The Hippo pathway promotes cell survival in response to chemical stress.

Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress.

Improved results in the management of surgical candidates with lung cancer.

BACKGROUND: Perioperative mortality and morbidity after lung resection for carcinoma are generally reported to be 3% to 6% and 15% to 30%, respectively, and higher in the elderly and those with limited cardiopulmonary reserve. METHODS: To minimize this risk and extend the surgical option to more high-risk patients, we adopted a protocol in 1991 that included preoperative digitalis, subcutaneous heparin and venoocclusive stockings, aggressive perioperative pulmonary toilet, and video-directed limited resections for many patients with limited pulmonary reserve. In October 1996, we reviewed our results with 173 consecutive patients (median age, 60 years; range, 17 to 89 years) undergoing operation for suspected lung carcinoma. Forty-one patients were 70 years old or older, and 70 patients were considered high risk on the basis of advanced age (> or = 70 years), poor cardiac or pulmonary reserve, or serious medical comorbidity. Procedures included pneumonectomy (n = 31), lobectomy (n = 83), bilobectomy (n = 12), and limited resection (n = 45). Two patients had unresectable disease. RESULTS: Hospital mortality was 1.6% (3/173) and morbidity was experienced by 15% (26/173). Among the high-risk subgroup mortality was 4.2% (3/70) and morbidity was 20% (14/70; p < 0.03). For the older patients these values were 4.8% (2/41) and 17.9% (7/41), respectively. CONCLUSIONS: Morbidity and mortality from lung resections may be minimized with the perioperative management strategy outlined above. This would allow more high-risk patients to benefit from surgical resection, and do so with an acceptably low risk.

The University of Virginia health promotion and disease prevention program.

INTRODUCTION: Proof of effectiveness now exists for many health promotion and disease prevention practices, yet the importance of this knowledge is not widely appreciated, and a large percentage of the population does not receive this care. Universities with comprehensive academic medical centers are particularly appropriate places for providing health promotion programs. The University of Virginia began a health promotion and disease prevention program for employees in 1990. METHODS: Periodic health risk appraisal, with follow-up and selected interventions, is offered to approximately 14,000 employees as a cost-free fringe benefit. Health risks are assessed with a modification of the Carter Center Health Risk Appraisal. Results are given to participants in group sessions; referrals are made for clinical preventive services and interventions, as needed. RESULTS: During the first three years, 29% of the employee population participated in the program. Participants were more likely to be young, female and not African American. Nearly 96% had one or more risk factors, with an average of 3.6 risk factors overall. Participants on average had 1.8 risk factors for cardiovascular disease; 0.3 for cancer; 0.6 for injury; 0.1 for alcohol abuse; and 0.7 for mental health. Nonparticipants were not receiving similar comprehensive health risk appraisal elsewhere. CONCLUSIONS: University of Virginia employees have multiple health risks, not detected through their usual health care, for which effective interventions are available. This population probably reflects conditions throughout the state and nation. Academic medical centers should place high priority on establishing health promotion programs as part of their responsibilities to society.