Targeting ribosome biogenesis reinforces ERK-dependent senescence in pancreatic cancer.

Pancreatic adenocarcinomas (PDAC) often possess mutations in K-Ras that stimulate the ERK pathway. Aberrantly high ERK activation triggers oncogene-induced senescence, which halts tumor progression. Here we report that low-grade pancreatic intraepithelial neoplasia displays very high levels of phospho-ERK consistent with a senescence response. However, advanced lesions that have circumvented the senescence barrier exhibit lower phospho-ERK levels. Restoring ERK hyperactivation in PDAC using activated RAF leads to ERK-dependent growth arrest with senescence biomarkers. ERK-dependent senescence in PDAC was characterized by a nucleolar stress response including a selective depletion of nucleolar phosphoproteins and intranucleolar foci containing RNA polymerase I designated as senescence-associated nucleolar foci (SANF). Accordingly, combining ribosome biogenesis inhibitors with ERK hyperactivation reinforced the senescence response in PDAC cells. Notably, comparable mechanisms were observed upon treatment with the platinum-based chemotherapy regimen FOLFIRINOX, currently a first-line treatment option for PDAC. We thus suggest that drugs targeting ribosome biogenesis can improve the senescence anticancer response in pancreatic cancer.

Cerebral palsy: what do medical students know and believe?

OBJECTIVES: Negative attitudes toward people with disabilities, including cerebral palsy, may be related to misunderstandings or lack of knowledge about the disability. If held by medical practitioners, they can have detrimental implications for the care of people with disabilities. The purposes of this study were to examine the knowledge and attitudes of medical students regarding cerebral palsy and to examine the effects of the videotape 'Understanding Cerebral Palsy' on these two areas. METHODS: The attitudes and knowledge regarding cerebral palsy of 54 medical students in their penultimate year were measured before and after watching a video produced to educate health professionals about cerebral palsy. They were assessed using a self-administered questionnaire constructed specifically for the study, adapted from previously validated questionnaires. RESULTS: These medical students generally had limited knowledge about cerebral palsy and displayed negative attitudes toward people with cerebral palsy. It was also found that males had less positive attitudes than females (P = 0.014) and that students educated mainly in Asia had less positive attitudes than students educated mainly in Australia (P = 0.012). The videotape was shown to be effective in improving the students' knowledge about cerebral palsy. A small but significant improvement in attitudes was also shown (P = 0.014), with the attitudes of some students improving dramatically. However, negative attitudes remained in many. CONCLUSIONS: Based on the findings, structured teaching about cerebral palsy is necessary within the medical curriculum at the University of Melbourne. Greater promotion of positive attitudes toward people with cerebral palsy and other disabilities is required.

The dream of consensus: finding common ground in a bioethical context.

Consensus is the holy grail of bioethics, the lynch pin of the assumption that well informed, well intentioned people may reach generally acceptable positions on ethically contentious issues. It has been especially important in bioethics, where advancing technology has assured an increasing field of complex medical dilemmas. This paper results on the use of a multicriterion decision making system (MCDM) analyzing group process in an attempt to better define hospital policy. In a pilot program at The Hospital for Sick Children, Toronto, a series of small scale focus groups was constituted to examine criteria defining organ transplant eligibility. Criteria were organized hierarchically using the Analytic Hierarchy Process, an MCDM approach, and the resulting data was analyzed using Expert Choice 9.0, software designed to facilitate AHP analysis. Qualitative and quantitative analysis map barriers to practical consensus in a way not previously possible.

Private enterprise and public good: ethical issues in the funding of clinical research.

Health-care centres, universities, and the researchers and clinicians working in them are encouraged to procure research funding through the development of commercial relationships. There are positive, practical, and morally relevant arguments in support of this initiative, but the move also raises ethical issues concerning potential conflicts of interest. These include conflicts between an institution's or researcher's responsibilities to each other, to research subjects, and to the public, and competing financial interests. This article examines developments in research funding and ethical difficulties that may arise in the present administrative context. It provides suggestions for the development of guidelines by institutions that are supportive of investigators in their endeavors to enhance clinical care through crucial external funding and the implementation of research.

A pilot study on transplant eligibility criteria: valuing the stories in numbers.

The medical and nursing literature often seem divided between numerical, qualitative studies, and quantitative, narrative-based case histories. Rarely are the numbers generated by the first informed by the experiences and insights offered by the second type of study. This paper reports on a pilot study carried out at the Hospital for Sick Children, Toronto, on a methodology combining qualitative and quantitative data. Using the Analytic Hierarchy Process (AHP), a type of multicriterion decision making, focus groups were used to analyze survey-based organ transplant eligibility criteria. Through this process, a portrait of the limits of that data was generated by staff members. Organ transplant eligibility was chosen because of its importance, and very public discussions arising from high profile cases in Canada and the United States.

