Sequence dependent exposure of mammary carcinoma cells to Taxotere® and the MEK1/2 inhibitor U0126 causes enhanced cell killing in vitro

Taxol (paclitaxel) and Taxotere (docetaxel) are considered as two of the most important anticancer chemotherapy drugs. The cytotoxic action of these drugs has been linked to their ability to inhibit microtubule depolymerization, causing growth arrest and subsequent cell death. Studies by a number of laboratories have also linked suppression of mitogen activated protein kinase (MAPK) signaling to enhanced Taxol toxicity. The present study examined the interactions of the semi-synthetic taxane Taxotere with MEK1/2 inhibitors in epithelial tumor cells. Concurrent treatment of MDA-MB-231 mammary and DU145 prostate carcinoma cells with Taxotere and MEK1/2 inhibitor resulted in protection from the anti-proliferative effects of Taxotere in MTT assays. In contrast, in MCF-7 mammary cells, concurrent Taxotere and MEK1/2 inhibitor treatment weakly enhanced the antiproliferative effects of the taxane. Sequential treatment of MDA-MB-231 and MCF-7 cells with Taxotere followed by MEK1/2 inhibitor also enhanced the anti-proliferative effects of the taxane in MTT assays. However, no enhancement was observed in DU145 or PC-3 cells. Colony formation assays, including isobologram analyses, provided a more definitive demonstration that MCF-7 and MDA-MB-231 cells were sensitized to the toxic effects of Taxotere by U0126. Similar data were observed using Laulimalide, which binds to tubulin at a different site to Taxotere. The enhancement in Taxotere anti-proliferative effects by U0126 correlated with increased cell killing, 48-72h after treatment of cells that was blocked by inhibition of caspase 9, but not caspase 8, function. This observation was associated with prolonged suppression of ERK1/2 and AKT activity, without alteration in either p38 or JNK1/2 activity. Collectively these findings demonstrate that sequential administration of Taxotere followed by MEK1/2 inhibition can lead to increased cell death and loss of reproductive capacity in some, but not all, human tumor cells. ©2003 Landes Bioscience.Fil: Yacoub, Adly. Virginia Commonwealth University; Estados UnidosFil: Han, Song Iy. Virginia Commonwealth University; Estados UnidosFil: Caron, Ruben Walter. Virginia Commonwealth University; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: Gilfor, Donna. Virginia Commonwealth University; Estados UnidosFil: Mooberry, Susan. Southwest Foundation for Biomedical Research; Estados UnidosFil: Grant, Steven. Virginia Commonwealth University; Estados UnidosFil: Dent, Paul. Virginia Commonwealth University; Estados Unido

Use of new and emerging cancer drugs: what the cardiologist needs to know

: The last decade has witnessed a paradigm shift in cancer therapy, from non-specific cytotoxic chemotherapies to agents targeting specific molecular mechanisms. Nonetheless, cardiovascular toxicity of cancer therapies remains an important concern. This is particularly relevant given the significant improvement in survival of solid and haematological cancers achieved in the last decades. Cardio-oncology is a subspecialty of medicine focusing on the identification and prevention of cancer therapy-related cardiovascular toxicity (CTR-CVT). This review will examine the new definition of CTR-CVT and guiding principles for baseline cardiovascular assessment and risk stratification before cancer therapy, providing take-home messages for non-specialized cardiologists

The impact of the resident duty hour regulations on surgical patients’ perceptions of care

Implementation of the 2003 Accreditation Council for Graduate Medical Education (ACGME) resident duty-hour regulations and access to publicly reported patient satisfaction measures have challenged administrators and clinicians to balance resident’s educational experience, patient care quality, and patients’ satisfaction and perceptions. A pre-post retrospective study design investigated association between implementation of ACGME regulations and patient satisfaction/perceptions using multinomial logistic regressions. The sample consisted of all surgical inpatients (July 2001 – June 2005), who responded to surveys at an academic medical center. Patients gave lower ratings for physician interactions (patient-physician interaction time, clinical updates, and courtesy) following the implementation of post-duty hour regulations. While the odds of patients rating “below good” post-implementation for physician survey questions (i.e., related to time spent, kept informed, and friendliness/ courtesy) were higher (i.e., 1.25 to 1.3) as compared to odds of rating “very good”, the overall rating of quality care improved post-implementation. This difference could be due to increased interaction of patients with other hospital personnel. To improve patient satisfactions and in turn their perceptions, initiatives such as workload balancing, hand-off protocols, patient communication, and interactive training for care providers are recommended. Finally, residency programs and institutions need to develop strategies for implementation of current and future ACGME duty hour regulations so as to balance patient safety, patient perceptions, and resident well-being

Multiparametric early detection and prediction of cardiotoxicity using myocardial strain, T1 and T2 mapping, and biochemical markers: A longitudinal cardiac resonance imaging study during 2 years of follow-up

