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PubMed1999

Stability and folding of the tumour suppressor protein p16.

The tumour suppressor p16 is a member of the INK4 family of inhibi tors of the cyclin D-dependent kinases, CDK4 and CDK6, that are involved in the key growth control pathway of the eukaryotic cell cycle. The 156 amino acid residue protein is composed of four ankyrin repeats (a helix-turn-helix motif) that stack linearly as two four-helix bundles resulting in a non-globular, elongated molecule. The thermodynamic and kinetic properties of the folding of p16 are unusual. The protein has a very low free energy of unfolding, Delta GH-2O/D-N, of 3.1 kcal mol-1 at 25 degreesC. The rate-determining transition state of folding/unfolding is very compact (89% as compact as the native state). The other unusual feature is the very rapid rate of unfolding in the absence of denaturant of 0.8 s-1 at 25 degreesC. Thus, p16 has both thermodynamic and kinetic instability. These features may be essential for the regulatory function of the INK4 proteins and of other ankyrin-repeat-containing proteins that mediate a wide range of protein-protein interactions. The mechanisms of inactivation of p16 by eight cancer-associated mutations were dissected using a systematic method designed to probe the integrity of the secondary structure and the global fold. The structure and folding of p16 appear to be highly vulnerable to single point mutations, probably as a result of the protein's low stability. This vulnerability provides one explanation for the striking frequency of p16 mutations in tumours and in immortalised cell lines.

Circular Dichroism↗

PubMed1991

Significance of fibrin formation and dissolution in the pathogenesis and treatment of cancer.

Despite increased concentration of plasminogen activators in malignant tumors, fibrinolytic potential in blood of cancer patients and tumor tissue is low. At the same time histochemical and microscopic examination revealed the presence of fibrin-like material coating tumor cells. It is postulated in the present paper that the increased concentrations of -SH groups and arginine-rich peptides, and the activation of tissue transglutaminases in the tumor tissue are responsible for the resistance of the fibrin coat to enzymatic degradation. The fibrin coat, in turn, causes neoplastic cells not to be recognized by the immunological system and thus makes them immune to the attack by the natural killer cells. Administration of naturally occurring, but diminished in cancer, derivatives of alpha ketoaldehydes resistant to glyoxalases, reverses the effect of -SH and arginine-rich peptides, and reactivates fibrinolysis. Consequently, removal of the fibrin coat from tumor cells makes them vulnerable to the attack of killer cells and their subsequent elimination.

Arginine↗

PubMed2006

Mitochondrial disease: maintenance of mitochondrial genome and molecular diagnostics.

Mitochondrial DNA (mtDNA) is essential for the aerobic ATP synthesis system that is responsible for about 80% of normal cellular energy demands. In addition to rare genetic disorders causing neuromyopathy, alterations of mtDNA have been found also in so-called common diseases such as heart failure, diabetes, and cancer. Although some of these alterations are inherited, some are considered to be generated and/or accumulated in somatic cells with age. One reason for the somatic mutations is that mtDNA is more vulnerable than is nuclear DNA. For example, mitochondrial respiratory chain produces a large amount of reactive oxygen species as inevitable byproducts of oxidative phosphorylation. However, the molecular mechanisms for maintenance of mitochondrial genome are much less elucidated than those for nuclear genome. In spite of its increasing importance, the molecular diagnosis of mitochondrial DNA-related diseases is well done only in very limited expert laboratories. In this chapter, we focus on maintenance of mtDNA in somatic cells, its clinical importance, and recent developments of molecular tests.

DNA, Mitochondrial↗

PubMed2004

A critical review of the clinical effects of therapeutic irradiation damage to the brain: the roots of controversy.

We critically examined the damaging affects of therapeutic irradiation by comparing results from cross-disciplinary studies of early- and late-delayed radiotherapy effects. Focus is attained by concentrating on clinical treatment issues (volume of brain, dose, timing of effects, age, modality types, and stereotactic treatment techniques), rather than on methodological means or problems, which is necessary to understand the mechanisms and characteristics of radiotherapy-induced behavioral dysfunction including cognition. We make observations and hypotheses about the actual risks from radiotherapy that could be informative in the treatment decision process, and which may lessen the concerns of some patients and their families about the risks they take when receiving radiation. Conditions that predispose to radiation injury are reviewed: (1) higher doses even to part of the brain versus lower doses to the whole brain, (2) combined treatment modalities, (3) malignancy itself, (4) radiation early during postnatal brain development, and (5) late-delayed effects (more than 3 years posttreatment). Current neurocognitive frameworks for understanding cognitive change over time in children and adults are summarized, along with the literature on effects of brain tumors and treatment on depression. No studies have as yet identified candidate brain regions that are more sensitive to radiotherapy. Two studies have provided early, preliminary evidence for a specific vulnerability of visual attention/memory to the early stage of late radiation damage. Furthermore, radiation effects appear severe only in a minority of patients. Risk is related to direct and indirect effects of cancer type, concurrent clinical factors, and premorbid risk factors.

Adult↗

PubMed1990

Failure of long limb Roux-en-Y reconstruction to prevent alkaline reflux esophagitis after total gastrectomy.

Postoperative reflux esophagitis is usually not seen in connection with Roux-en-Y reconstruction after total or subtotal gastrectomy. An isoperistaltic jejunal limb of adequate length (over 40 cm) is considered to prevent reflux of duodenal contents into the esophagus with consequent injury of the esophageal mucosa that otherwise may ensue. The present paper describes four patients who developed postoperative reflux esophagitis as a complication after total gastrectomy, despite a well-functioning Roux-en-Y reconstruction. It is possible that the intraabdominal generalization of cancer which was concomitantly observed in three of our four patients, may have had a contributory influence on the development of the condition by decreasing esophageal mucosal resistance, thus rendering the mucosa vulnerable to even minimal amounts of intra-esophageal regurgitation of duodenal contents, and that alkaline reflux esophagitis appearing after an interval in a patient who had an adequate Roux-en-Y reconstruction after total gastrectomy, may be the first sign of intraabdominal tumor recurrence despite negative x-ray examinations.

Adult↗

PubMed1981

Understanding the cancer patient: the syndrome of caregiver's plight.

Comprehensive cancer care is a combination of tumor treatment with understanding the special concerns and needs of cancer patients. To understand the psychosocial problems of cancer patients requires knowledge of protocol (treatment of the tumor), plight (nonmedical ramifications of cancer), and promise (the caregiver's view of the patient's predicament). Caregivers can sometimes be more distressed by the plight of their patients than are patients themselves. In extreme instances, their vulnerability leads to what is called "Caregiver's Plight," a set of responses which interfere with adequate understanding and may result in progressive vocational demoralization, change to another field, and drastic impairment of self-esteem. Therapeutic suggestions for identifying and correcting caregiver's plight are proposed, including knowing how to cope better and how much to promise, sharing concern with colleagues, attempting to make smaller contributions, and using an exercise called the "Absent Witness," an imaginary self-monitoring review.

Adult↗

PubMed2006

Parent and family factors associated with child adjustment to pediatric cancer.

OBJECTIVE: To identify factors that influence the association between parent and child distress among families of children with cancer and comparison peers. METHODS: Parent and child distress, social support, and family environment were assessed among families of 95 children with cancer (94 mothers, 67 fathers) and 98 comparison peers (97 mothers, 77 fathers). RESULTS: Significant associations were found between parent and child distress. For models examining the impact of fathers' distress on children, several moderators were identified (i.e., family environment, child age and gender, a cancer diagnosis, and treatment severity). Family environment also partially mediated father and child distress. CONCLUSIONS: Children whose parents were distressed were more likely to be distressed themselves. Subgroups of children were particularly vulnerable, indicating a need to identify further mechanisms of risk and resilience and to develop family-based interventions. Support was found for including fathers as independent sources of information in pediatric psychology research and clinical practice.

Adaptation, Psychological↗

PubMed1991

Sun protection in childhood.

There is compelling evidence that childhood is a particularly vulnerable time for the photocarcinogenic effects of sun exposure on the skin. Studies indicate that excessive sun exposure during the first 10-20 years of life greatly increases the risk of skin cancer. Nonmelanoma skin cancer (basal cell and squamous cell carcinoma) has been associated with cumulative sun exposure, whereas melanoma has been associated with short, intense sun exposure or blistering sunburn. Under normal circumstances, children receive three times the annual sun exposure of adults; most of one's lifetime sun exposure occurs in childhood. Depletion of the earth's protective ozone layer adds to the photodamage problem. It is clear that sun protection is most vital in the early years. Those with fair skin are at highest risk. Photoprotective measures including sunscreen, clothing, and sun avoidance in childhood may significantly reduce the occurrence of melanoma and other skin cancer in later life. Regular use of sunscreen with a sun protection factor of 15 during the first 18 years of life could reduce the lifetime incidence of nonmelanoma skin cancer by 78%. Pediatricians can play a major role in educating parents and children.

Child↗

PubMed1997

Cancer chemotherapy in the older patient: what the medical oncologist needs to know.

This review explores the effectiveness and safety of cancer chemotherapy in older individuals and outlines potential guidelines for the management of these patients. Cancer chemotherapy appears less effective in three neoplasms of older individuals: acute myelogenous leukemia, large cell lymphoma, and coelomic carcinoma of the ovary. In the case of acute myelogenous leukemia, a higher prevalence of MDR-1 expression and involvement of the pluripotent hematopoietic stem cells in the neoplastic process contribute to chemotherapy resistance. Chemotherapy-related myelodepression, cardiotoxicity, and peripheral and central neurotoxicity are more common and more severe in older individuals. This toxicity results from the increased vulnerability of target organs and delayed excretion of renally excretable agents. The complications of chemotherapy may be ameliorated by modifying the doses of drugs according to the patient's creatinine clearance, by using antidotes to drug toxicity, and by the early diagnosis and timely management of therapeutic complications. A comprehensive assessment of the older person with cancer allows clinicians to predict the benefits and risks of cancer chemotherapy in individual circumstances.

Aged↗

PubMed2001

The priority of basic research on ageing vulnerability in a comprehensive research agenda on ageing for the 21st century.

The prospects for individual and population ageing as we enter a new century pose some of the greatest social, economic and humanitarian challenges humankind as a whole has ever faced. The basic biological mechanisms that control human ageing remain ill understood but it is clear that for many individuals exhibiting predisposition to risk factors for certain chronic diseases, such as coronary heart disease, diabetes, osteoporosis, certain cancers and Alzheimer's disease, such predisposition is mediated through genetic processes that operate at a most fundamental biomolecular level interacting with nongenetic attributes. The prospect of improved understanding of the fundamental processes underlying the pathogenesis of common age-related diseases that may lead to identification of interventions that are effective in preventing, delaying or ameliorating the diseases and their consequences is compelling. It is this prospect that provides the prime justification for giving high priority to research on ageing vulnerability in a comprehensive research agenda on ageing for the 21st century.

Aged↗

PubMed1993

Home parenteral and enteral nutrition in cancer patients.

The clinical outcomes of 2968 patients with active cancer receiving home nutrition support are described. Of these patients 1672 were receiving home parenteral nutrition and 1296 were receiving home enteral nutrition. The outcomes of these active cancer patients are compared to those of 123 radiation enteritis ("cured" cancer) and 480 Crohn's disease patients receiving home parenteral nutrition and 918 noncancer dysphagic patients receiving home enteral nutrition. This longitudinal clinical information was reported to the North American Home Parenteral and Enteral Nutrition Patient Registry between 1985 and 1990. Evidence indicates that the number of home parenteral and enteral nutrition patients has increased nationally by about 25% each year between 1989 and 1990. In a subsample of 37 home nutrition support programs that have consistently reported their data to the registry since 1985, more than 90% of their program growth was accounted for by new patients with active cancer. This is now the largest single diagnosis of patients starting home parenteral and enteral nutrition. The mean survival time of cancer patients is 6 months after starting home parenteral and enteral nutrition, but 25% live beyond a year and 20% resume full oral nutrition. Although most active cancer patients experience only partial rehabilitation, for those patients with longer survival, rehabilitation is more complete. The outcome is relatively better for children and for patients whose neoplasm is leukemia, lymphoma, small bowel, or liver. In comparison, 96% of home parenteral nutrition Crohn's patients, 80% of home parenteral nutrition radiation enteritis patients, and 60% of home enteral nutrition noncancer dysphagic patients survive at least 1 year. Adult active cancer home parenteral and enteral nutrition patients do not have a greater incidence of therapy-related readmissions than other patient groups, however, their overall rehospitalization rate is much more frequent. This article discusses factors that may have contributed to this growth in home nutrition support in active cancer patients. It attempts to clarify where this therapy is clearly justified and where more information is needed. It emphasizes some of the special issues that need to be addressed in treating these vulnerable patients.

