Publications

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction.

Effective clinical text processing requires accurate extraction and representation of temporal expressions. Multiple temporal information extraction models were developed but a similar need for extracting temporal expressions in eligibility criteria (e.g., for eligibility determination) remains. We identified the temporal knowledge representation requirements of eligibility criteria by reviewing 100 temporal criteria. We developed EliXR-TIME, a frame-based representation designed to support semantic annotation for temporal expressions in eligibility criteria by reusing applicable classes from well-known clinical temporal knowledge representations. We used EliXR-TIME to analyze a training set of 50 new temporal eligibility criteria. We evaluated EliXR-TIME using an additional random sample of 20 eligibility criteria with temporal expressions that have no overlap with the training data, yielding 92.7% (76 / 82) inter-coder agreement on sentence chunking and 72% (72 / 100) agreement on semantic annotation. We conclude that this knowledge representation can facilitate semantic annotation of the temporal expressions in eligibility criteria.

OBJECTIVE

To investigate the cross-sectional association between COPD severity and disturbed sleep and the longitudinal association between disturbed sleep and poor health outcomes.

METHODS

Ninety eight adults with spirometrically-confirmed COPD were recruited through population-based, random-digit telephone dialing. Sleep disturbance was evaluated using a 4-item scale assessing insomnia symptoms as: difficulty falling asleep, nocturnal awakening, morning tiredness, and sleep duration adequacy. COPD severity was quantified by: FEV(1) and COPD Severity Score, which incorporates COPD symptoms, requirement for COPD medications and oxygen, and hospital-based utilization. Subjects were assessed one year after baseline to determine longitudinal COPD exacerbations and emergency utilization and were followed for a median 2.4 years to assess all-cause mortality.

RESULTS

Sleep disturbance was cross-sectionally associated with cough, dyspnea, and COPD Severity Score, but not FEV(1). In multivariable logistic regression, controlling for sociodemographics and body-mass index, sleep disturbance longitudinally predicted both incident COPD exacerbations (OR=4.7; p=0.018) and respiratory-related emergency utilization (OR=11.5; p=0.004). In Cox proportional hazards analysis, controlling for the same covariates, sleep disturbance predicted poorer survival (HR=5.0; p=0.013). For all outcomes, these relationships persisted after also controlling for baseline FEV(1) and COPD Severity Score.

CONCLUSIONS

Disturbed sleep is cross-sectionally associated with worse COPD and is longitudinally predictive of COPD exacerbations, emergency health care utilization, and mortality.

BACKGROUND

Decline in forced vital capacity (FVC) over time reliably predicts mortality in patients with idiopathic pulmonary fibrosis. The use of this measure in clinical practice is recommended by current evidence-based guidelines. It is unknown if the method of calculating decline in FVC (relative vs. absolute change) impacts its frequency or its ability to predict mortality.

METHODS

Patients with idiopathic pulmonary fibrosis from two prospective cohorts were included if they had a baseline and 12-month follow-up FVC. A ≥10% decline in FVC from baseline was calculated in two ways: a relative decline of 10% (e.g., from 60% predicted to 54% predicted) and an absolute decline of 10% (e.g., from 60% predicted to 50% predicted). The frequency of a ≥10% decline in FVC and its ability to predict 2-year transplant-free survival were compared between these two methods. Declines in FVC of ≥5% and ≥15% were similarly compared. Analyses were performed unadjusted and adjusted for age, gender, use of oxygen, baseline FVC and baseline diffusion capacity for carbon monoxide.

RESULTS

The frequency of any given FVC decline was significantly greater using the relative change in FVC method. For ≥10% decline, both methods predicted 2-year transplant-free survival with similar accuracy, and remained significant predictors after adjusting for baseline characteristics. The absolute change method appeared more predictive for ≥5% decline.

CONCLUSIONS

Using the relative change in FVC maximises the chance of identifying a ≥10% decline in FVC without sacrificing prognostic accuracy. This may not hold true for ≥5% decline in FVC. These findings have important implications for clinical practice and the design of clinical trials.

Cardiac calsequestrin (Casq2) is the major Ca2+ binding protein in the sarcoplasmic reticulum, which is the principle Ca2+ storage organelle of cardiac muscle. During the last decade, experimental studies have provided new concepts on the role of Casq2 in the regulation of cardiac muscle Ca2+ handling. Furthermore, mutations in the gene encoding for cardiac calsequestrin, CASQ2, cause a rare but severe form of catecholaminergic polymorphic ventricular tachycardia (CPVT). Here, we review the physiology of Casq2 in cardiac Ca2+ handling and discuss pathophysiological mechanisms that lead to CPVT caused by CASQ2 mutations. We also describe the clinical aspects of CPVT and provide an update of its contemporary clinical management.