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Topoisomerase II (TOP2) targeting drugs like doxorubicin and etoposide are frontline chemotherapeutics for a wide variety of solid and hematological malignancies, including breast and ovarian adenocarcinomas, lung cancers, soft tissue sarcomas, leukemias and lymphomas. These agents cause a block in DNA replication leading to a pronounced DNA damage response and initiation of apoptotic programs. Resistance to these agents is common, however, and elucidation of the mechanisms causing resistance to therapy could shed light on strategies to reduce the frequency of ineffective treatments. To explore these mechanisms, we utilized an unbiased shRNA screen to identify genes that regulate cell death in response to doxorubicin treatment. We identified the Filamin A interacting protein 1-like (FILIP1L) gene as a crucial mediator of apoptosis triggered by doxorubicin. FILIP1L shares significant similarity with bacterial SbcC, an ATPase involved in DNA repair. FILIP1L was originally described as DOC1, or "down-regulated in ovarian cancer" and has since been shown to be downregulated in a wide variety of human tumors. FILIP1L levels increase markedly through transcriptional mechanisms following treatment with doxorubicin and other TOP2 poisons, including etoposide and mitoxantrone, but not by the TOP2 catalytic inhibitors merbarone or dexrazoxane (ICRF187), or by UV irradiation. This induction requires the action of the OCT1 transcription factor, which relocalizes to the FILIP1L promoter and facilitates its expression following doxorubicin treatment. Our findings suggest that the FILIP1L expression status in tumors may influence the response to anti-TOP2 chemotherapeutics.

Cellular DNA damage triggers the DNA damage response pathway and leads to enforcement of cell cycle checkpoints, which are essential for the maintenance of genomic integrity and are activated in early stages of tumorigenesis. A special feature of prostate cancer is its high incidence and multifocality. To address the functionality of DNA damage checkpoints in the prostate, we analyzed the responses of human primary prostate epithelial cells (HPECs) and freshly isolated human prostate tissues to [gamma]-irradiation. We find that [gamma]-irradiation activates the ataxia telangiectasia mutated-associated DNA damage response pathway in the HPECs but that the clearance of phosphorylated histone H2AX ([gamma]H2AX) foci is delayed. Surprisingly, [gamma]-irradiated HPECs were unable to enforce cell cycle checkpoint arrest and had sustained cyclin-dependent kinase 2 (Cdk2)-associated kinase activity because of a lack of inhibitory Cdk phosphorylation by Wee1A tyrosine kinase. We further show that HPECs express low levels of Wee1A and that ectopic Wee1A efficiently rescues the checkpoints. We recapitulate the absence of checkpoint responses in epithelium of ex vivo irradiated human prostate tissue despite robust induction of [gamma]H2AX. The findings show that prostate epithelium has a surprising inability to control checkpoint arrest, the lack of which may predispose to accrual of DNA lesions. p53 | irradiation | cyclin-dependent kinase

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ahj.2006.04.021 Byline: Michael A. Brodsky (a), John McAnulty (b), Douglas P. Zipes (c), Christina Baessler (d), Alfred P. Hallstrom (e) Abstract: In survivors of life-threatening ventricular tachycardia (VT), a history of CHF (HxCHF) before the VT episode may provide different prognostic information than their measured left ventricular ejection fraction (LVEF). Author Affiliation: (a) Kaiser Permanente, Honolulu, HI (b) Division of Cardiology, Oregon Health and Science University, Portland, OR (c) Indiana University, Indianapolis, IN (d) MCP Hahnemann University, Philadelphia, PA (e) Department of Biostatistics, University of Washington, Seattle, WA Article History: Received 1 August 2005; Accepted 3 April 2006

Introduction: Consumption of coffee and tea, and total intake of caffeine has been claimed to be associated with osteoporotic fracture risk. However, results of earlier studies lack consistency. Methods: We examined this relation in a cohort of 31,527 Swedish women aged 40-76 years at baseline in 1988. The consumption of coffee, caffeinated tea and the intake of caffeine were estimated from a self-administered food frequency questionnaire (FFQ). Multivariate-adjusted hazards ratios (HRs) of fractures with 95% confidence intervals (95% CIs) were estimated by Cox proportional hazards models. Results: During a mean follow-up of 10.3 years, we observed 3,279 cases with osteoporotic fractures. The highest (>330 mg/day) compared with the lowest ( Keywords Caffeine * Coffee * Cohort study * Fracture * Tea

A study was conducted to compare resuscitation outcomes following out-of-hospital cardiac arrest when an automated load distributing band-cardio pulmonary resuscitation (LDB-CPR) devise was added to standard emergency medical service (EMS) care with manual CPR. It was found that use of an automated LDB-CPR device was associated with worse neurological outcomes and a trend toward worse survival than manual CPR.

Heteroaromatic thiols might be oxidized to the sulfonyl chloride at low temperature by using 3.3 equiv of aqueous sodium hypochlorite and the reaction is rapid, avoids the use of chlorine gas, and succeeds with substrates that have previously been found to afford little or none of the sulfonamide product with other procedures. The method allows the preparation of the sulfonyl fluorides, which are stable enough to be purified and stored, making them potentially useful monomers in parallel chemistry efforts.

Hematopoietic progenitors undergo differentiation while navigating several cell division cycles, but it is unknown whether these two processes are coupled. We addressed this question by studying erythropoiesis in mouse fetal liver in vivo. We found that the initial upregulation of cell surface CD71 identifies developmentally matched erythroblasts that are tightly synchronized in S-phase. We show that DNA replication within this but not subsequent cycles is required for a differentiation switch comprising rapid and simultaneous committal transitions whose precise timing was previously unknown. These include the onset of erythropoietin dependence, activation of the erythroid master transcriptional regulator GATA-1, and a switch to an active chromatin conformation at the β-globin locus. Specifically, S-phase progression is required for the formation of DNase I hypersensitive sites and for DNA demethylation at this locus. Mechanistically, we show that S-phase progression during this key committal step is dependent on downregulation of the cyclin-dependent kinase p57(KIP2) and in turn causes the downregulation of PU.1, an antagonist of GATA-1 function. These findings therefore highlight a novel role for a cyclin-dependent kinase inhibitor in differentiation, distinct to their known function in cell cycle exit. Furthermore, we show that a novel, mutual inhibition between PU.1 expression and S-phase progression provides a "synchromesh" mechanism that "locks" the erythroid differentiation program to the cell cycle clock, ensuring precise coordination of critical differentiation events.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jeem.2005.05.002 Byline: Daniel G. Hallstrom, V. Kerry Smith Keywords: Repeat sales; Hurricane risk; Hedonic property model Abstract: This paper uses one of the strongest hurricanes to hit the US, Andrew in 1992, to define a quasi-random experiment that permits estimation of the responses of housing values to information about new hurricanes. Lee County, Florida did not experience damage from Andrew. The storm was a 'near-miss.' We hypothesize that Andrew conveyed risk information to homeowners in the county. A difference-in-differences (DND) framework identifies the effect of this information on property values in areas likely to experience significant storm damage. The DND findings indicate at least a 19 percent decline in property values. Author Affiliation: Center for Environmental and Resource Economic Policy, Department of Agricultural and Resource Economics, Campus Box 8109, North Carolina State University, Raleigh, NC 27695, USA Article History: Received 9 February 2004

The E2F family of transcription factors provides essential activities for coordinating the control of cellular proliferation and cell fate. Both E2F1 and E2F3 proteins have been shown to be particularly important for cell proliferation, whereas the E2F1 protein has the capacity to promote apoptosis. To explore the basis for this specificity of function, we used DNA microarray analysis to probe for the distinctions in the two E2F activities. Gene expression profiles that distinguish either E2F1- or E2F3-expressing cells from quiescent cells are enriched in genes encoding cell cycle and DNA replication activities, consistent with many past studies. E2F1 profile is also enriched in genes known to function in apoptosis. We also identified patterns of gene expression that specifically differentiate the activity of E2F1 and E2F3; this profile is enriched in genes known to function in mitosis. The specificity of E2F function has been attributed to protein interactions mediated by the marked box domain, and we now show that chimeric E2F proteins generate expression signatures that reflect the origin of the marked box, thus linking the biochemical mechanism for specificity of function with specificity of gene activation. DNA microarray | transcriptional control

This study shows that enhancing a well-developed, monitored, layperson-enacted cardiopulmonary resuscitation (CPR) response plan by adding automated external defibrillators (AEDS) and AED training can increase the number of survivors of out-of-hospital cardiac arrest in public locations. Training and equipping volunteers to attempt early defibrillation with in a structured response system can increase the number of survivors to hospital discharge after out-of-hospital cardiac arrest in public locations.

