> <p>Conclusion</p> <p>Consumers generally did not report their suspected NHP-related ADRs to healthcare providers or to Health Canada. Passive reporting systems for collecting information on NHP-related ADRs cannot be effective if consumers who experience NHP-related ADRs do not report their experiences. Healthcare providers, health food store personnel, manufacturers and other stakeholders also need to take responsibility for reporting ADRs in order to improve current pharmacovigilance of NHPs.</p

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Rise of the virtual nurse

As the process of providing health care becomes increasingly complex and the foundation of the nursing profession changes, nursing leaders will need to think differently about how to support their colleagues more efficiently and effectively. The role of the virtual nurse is expanding as part of the effort to address these complexities and develop innovative solutions. Although more work is necessary to define best practices in the variations of virtual nursing, current examples have had a positive impact on nursing and patient care. This article describes the ways in which virtual nursing has grown over the years and how it continues to adapt to support the nursing profession

A mixed-methods survey of physiotherapists who practice acupuncture and dry needling in Ontario, Canada: practice characteristics, motivations, and professional outcomes

Abstract Background Physiotherapists (PTs) across the globe are increasingly incorporating filiform needling techniques (e.g., acupuncture, dry needling) into their clinical toolkits; and, the evidence base for these complementary therapies is becoming progressively more robust. However, to date, little is known about needling PTs themselves. Methods Using a cross-sectional survey design, PTs authorized to perform needling therapies in Ontario, Canada were recruited for anonymous participation (n = 2061) in an online survey. The survey asked providers about their demographics and practice characteristics, rationale for and views about therapeutic needling, and their related clinical and professional outcomes. The response rate was 20.7% (n = 426), and 22.3% (n = 95) of respondents provided textual responses to an open-ended qualitative question. Results While study respondents’ demographic features appear similar to their broader professional population, Ontario’s needling PTs are less likely to work in public sector settings. Most completed training in medical acupuncture rather than dry needling, and typically used needling in over one-third of patient visits. Almost all endorsed needling as an effective musculoskeletal treatment, the primary factor informing their adoption of the practice. While many viewed traditional Chinese medical theories as a useful explanatory framework, most relied on biomedical epistemology to drive their needling work. A majority of respondents reported that the inclusion of needling within their clinical toolkits had improved their likelihood of achieving excellent clinical results, helped support patient recruitment and retention, and heightened their professional satisfaction. While a few reported earning a higher income as a result, most reported that their clinical use of needling in addition to other PT modalities reduced their physical fatigue after a day’s work. Conclusions This study represents a first scholarly investigation into the motivations, training backgrounds and practice patterns of PTs who use acupuncture or dry needling. Additional research from other jurisdictions is needed to evaluate the transferability of study findings

A Tale of Two Disasters: Biases in Risk Communication

Risk communication, where scientists inform policy-makersor the populace of the probability and magnitude of possibledisasters, is essential to disaster management – enablingpeople to make better decisions regarding preventative steps,evacuations, etc. Psychological research, however, hasidentified multiple biases that can affect people’sinterpretation of probabilities and thus risk. For example,availability (Tversky &amp; Kahneman, 1973) is known toconfound probability estimates while the description-experience gap (D-E Gap) (Hertwig &amp; Erev, 2009) shows lowprobability events being over-weighted when described andunder-weighted when learnt from laboratory tasks. This paperexamines how probability descriptions interact with realworld experience of events. Responses from 294 participantsacross 8 conditions showed that people’s responses, given thesame described probabilities and consequences, were alteredby their familiarity with the disaster (bushfire vs earthquake)and its salience to them personally. The implications of thisfor risk communication are discussed

Supportive but “worried”: perceptions of naturopaths, homeopaths and Chinese medicine practitioners through a regulatory transition in Ontario, Canada

Abstract Background In line with recent World Health Organization recommendations, many jurisdictions are taking steps to regulate practitioners of traditional, complementary and alternative medicine (TCAM). Previous studies have examined TCAM practitioners’ generally-supportive views about professional regulation; however, little research has been conducted on TCAM practitioners’ experiences and perspectives amidst an active regulatory process. In 2006 and 2007, the province of Ontario, Canada announced it would grant self-regulatory status to three TCAM practitioner groups - homeopaths, naturopaths and Chinese medicine practitioners/acupuncturists. Methods In 2011 and 2012, part-way through each group’s regulatory process, we surveyed all practitioners from these three groups (n = 1047) that could be identified from public registries and professional associations. The data presented here are derived from the sub-sample of homeopaths (n = 234), naturopaths (n = 273) and Chinese medicine practitioners/acupuncturists (n = 181) who provided answers to an open-ended question about their opinions of the regulatory process at the end of the survey. An inductive, thematic analysis of qualitative survey responses was conducted. Results Survey responses affirmed a pro-regulatory stance across all groups, but revealed considerable ‘worry’ amongst practitioners as to how the regulations might be implemented. Four primary ‘worry-related’ themes emerged: a) regulation’s potential administrative and financial burden on practitioners; b) scope-related concerns; c) implementation of fair registration standards; and d) whether regulation might erode the groups’ distinctive worldviews. Some occupationally-specific concerns appeared related to each group’s particular stage of professionalization. Other ‘worries’ may be related to the relative marginality of TCAM practitioner groups within biomedically-dominant national health care systems, and the possibility that inter-professional hierarchies may be emerging between particular TCAM groups. Specific concerns around overlapping practice scopes between TCAM and other professions raised questions about the implementation of non-monopolistic regulatory models such as Ontario’s. Conclusions Overall, this study will help inform regulators and TCAM practitioner groups to navigate the unique challenge of regulating health care providers long excluded from national health care systems, who frequently work from within paradigms distinct from mainstream biomedicine