The retinoblastoma tumor suppressor modifies the therapeutic response of breast cancer

The retinoblastoma tumor suppressor (RB) protein is functionally inactivated in the majority of human cancers and is aberrant in one-third of all breast cancers. RB regulates G(1)/S-phase cell-cycle progression and is a critical mediator of antiproliferative signaling. Here the specific impact of RB deficiency on E2F-regulated gene expression, tumorigenic proliferation, and the response to 2 distinct lines of therapy was investigated in breast cancer cells. RB knockdown resulted in RB/E2F target gene deregulation and accelerated tumorigenic proliferation, thereby demonstrating that even in the context of a complex tumor cell genome, RB status exerts significant control over proliferation. Furthermore, the RB deficiency compromised the short-term cell-cycle inhibition following cisplatin, ionizing radiation, and antiestrogen therapy. In the context of DNA-damaging agents, this bypass resulted in increased sensitivity to these agents in cell culture and xenograft models. In contrast, the bypass of antiestrogen signaling resulted in continued proliferation and xenograft tumor growth in the presence of tamoxifen. These effects of aberrations in RB function were recapitulated by ectopic E2F expression, indicating that control of downstream target genes was an important determinant of the observed responses. Specific analyses of an RB gene expression signature in 60 human patients indicated that deregulation of this pathway was associated with early recurrence following tamoxifen monotherapy. Thus, because the RB pathway is a critical determinant of tumorigenic proliferation and differential therapeutic response, it may represent a critical basis for directing therapy in the treatment of breast cancer.     

Predictive value of local and core laboratory echocardiographic assessment of cardiac function in patients with chronic stable angina: The ACTION study.

AIMS: To evaluate the relationship between echocardiographic cardiac function and outcome in patients with stable symptomatic angina. METHODS: Baseline echo left ventricular ejection fraction and volume data measured in a central laboratory was available for 7016 patients (92% of the total) participating in the ACTION trial (A Coronary disease Trial Investigating Outcome with Nifedipine GITS). Ejection fraction was also measured by investigators. Evaluation of the different echocardiographic variables was based on adjusted hazard ratios comparing the unfavourable limit of the 90% range of the variable concerned to the favourable limit. RESULTS: The centrally measured ejection fraction was the most powerful predictor of all-cause death (adjusted hazard ratio=2.5), myocardial infarction, any stroke or transient ischaemic attack and overt heart failure (adjusted hazard ratio=4.5). The addition of either end systolic volume or end diastolic volume to ejection fraction did not materially affect the power of prediction. Compared to the central ejection fraction measurement, the investigator-measured ejection fraction was a less powerful predictor for all outcomes considered. CONCLUSION: Routine echocardiography carefully analysed by standardised methods provides useful prognostic information in patients with stable angina, including for total mortality.     

Diabetes in treated hypertension is common and carries a high cardiovascular risk: results from a 28-year follow-up

OBJECTIVE: The objective of this study was to analyse predictive factors for development of type 2 diabetes during life-long therapy for hypertension and the alleged additional cardiovascular risk this constitutes. METHODS: The study group (n = 754) comprised the hypertensive subgroup of a randomized population sample of 7500 men, aged 47-54 years, screened for cardiovascular risk factors and followed for 25-28 years. The patients were treated with thiazide diuretics and beta-adrenergic blocking drugs with the addition of hydralazin during the first decade. Calcium antagonists were substituted for hydralazin and, if needed, angiotensin-converting enzyme inhibitors were added when these drugs became available. RESULTS: A total of 148 (20.4%) treated hypertensive patients developed diabetes during 25 years, and in multivariate Cox regression analysis body mass index, serum triglycerides and treatment with beta-blockers were positively related with this complication. New-onset diabetes implied a significantly increased risk for stroke [hazard ratio (HR): 1.67; 95% confidence interval (95% CI): 1.1-2.6; P < 0.05], myocardial infarction (OR: 1.66; 95% CI: 1.1-2.5; P < 0.05) and mortality (OR: 1.42; 95% CI: 1.1-1.9; P < 0.05). The greatest risk for stroke was new-onset diabetes, followed by smoking (OR: 1.46; 95% CI: 1-2.2; P = 0.07) and the greatest risk for myocardial infarction was new-onset diabetes, followed by smoking (HR: 1.64; 95% CI: 1.1-2.4; P < 0.01). The greatest risk for mortality was smoking (HR: 1.73; 95% CI: 1.3-2.2; P < 0.005). Achieved systolic and diastolic blood pressure were not predictive of cardiovascular complications or death. The mean observation time from onset of diabetes mellitus to a first stroke was 9.1 years and to a first myocardial infarction 9.3 years. CONCLUSION: Diabetes in treated hypertensive patients is alarmingly common and carries a high risk for cardiovascular complications and mortality.     

Sources of error and interpretation of plaque morphology by optical coherence tomography

This study was performed to assess the strengths and weaknesses of optical coherence tomography (OCT) intravascular imaging in identifying plaque morphology. Seventy-nine postmortem human coronary arterial sections classified as fibrous-cap atheromas, calcific plaques, fibrous plaques, and complicated lesions were studied. OCT was able to identify 45% of fibrous-cap atheromas (kappa=0.27, p<0.01), 68% of fibrocalcific plaques (kappa=0.40, p<0.001), 83% of fibrous plaques (kappa=0.37, p<0.001), and 100% of complicated lesions (all thrombi; kappa=1, p<0.001). Misinterpretation was caused mainly by the low OCT signal penetration, which could not detect lipid pools or calcium behind thick fibrous caps, and by an inability to distinguish calcium deposits from lipid pools or the opposite. Lesions with thick (>150 microm) caps were histologically identified as 25 thick fibrous-cap atheromas, 8 fibrocalcific plaques, and 5 fibrous plaques; all these lesions were relatively "stable." In contrast, lesions with fibrous caps<150 microm were either vulnerable or stable lesions (11 thin-fibrous-cap atheromas and 11 fibrocalcific plaques). In conclusion, although OCT images may give an indication of the overall composition of large homogenous signal-poor regions, such as lipids or calcified areas, they could be unreliable in differentiating areas with heterogenous compositions. OCT may easily recognize relatively stable lesions.     

High gamma activity in response to deviant auditory stimuli recorded directly from human cortex

We recorded electrophysiological responses from the left frontal and temporal cortex of awake neurosurgical patients to both repetitive background and rare deviant auditory stimuli. Prominent sensory event-related potentials (ERPs) were recorded from auditory association cortex of the temporal lobe and adjacent regions surrounding the posterior Sylvian fissure. Deviant stimuli generated an additional longer latency mismatch response, maximal at more anterior temporal lobe sites. We found low gamma (30-60 Hz) in auditory association cortex, and we also show the existence of high-frequency oscillations above the traditional gamma range (high gamma, 60-250 Hz). Sensory and mismatch potentials were not reliably observed at frontal recording sites. We suggest that the high gamma oscillations are sensory-induced neocortical ripples, similar in physiological origin to the well-studied ripples of the hippocampus.     

Hfq-dependent regulation of OmpA synthesis is mediated by an antisense RNA

This paper shows that the small RNA MicA (previously SraD) is an antisense regulator of ompA in Escherichia coli. MicA accumulates upon entry into stationary phase and down-regulates the level of ompA mRNA. Regulation of ompA (outer membrane protein A), previously attributed to Hfq/mRNA binding, is lost upon deletion of the micA gene, whereas overexpression of MicA inhibits the synthesis of OmpA. In vitro, MicA binds to the ompA mRNA leader. Enzymatic and chemical probing was used to map the structures of MicA, the ompA mRNA leader, and the complex formed upon binding. MicA binding generates a footprint across the ompA Shine-Dalgarno sequence, consistent with a 12 + 4 base-pair interaction, which is additionally supported by the effect of mutations in vivo and by bioinformatics analysis of enterobacterial micA/ompA homolog sequences. MicA is conserved in many enterobacteria, as is its ompA target site. In vitro toeprinting confirmed that binding of MicA specifically interferes with ribosome binding. We propose that MicA, when present at high levels, blocks ribosome binding at the ompA translation start site, which-in line with previous work-secondarily facilitates RNase E cleavage and subsequent mRNA decay. MicA requires the presence of the Hfq protein, although the mechanistic basis for this remains unclear.     

Use of Antibodies in Lymphocyte Secretions for Detection of Subclinical Tuberculosis Infection in Asymptomatic Contacts

We have previously demonstrated that Mycobacterium bovis BCG-specific immunoglobulin G antibodies in lymphocyte secretions (ALS) can be employed as a marker for active tuberculosis (TB). We aimed to determine whether the ALS method allows detection of subclinical TB infection in asymptomatic individuals. A prospective study of family contacts (FCs) of patients with active TB and healthy controls was performed. Thirteen of 42 FCs had high ALS responses, including 6 FCs who subsequently developed active TB. No correlation was observed between the tuberculin skin test and the ALS responses in the FCs (r = 0.1, P = 0.23). Among patients with active TB, BCG-specific ALS responses steadily declined from the time of diagnosis through 6 months following antimycobacterial chemotherapy (P = 0.001). The ALS assay enabled detection of infection in exposed symptom-free contacts, who are at greater risk for developing active TB. The method may also allow discrimination between effective treatment of active infection and suboptimal response to therapy.     

Feasibility of noncontact piezoelectric detection of photoacoustic signals in tissue-mimicking phantoms

The feasibility of air-coupled ultrasound transducers to detect laser-induced ultrasound from artificial blood vessels embedded in an optically scattering phantom is demonstrated. These air-coupled transducers allow new applications in biomedical photoacoustic imaging where contact with tissue is not preferred. One promising application of such transducers is the addition of photoacoustic imaging to the regular x-ray mammographic screening procedure.