Enteral Nutrition↗

PubMed1985

In vitro synergism between estrogens and cytotoxic agents.

Two lines of research intending to achieve synergism between cytotoxic agents and estrogens for breast cancer treatment are pursued in our laboratory. According to a screening procedure we select cytotoxic-linked estrogens which bind to estrogen receptors and thereby would be specifically concentrated into the tumor cells. A mesylate derivative of estrone has emerged from our investigations. This compound displays a very strong binding affinity for the receptors and inhibits the growth of the receptor-positive MCF-7 breast cancer cell line. The lack of growth inhibition in the receptor-negative line Evsa-T indicates that it is devoid of major non-specific cytotoxicity. We attempt to enhance the vulnerability of the tumor cells by producing an estrogen-induced modification of their chromatin. The in vitro exposure of isolated uterine nuclei to uterine cytosol preincubated with estradiol increases their ability to bind [3H]actinomycin D. Identical results are obtained with MXT mouse mammary tumors. Experiments are in progress to settle whether these changes are associated with enhanced cell killing.

Animals↗

PubMed2003

Epidemiology of substance use disorders in women.

Significant gender differences exist in the prevalence of substance use disorders in the United States. There is a trend among boys and girls aged 12 to 17 years toward comparable rates of use and initiation for alcohol, cocaine, heroin, and tobacco. If this trend continues, over time there may be a narrowing of the male-to-female prevalence ratios of substance abuse in the older age groups. This possibility is particularly disturbing because women have a heightened vulnerability to medical, physical, mental, and social consequences of substance use. Women also carry additional unique risks during pregnancy because of the effect on neonates. In addition, they have certain gender-specific cancer risks. Given this and the declining age of initiation of substance use in women, prevention and treatment efforts especially geared toward women (eg, education of all medical and paramedical staff, screening in primary care clinics, detection of drug use early in pregnancy or before conception, brief interventions and treatment programs that integrate women's needs) are exceedingly important to stop and ultimately reverse this growing trend.

Adolescent↗

PubMed2003

The psychological impact of cancer on patients' partners and other key relatives: a review.

Partners and other family members are key supports for cancer patients. Most cope well with the caregiving role, but an important minority become highly distressed or develop an affective disorder. Female carers and those with a history of psychiatric morbidity are more vulnerable, as are those who take a more negative view of the patient's illness and its impact on their lives. Carers are likely to become more distressed and develop psychiatric morbidity as the illness advances and treatment is palliative. Carers are also more at risk when they lack a support network of their own and when there are relationship difficulties with the patient. The review discusses why, given this evidence, carers fail to take advantage of interventions designed to help them and those who participate derive only limited psychological benefits.

Adaptation, Psychological↗

PubMed1994

[p53: an important or most overvalued tumor gene?].

Mutations in the tumour-suppressor gene p53 are the most frequent molecular alterations detected in human tumours. p53 protein, which has been called "guardian of the genome", seems to play a key role in cellular DNA repair. Loss of p53 protein function by genetic mutation thereby makes the cell vulnerable to DNA damage, and disposes it to malignant transformation. In different human tumour types the prognostic relevance of p53 alterations is quite variable: While there is evidence of poor prognosis in breast cancer carrying p53 alterations, no such prognostic correlation could be found in low grade astrocytic gliomas. In both tumour types p53 mutations are equally frequent. Malignant transformation is considered a multistep process, and p53 mutations occur at different positions in this cascade in different tumour types. While p53 mutations seem to be an early event in astrocytic gliomas, they affect e.g. colon tumours rather late, during malignant progression from adenoma to carcinoma. These observations underscore the biological importance of p53 mutations in human tumour formation, even if the simple investigation for a prognostic relevance may lead to different results in tumours of different tissues.

Astrocytoma↗

PubMed2004

The influence of socio-economic and locational disadvantage on patterns of surgical care for lung cancer in Western Australia 1982-2001.

OBJECTIVE: Patterns of in-hospital surgical care for lung cancer in Western Australia were examined, including the effects of demographic, locational and socio-economic disadvantage and the possession of private health insurance, on the likelihood of receiving surgery. PATIENTS AND METHODS: The WA Record Linkage Project was used to extract hospital morbidity, cancer and death records of all people with lung cancer in Western Australia from 1982 to 2001. The likelihood of receiving lung cancer surgery was estimated, after adjustment for co-variates, using logistic regression. RESULTS: Overall, 16% of patients received surgery for their lung cancer, although this varied according to histology. Patients who received surgery were typically younger, female, non-indigenous and had less comorbidity. Patients from socio-economically disadvantaged groups tended to be less likely to receive surgery (OR 0.79; 95% CI 0.61-1.04) although this was not significant for each category of disadvantage. Those who had their first hospital admission, with a mention of lung cancer, in a rural hospital were less likely to receive surgery (OR 0.26; 95% CI 0.19-0.36) than those in metropolitan hospitals, although residential location generally had less effect (OR 0.36; 95% CI 0.14-0.92). Patients admitted as a private patient either to a private or public hospital for their first mention of lung cancer had increased likelihood of receiving surgery (OR 1.15; 95% CI 1.02-1.30); however first admission to a private hospital had no effect (OR 0.99: 95% CI 0.85-1.16). CONCLUSION: The utilisation of lung cancer surgery was low with several factors found to affect the rate. Patients from socio-economically or locationally disadvantaged backgrounds, indigenous patients or patients without private health insurance were less likely to receive lung cancer surgery than those from more advantaged groups.

Comorbidity↗

PubMedDate not supplied

Predictors of quality of life in women with a bilateral prophylactic mastectomy.

The purpose of this study was to assess the quality of life in women who had previously undergone a bilateral prophylactic mastectomy and to determine what factors predict quality of life in this population. Women in Ontario who had undergone prophylactic mastectomy between 1991 and 2000 were asked to complete several questionnaires that assessed current psychosocial functioning, including the Quality of Life Index (QLI). The mean score for the QLI was 23.34 (range 9.53-30.00). QLI scores were negatively correlated with cancer-related distress, body image difficulties, and psychological distress. Conversely, QLI scores were positively correlated with social support. Significant predictors of quality of life included psychological distress and one subscale of body image (vulnerability). Vulnerability and psychological distress are important predictors of quality of life in women who have previously undergone bilateral prophylactic mastectomy.

Adult↗

PubMed2004

Oral mucosal and osseous disorders in frail elders.

OBJECTIVE: This paper reviews the implications of frailty for oral health in old age due to the incidence of oral pathoses following on mucosal atrophy, tooth loss, trauma from dentures, polypharmacy, malnutrition, salivary disorders, degeneration of jawbone and cancer. BACKGROUND: Frailty as a condition of old age occurs when elders have energy levels below a critical threshold, or when the social or cultural environment is limited. RESULTS: Frail elders are particularly vulnerable to pathoses, but not simply because of old age per se. Oral diseases accompanying frailty are due to a complicated mixture of biopsychosocial changes that accompany old age. CONCLUSIONS: Management of oral mucosal and osseous disorders in frail elders requires an understanding of the changes that occur with advancing age.

Aged↗