Bioethics for clinicians: 9. Involving children in medical decisions.

Medical decisions involving children raise particular ethical issues for physicians and other members of the health care team. Although parents and physicians have traditionally made most medical decisions on behalf of children, the developing autonomy of children is increasingly being recognized in medical decision-making. This poses a challenge for physicians, who must work with the child's family and with other health care practitioners to determine the child's role in decision-making. A family-centred approach respects the complex nature of parent-child relationships, the dependence and vulnerability of the child and the child's developing capacity for decision-making.

Ethics teaching and learning in pediatric training: development of a curriculum.

The Royal College of Physicians and Surgeons of Canada has stated that residency programs "must provide opportunities for residents to gain an understanding of the basic principles of biomedical ethics as it relates to the specialty." This article presents the steps taken to develop a curriculum for teaching and learning biomedical ethics in Canadian pediatric residency programs, and to provide a model for teaching ethics in this context. Using literature reviews, and opinion surveys of departmental chairpersons, pediatric residents, and practising pediatricians across Canada, we have developed a teachers' handbook to help faculty members in teaching ethics. It can also be used as a tool to enhance faculty development in ethics. The manual is to be distributed to all pediatric training programs throughout Canada in 1997, and its use will be evaluated over the subsequent year. It offers a prototype that is adaptable to Royal College programs other than pediatrics.

The ethical boundaries of drug research in pediatrics.

Research abuses in the pediatric setting, mistakes, regulation, minimal investment, and professional misconceptions may contribute to children becoming therapeutic orphans. The moral imperative to expand pediatric pharmacology is urgent but the enterprise is not without risk. Pediatricians as experts in child care are privileged to be able to advocate for the expansion of this invaluable research while simultaneously advocating for the children who are to be involved. In the development of ethical drug research, children's well-being and empowerment can be realized. A shared commitment will help to ensure that in the future we will be better able to provide safe and effective medication and so greatly enhance the care of children.

Eradication of vitamin A deficiency with 5 cents and a vegetable garden.

1. It is estimated that 10 million children are vitamin A deficient. Of these children, over 1 million needlessly die, go blind, or suffer lesser degrees of visual impairment every year. This problem--along with all forms of malnutrition--is likely to be seriously magnified by the year 2000. The scope of the problem is immense, and the need to address it is urgent. 2. Interventions for the prevention of vitamin A deficiency and its consequences are considered to be some of the most cost-effective and health-productive in the Third World--and yet the problem remains immense, representing one of the greatest failures in global public health planning. 3. As ophthalmic professionals, we are at the center of this urgent public health concern. We have an important responsibility in the initiation and development of sustainable programs for health promotion and disease prevention.

Phyllodes tumors.

Phyllodes tumors are rare lesions of the breast with unpredictable behavior. A review of 18 patients with phyllodes tumors was performed to determine if pathologic and cellular characteristics correlated with clinical behavior and to determine the influence of the extent of the operation performed on clinical outcome. Local excision, primarily breast biopsy, was performed in 14 of the 18 patients. At a median follow-up of 26 months (range: 3 to 164 months), there have been three recurrences, two in patients with low-grade tumors and one in a patient with a high-grade lesion, who eventually died as a result of widespread metastases. Recurrences were noted from 2 to 56 months after the original operation. Poor correlation was noted between standard pathologic criteria or flow cytometry and the risk of recurrence. Phyllodes tumors exhibit a wide spectrum of clinical behavior. Most patients will not experience a recurrence, but even small, low-grade tumors may recur if inadequately excised. Occasional patients have extremely aggressive disease that may result in death.

Role of Franzen needle aspiration biopsy in carcinoma of the prostate.

A retrospective study is reported of all Franzen fine-needle aspiration cytology undertaken at Southmead Hospital between January 1978 and December 1981. A total of 1043 aspirates were examined from 753 patients. The diagnosis of carcinoma of the prostate was missed in 2 patients. Twenty-one patients with cytologically-proven carcinoma in histologically-benign prostates were detected, and the role of the Franzen needle in the diagnosis of early prostatic cancer is discussed. Of the 218 patients proceeding to prostatectomy, there were 91 patients with carcinoma and in 65 (72%) the cytological and histological grading was identical. A significant disparity occurred in 8 cases and the reasons are discussed.