BACKGROUND: Our goal was to evaluate the ability of cardiovascular magnetic resonance for detecting and predicting cardiac dysfunction in patients receiving cancer therapy. Left ventricular ejection fraction, global and regional strain utilizing fast-strain-encoded, T1 and T2 mapping, and cardiac biomarkers (troponin and BNP [brain natriuretic peptide]) were analyzed. METHODS: Sixty-one patients (47 with breast cancer, 11 with non-Hodgkin lymphoma, and 3 with Hodgkin lymphoma) underwent cardiovascular magnetic resonance scans at baseline and at regular intervals during 2 years of follow-up. The percentage of all left ventricular myocardial segments with strain ≤-17% (normal myocardium [%]) was analyzed. Clinical cardiotoxicity (CTX) and sub-CTX were defined according to standard measures. RESULTS: Nine (15%) patients developed CTX, 26 (43%) had sub-CTX. Of the 35 patients with CTX or sub-CTX, 24 (69%) were treated with cardioprotective medications and showed recovery of cardiac function. The amount of normal myocardium (%) exhibited markedly higher accuracy for the detection of CTX and sub-CTX compared with left ventricular ejection fraction, T1, and T2 mapping as well as troponin I (Δareas under the curve=0.20, 0.24, and 0.46 for normal myocardium (%) versus left ventricular ejection fraction, troponin I, and T1 mapping, CONCLUSIONS: Normal myocardium (%) derived by fast-strain-encoded cardiovascular magnetic resonance, is an accurate and sensitive tool that can establish cardiac safety in patients with cancer undergoing cardiotoxic chemotherapy not only for the early detection but also for the prediction of those at risk of developing CTX. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03543228

Initial validation of a diagnostic questionnaire for gastroesophageal reflux disease

Brief, reliable, and valid self-administered questionnaires could facilitate the diagnosis of gastroesophageal reflux disease in primary care. We report the development and validation of such an instrument. Methods Content validity was informed by literature review, expert opinion, and cognitive interviewing of 50 patients resulting in a 22-item survey. For psychometric analyses, primary care patients completed the new questionnaire at enrollment and at intervals ranging from 3 days to 3 wk. Multitrait scaling, test–retest reliability, and responsiveness were assessed. Predictive validity analyses of all scales and items used specialty physician diagnosis as the “gold standard.” Results Iterative factor analyses yielded three scales of four items each including heartburn, acid regurgitation, and dyspepsia. Multitrait scaling criteria including internal consistency, item interval consistency, and item discrimination were 100% satisfied. Test–retest reliability was high in those reporting stable symptoms. Scale scores significantly changed in those reporting a global change. Regressing specialty physician diagnosis on the three scales revealed significant effects for two scales (heartburn and regurgitation). Combining the two significant scales enhanced the strength of the model. Symptom response to self-directed treatment with nonprescription antisecretory medications was highly predictive of the diagnosis also, although the item demonstrated poor validity and reliability. Conclusions A brief, simple 12-item questionnaire demonstrated validity and reliability and seemed to be responsive to change for reflux and dyspeptic symptoms.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72526/1/j.1572-0241.2001.03451.x.pd

Relationship between quality of life indicators and cardiac status indicators in chemotherapy patients

AIM: With the aim of improving personalized treatment of patients on chemotherapy, the objective of the study was to assess the degree of association between selected Quality of life (QoL) indicators and both clinical and imaging cardiac status indicators when detecting deterioration in QoL of these patients. METHODS: In a cohort clinical study in Hamburg, from August 2017 through October 2020, 59 cancer patients, aged 18-80 years, were evaluated before chemotherapy, and at several follow-ups, using EQ-5D and SF-36 QoL questionnaires, fast strain-encoded (fast-SENC) cardiac magnetic resonance (CMR), conventional CMR, and echocardiography, and further received a clinical and biomarker examination. Data was analyzed using survival analyses. A decline of more than 5% in each observed QoL metric value was defined as the observed event. Patient were separated into groups according to the presentation of cardiotoxicity as per its clinical definition, the establishment of the indication for cardioprotective therapy initiation, and by a worsening in the value of each observed imaging metric by more than 5% in the previous follow-up compared to the corresponding pre-chemotherapy baseline value. RESULTS: Among clinical cardiac status indicators, the indication for cardioprotective therapy showed statistically good association with QoL scores (EQ-5D p=0.028; SF-36 physical component p=0.016; SF-36 mental component p=0.012). In terms of imaging metrics, the MyoHealth segmental myocardial strain score was the only one demonstrating consistently good QoL score association (EQ-5D p=0.005; SF-36 physical component p=0.056; SF-36 mental component p=0.002). CONCLUSIONS: Established fast-SENC CMR scores are capable of highlighting patients with reduced QoL, who require more frequent/optimal management

Changes in Local School Policies and Practices in Washington State After an Unfunded Physical Activity and Nutrition Mandate

Introduction: Policies and practices in schools may create environments that encourage and reinforce healthy behaviors and are thus a means for stemming the rising rates of childhood obesity. We assessed the effect of a 2005 statewide school physical activity and nutrition mandate on policies and practices in middle and high schools in Washington State. Methods: We used 2002, 2004, and 2006 statewide School Health Profiles survey data from Washington, with Oregon as a comparison group, to create longitudinal linear regression models to describe changes in relevant school policies after the Washington statewide mandate. Policy area composite measures were generated by principal component factor analysis from survey questions about multiple binary measure policy and practice. Results: Relative to expected trends without the mandate, we found significant percentage-point increases in various policies, including restricted access to competitive foods in middle and high schools (increased by 18.8-20.0 percentage points); school food practices (increased by 10.4 percentage points in middle schools); and eliminating exemptions from physical education (PE) for sports (16.6 percentage-point increase for middle schools), exemptions from PE for community activities (12.8 and 14.4 percentage-point increases for middle and high schools, respectively) and exemptions from PE for academics (18.1 percentage-point increase for middle schools). Conclusion: Our results suggest that a statewide mandate had a modest effect on increasing physical activity and nutrition policies and practices in schools. Government policy is potentially an effective tool for addressing the childhood obesity epidemic through improvements in school physical activity and nutrition environments.This is the publisher’s final pdf. The published article is copyrighted by the Centers for Disease Control and Prevention, United States Government and can be found at: http://www.cdc.gov/pcd/current_issue.ht

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation