Citations

Purpose The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant regimen. Doxorubicin and docetaxel (AT) is one of the most active cytotoxic regimens for metastatic breast cancer. The purpose of this trial was to determine whether adjuvant AT improved disease-free survival compared with AC in operable breast cancer. Patients and Methods Women with invasive breast cancer were eligible if there were one to three positive lymph nodes or if the node-negative tumor was greater than 1 cm. Patients were randomly assigned after surgery to receive doxorubicin (60 mg/m2) plus either cyclophosphamide (600 mg/m2; AC) or docetaxel (60 mg/m2; AT) given every 3 weeks for four cycles, followed by hormone therapy for patients with estrogen receptor (ER) and/or progesterone receptor (PR)–positive tumors. Results There were 2,882 eligible patients enrolled. After a median follow-up of 79.5 months, there was no significant difference in disease-free survival (DFS; 85% in both arms) or overall survival (91% v 92%) at 5 years. The hazard ratio for AC versus AT was 1.02 (95% CI for DFS, 0.86 to 1.22; P = .78). In an exploratory analysis of prespecified stratification factors by ER and PR expression there were trends toward improved DFS for AT in ER/PR-negative disease. Grade 3 neutropenia associated with fever or infection occurred more often with AT (26% v 10%; P < .05). Conclusion AT did not improve DFS or overall survival in this population, and was associated with more toxicity.

The product of the Nijmegen breakage syndrome gene (NBS1) plays crucial roles in DNA damage response through its association with many proteins, including MRE11 and RAD50. However, it remains to be determined exactly how NBS1 accumulates at or near DNA double-strand breaks. Here we report that MDC1 directly binds to NBS1 and targets NBS1 to the sites of DNA damage. The MDC1–NBS1 interaction occurs through a specific region (residues 200–420) of MDC1, which contains multiple consensus casein kinase 2 (CK2) phosphorylation sites. In addition, this interaction requires both the forkhead-associated (FHA) and tandem BRCA1 C-terminal (BRCT) domains of NBS1. Disruption of the MDC1–NBS1 interaction results in failure of NBS1 accumulation at DNA double-strand breaks and impairment of intra-S checkpoint activation. These studies provide important mechanistic insights as to how MDC1 regulates NBS1 and the intra-S-phase checkpoint in response to DNA damage.

Background— Smoothelins are actin-binding proteins that are abundantly expressed in healthy visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Their expression is strongly associated with the contractile phenotype of smooth muscle cells. Analysis of mice lacking both smoothelins ( Smtn-A/B −/− mice) previously revealed a critical role for smoothelin-A in intestinal smooth muscle contraction. Here, we report on the generation and cardiovascular phenotype of mice lacking only smoothelin-B ( Smtn-B −/− ). Methods and Results— Myograph studies revealed that the contractile capacity of the saphenous and femoral arteries was strongly reduced in Smtn-B −/− mice, regardless of the contractile agonist used to trigger contraction. Arteries from Smtn-A/B −/− compound mutant mice exhibited a similar contractile deficit. Smtn-B −/− arteries had a normal architecture and expressed normal levels of other smooth muscle cell–specific genes, including smooth muscle myosin heavy chain, α-smooth muscle actin, and smooth muscle-calponin. Decreased contractility of Smtn-B −/− arteries was paradoxically accompanied by increased mean arterial pressure (20 mm Hg) and concomitant cardiac hypertrophy despite normal parasympathetic and sympathetic tone in Smtn-B −/− mice. Magnetic resonance imaging experiments revealed that cardiac function was not changed, whereas distension of the proximal aorta during the cardiac cycle was increased in Smtn-B −/− mice. However, isobaric pulse wave velocity and pulse pressure measurements indicated normal aortic distensibility. Conclusions— Collectively, our results identify smoothelins as key determinants of arterial smooth muscle contractility and cardiovascular performance. Studies on mutations in the Smtn gene or alterations in smoothelin levels in connection to hypertension in humans are warranted.

Numerous authors have associated gaseous microembolization with adverse cerebral outcomes during cardiopulmonary bypass (CPB). The introduction to this review provides background on the connection between microemboli and adverse cerebral outcomes. This connection is often difficult to quantify, as outcomes depend on a number of factors, including the size of the bubble, where it passes through the patient, patient co-morbidities and other factors. Nonetheless, numerous studies have shown statistically significant differences in the mean number of cerebral emboli detected in patients that stroked and those that did not, as well as for patients with major cardiac complications and patients with a longer length of hospital stay. Our introduction is followed by case reports and laboratory studies showing how monitoring for gaseous microemboli (GME) can be used to reduce the embolic load delivered to the patient through the bypass circuit. These methods include improved qualification of bypass circuit design prior to surgery, modification of priming procedures to reduce air in the circuit at the start of surgery, new methods for injecting drugs into the circuit during surgery, and better detection of removal of sources of air during surgery. The review concludes with background on the ultrasonic detection of GME, comparing through-transmission gross air detectors and Doppler ultrasound technology with fixed-beam ultrasonic imaging of emboli, a new ultrasonic technique that images moving emboli in the blood using a single ultrasound transducer element in a fixed position. This overview is meant to shed light on why different ultrasonic detection technologies report widely varying counts and emboli loads, and why fixed-beam ultrasonic imaging represents an improvement in the ability to monitor, measure and quantitate embolic load during CPB.

Abstract Background: Sophisticated methods of cardiac imaging have the potential to revolutionize the care of patients with cardiovascular disease. The benefits of these state-of-the art imaging techniques can be enhanced by their use in combination with new cardiac biomarkers. This review addresses potentially useful interactions between imaging and biomarkers. Content: Areas were defined in which the combined use of novel imaging techniques and biomarkers would be most beneficial. This review addresses multiple cardiovascular conditions for which the useful aspects of imaging and biomarkers are likely to be positively synergistic, including acute and chronic ischemic heart disease, heart failure, myocarditis, hypertension, and atherosclerosis. Conclusions: The synergistic use of imaging techniques and biomarkers will enhance the investigation of many key issues and questions and will be an important resource in the future.

Objective: Colorectal cancer is the second most common cause of cancer death in Europe and North America. Alarm features are used to prioritise access to urgent investigation, but there is little information concerning their utility in the diagnosis of colorectal cancer. Methods: A systematic review and meta-analysis of the published literature was carried out to assess the diagnostic accuracy of alarm features in predicting colorectal cancer. Primary or secondary care-based studies in unselected cohorts of adult patients with lower gastrointestinal symptoms were identified by searching MEDLINE, EMBASE and CINAHL (up to October 2007). The main outcome measures were accuracy of alarm features or statistical models in predicting the presence of colorectal cancer after investigation. Data were pooled to estimate sensitivity, specificity, and positive and negative likelihood ratios. The quality of the included studies was assessed according to predefined criteria. Results: Of 11 169 studies identified, 205 were retrieved for evaluation. Fifteen studies were eligible for inclusion, evaluating 19 443 patients, with a pooled prevalence of colorectal carcinoma of 6% (95% CI 5% to 8%). Pooled sensitivity of alarm features was poor (5% to 64%) but specificity was >95% for dark red rectal bleeding and abdominal mass, suggesting that the presence of either rules the diagnosis of colorectal cancer in. Statistical models had a sensitivity of 90%, but poor specificity. Conclusions: Most alarm features had poor sensitivity and specificity for the diagnosis of colorectal carcinoma, whilst statistical models performed better in terms of sensitivity. Future studies should examine the utility of dark red rectal bleeding and abdominal mass, and concentrate on maximising specificity when validating statistical models.

Abstract AZD6244 (ARRY 142886) is a potent and selective mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor currently in early clinical trials. We examined the activity of AZD6244 in a panel of non–small cell lung cancer and a panel of cell lines representing many cancer types using in vitro growth assays. AZD6244 induced G0-G1 cell cycle arrest in sensitive cell lines that primarily included cells containing the BRAF V600E mutation. In these cells, G0-G1 arrest is accompanied by the up-regulation of the cell cycle inhibitors p21WAF1 and p27Kip1 and down-regulation of cyclin D1. In the majority of cell lines tested, including those with K-ras or non-V600E BRAF mutations, AZD6244 induced the accumulation of phospho-MEK, an effect not observed in the most sensitive BRAF V600E-containing cells. Accumulation of phospho-MEK in non–V600E-containing cell lines is due to abrogation of negative feedback pathways. BRAF V600E disrupts negative feedback signaling, which results in enhanced baseline phospho-MEK expression. Exogenous expression of BRAF V600E disrupts feedback inhibition but does not sensitize cells to AZD6244. Specific suppression of endogenous BRAF V600E does not confer resistance to AZD6244 but enhances sensitivity to AZD6244. Thus, our findings show that BRAF V600E marks cells with an in vitro requirement for MAPK signaling to support proliferation. These cells are exquisitely sensitive to AZD6244 (IC50, &lt;100 nmol/L), have high baseline levels of phospho-MEK, and lack feedback inhibition between ERK and Raf. These data suggest an approach to identifying cells that may be sensitive to AZD6244 and other MEK inhibitors. [Cancer Res 2008;68(15):6145–53]