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Query: UMLS:C0392674 (exhaustion)
 13,658 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cellular senescence prevents the proliferation of cells at risk for neoplastic transformation. Nonetheless, the senescence response is thought to be antagonistically pleiotropic and thus contribute to aging phenotypes, including, ironically, late life cancers. The cancer-promoting activity of senescent cells is likely due to secreted molecules, the identity of which remains largely unknown. Here, we have shown that senescent fibroblasts, much more than presenescent fibroblasts, stimulate tumor vascularization in mice. Weakly malignant epithelial cells co-injected with senescent fibroblasts had larger and greater numbers of blood vessels compared with controls. Accordingly, increased vascular endothelial growth factor (VEGF) expression was a frequent characteristic of senescent human and mouse fibroblasts in culture. Importantly, conditioned medium from senescent fibroblasts, more than medium from presenescent cells, stimulates cultured human umbilical vein endothelial cells to invade a basement membrane, a hallmark of angiogenesis. Increased VEGF expression was specific to the senescent phenotype and increased whether senescence was induced by replicative exhaustion, overexpression of p16(Ink4a), or overexpression of oncogenic RAS. The senescence-dependent increase in VEGF production was accompanied by very little increase in hypoxic-inducible (transcription) factor 1 alpha protein levels, and hypoxia further induced VEGF in senescent cells. This result suggests the rise in VEGF expression at senescence is not a hypoxic response. Our findings may in part explain why senescent cells stimulate tumorigenesis in vivo and support the idea that senescent cells may facilitate age-associated cancer development by secreting factors that promote malignant progression.
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PMID:Secretion of vascular endothelial growth factor by primary human fibroblasts at senescence. 1688 Feb 8

While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient- and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked. Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macula-degeneration, Alzheimer's and Parkinson's diseases. Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, 'wear and tear', Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.
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PMID:Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. 1701 37

Cancer-related fatigue (CRF) is a highly prevalent and debilitating symptom experienced by most cancer patients during, and often for considerable periods after, treatment. This symptom affects patients' overall quality of life and is characterized by persistent exhaustion and a decreased capacity to perform daily social and cognitive tasks. CRF is also one of the most commonly reported side effects of cancer and cancer treatments, including surgery, chemotherapy, radiotherapy, hormonal therapy, and biologic response modification therapy. Pharmacologic methods for treating CRF are not always reliable, and many patients continue to experience this symptom following pharmacologic interventions. Managing CRF is of importance to oncology researchers and clinical service providers. As of March 15, 2006, 76 National Institutes of Health sponsored studies examining CRF were actively recruiting subjects, and 15% of these studies were being conducted through the National Cancer Institute (NCI) Community Clinical Oncology Program (CCOP). This article will provide a description of-the NCI CCOP, its functions, and a brief overview of ongoing research on CRF both at our institution and other locations across the United States.
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PMID:Community-based clinical oncology research trials for cancer-related fatigue. 1713 69

While cisplatin and carboplatin are active versus most common cancers, epithelial malignancies are incurable when metastatic. Even if an initial response occurs, acquired resistance due to mutations and epigenetic events limits efficacy. Resistance may be due to excess of a resistance factor, to saturation of factors required for tumor cell killing, or to mutation or alteration of a factor required for tumor cell killing. Platinum resistance could arise from decreased tumor blood flow, extracellular conditions, reduced platinum uptake, increased efflux, intracellular detoxification by glutathione, etc., decreased binding (e.g., due to high intracellular pH), DNA repair, decreased mismatch repair, defective apoptosis, antiapoptotic factors, effects of several signaling pathways, or presence of quiescent non-cycling cells. In lung cancer, flattening of dose-response curves at higher doses suggests that efficacy is limited by exhaustion of something required for cell killing, and several clinical observations suggest epigenetic events may play a major role in resistance.
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PMID:Mechanisms of resistance to cisplatin and carboplatin. 1733 87