Decreased left ventricular ejection fraction is the most commonly used risk factor for identification of patients at high-risk for lethal ventricular arrhythmic events. Twenty-four-hour electrocardiographic (ECG) approaches to risk stratification include: counts of ventricular premature contractions (VPCs), measures of heart rate variability (HRV), and heart rate turbulence (HRT) which has two components, turbulence onset and turbulence slope (TS). Refinement of these ECG risk stratifiers could enhance their clinical utility. We explored the structural relationships between heart rate (HR) and HRV and HRT measures, Our goal was to separate out the component of these measures due to the underlying average heart rate (HR), thus potentially reducing the variability of the measures and increasing their power to stratify risk. We proposed re-scaling tachograms of heart-beat intervals so that the re-scaled tachogram has a HR of 75 (or equivalently an average interval of 800 ms) and calculating HRV and HRT from the rescaled time series. We also explored the relationship between the number of VPCs and HRT. We showed that TS is structurally related to the number of VPCs (and hence to the length of the ECG recording). We proposed an adjusted TS that is independent of the number of VPCs. We also addressed the ability of shorter ECG recording to estimate HRV and HRT measures. We evaluated standard and rescaled HRV and HRT measures using qualifying ambulatory ECG recordings from 744 patients in the Cardiac Arrhythmia Suppression Trial. We found that measures based on the rescaled tachogram had reduced variance (20% to 40%). Correlations between measures were also substantially reduced. We also found substantial circadian effects on some, but not all HRV indices, not explained by the circadian pattern in HR and possibly pointing to additional measures for risk prediction. In conclusion, we found that adjusting for HR and the number of VPCs in heart-beat related ambulatory ECG measures has the potential to significantly improve the power of these measures to risk stratify cardiac patients. Index Terms--Ambulatory electrocardiography, coronary heart disease, myocardial infarction, risk stratification, sudden cardiac death.

Byline: Tulay Yucel-Lindberg (1), Therese Hallstrom (1), Anna Kats (1), Manal Mustafa (1), Thomas Modeer (1) Keywords: prostaglandin E synthase; prostaglandin E.sub.2; IL-1[beta]; TNF[alpha]; COX-2 Abstract: It is well established that prostaglandin E.sub.2 (PGE.sub.2) plays an important role in inflammatory diseases including periodontitis. Previously we have reported that the inflammatory mediators interleukin-1[beta] (IL-1[beta]) and tumor necrosis factor [alpha] (TNF[alpha] ) stimulate PGE.sub.2 synthesis by inducing mRNA expression of cyclooxygenase-2 (COX-2) in human gingival fibroblasts. In present study the involvement of microsomal prostaglandin E synthase-1 (mPGES-1) in relation to PGE.sub.2 production was investigated. The results showed that IL-1[beta] as well as TNF[alpha] induced mPGES-1 mRNA and protein expression accompanied by enhanced PGE.sub.2 production in gingival fibroblasts. The anti-inflammatory steroid dexamethasone (DEX) inhibited mPGES-1 mRNA and protein expression as well as PGE.sub.2 production induced by IL-1[beta] or TNF[alpha]. The COX-2 specific inhibitor, celecoxib, in contrast to the nonspecific COX inhibitor, indomethacin, markedly reduced mPGES-1 expression induced by IL-1[beta]. The results demonstrate that mPGES-1 regulates PGE.sub.2 production in gingival fibroblasts stimulated by inflammatory mediators IL-1[beta] and TNF[alpha]. This novel pathway may be a potential target for treatment strategies of periodontal disease. Author Affiliation: (1) Department of Pediatric Dentistry, Institute of Odontology, Karolinska Institutet, Huddinge, Sweden Article History: Registration Date: 28/09/2004

We develop a conceptual framework for quantifying fixed transactions costs facing semisubsistence households. Using household survey data from a sample of 324 Kenyan maize farmers, we jointly estimate household supply and demand schedules and transactions costs. Econometric results indicate that on average the ad valorem tax equivalent of fixed transactions costs for households in our sample is 15%. Additional analysis indicates that economic isolation is positively associated with the size of transactions costs. To the best of our knowledge, ours are the first empirical estimates of the magnitude of fixed transactions costs for agricultural households in developing countries. JEL classification: O1 Keywords: Transactions costs; Semisubsistence households; Market participation

Previous work has demonstrated a role for the E2F1 gene product in signaling apoptosis, both as a result of the deregulation of the Rb/E2F pathway as well as in response to DNA damage. We now show that the ability of cells to suppress the apoptotic potential of E2F1, as might occur during the course of normal cellular proliferation, requires the action of the Ras-phosphoinositide 3-kinase--Akt signaling pathway. In addition, we also identify a domain within the E2F1 protein, previously termed the marked-box domain, that is essential for the apoptotic activity of E2F1 and that distinguishes the E2F1 protein from E2F3. We also show that the E2Fl-marked-box domain is essential for the induction of both p53 and p73 accumulation. Importantly, a role for the marked-box domain in the specificity of E2Fl-mediated apoptosis coincides with recent work demonstrating a role for this domain in achieving specificity in the activation of transcription. We conclude that the unique capacity of E2F1 to trigger apoptosis reflects a specificity of transcriptional activation potential, and that this role for E2F1 is regulated through the action of the Akt protein kinase.