We worked out an experimental protocol able to purge the stem cell compartment of the SH-SY5Y neuroblastoma clone. This protocol was based on the prolonged treatment of the wild-type cell population with either hypoxia or the antiblastic etoposide. Cell fate was monitored by immunocytochemical and electrophysiologic (patch-clamp) techniques. Both treatments produced the progressive disappearance of neuronal type (N) cells (which constitute the bulk of the tumor), leaving space for a special category of epithelial-like substrate-adherent cells (S(0)). The latter represent a minimal cell component of the untreated population and are endowed with immunocytochemical markers (p75, c-kit, and CD133) and the electrophysiologic "nude" profile, typical of the neural crest stem cells. S(0) cells displayed a highly clonogenic potency and a substantial plasticity, generating both the N component and an alternative subpopulation terminally committed to the fibromuscular lineage. Unlike the N component, this lineage was highly insensitive to the apoptotic activity of hypoxia and etoposide and developed only when the neuronal option was abolished. Under these conditions, the fibromuscular progeny of S(0) expanded and progressed up to the exhaustion of the staminal compartment and to the extinction of the tumor. When combined, hypoxia and etoposide cooperated in abolishing the N cell generation and promoting the conversion of the tumor described. This synergy might mirror a natural condition in the ischemic areas occurring in cancer. These results have relevant implications for the understanding of the documented tendency of neuroblastomas to regress from a malignant to a benign phenotype, either spontaneously or on antiblastic treatment.
Cancer Res 2007 Mar 15
PMID:Purging of the neuroblastoma stem cell compartment and tumor regression on exposure to hypoxia or cytotoxic treatment. 1736 56

Exercise and digestive processes are known to elevate the metabolic rate of organisms independently. In this study, the effects of simultaneous exercise and digestion were examined in the graceful crab Cancer gracilis. This species exhibited resting oxygen uptake levels between 29 and 42 mg O(2) kg(-1) h(-1). In postprandial crabs, oxygen uptake was approximately double that of unfed crabs. During exercise, oxygen uptake increased three- to fourfold, reaching maximal levels of more than 130 mg O(2) kg(-1 ) h(-1). However, there was no difference in oxygen uptake during activity between unfed and postprandial animals. There was also no difference in exercise endurance levels between unfed and postprandial animals; both sets of animals were unable to right themselves after being turned on their backs, reaching exhaustion after 13-15 attempts. To determine whether increased activity affected gastric processes, the passage of a meal through the digestive system was followed using a fluoroscope. Passage of digesta through the gut system was slower in active animals than in resting crabs. Resting crabs cleared the foregut after approximately 18 h, which was significantly faster than the 34.5 h for constantly active animals. Likewise, the midgut region of resting animals was cleared at a faster rate than that of active animals. Because of residual amounts of digesta remaining in the hindgut, no difference in clearance rates of this section of the gut was evident. The slower clearance times of the foregut were due to a significantly slower rate of mastication of food, as evidenced by a lower cardiac stomach contraction rate. Contraction of the pyloric region of the foregut functions to move the digesta along the midgut, and there was a direct correlation between slower contraction rates of this region and the increased time of passage for digesta through the midgut of active animals. Because increased activity levels affected gastric processing, the crabs exhibited a behavioral response. During a 24-h period after feeding, there was a significant reduction in locomotor activity. The findings of this study suggest a prioritization of metabolic responses toward activity at the expense of digestion. This is discussed in relation to the ability of the crabs to balance the demands of competing physiological systems.
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PMID:The interactive effects of exercise and feeding on oxygen uptake, activity levels, and gastric processing in the graceful crab Cancer gracilis. 1739 Feb 89

In 1941 Huggins and Hodges published for the first time the favorable effects of surgical castration and estrogen treatment on the progression of metastatic prostate cancer. However, this hormonal therapy is not without side effects. Since this pioneering milestone in history of prostate cancer, a further tremendous innovation did not take place. Today, due to intensive clinical, biochemical, nuclear-biological and molecular-biological research, many hormone active treatment variations are available. Besides traditional hormonal therapy, surgical or chemical castration, maximal androgen blockade, nontraditional forms of hormonal therapy, intermittent hormonal therapy, antiandrogens, 5-alpha-reductase inhibitors, and their combinations, we discuss options toward creating an increased number of side effect-oriented offers of hormonal treatment options, guaranteeing a longer and more comfortable exhaustion of the individual hormonal period of response and probably a longer survival. The prerequisite is a closer-than-ever monitoring by tumor marker and an early observation of symptomatic changes.
Recent Results Cancer Res 2007
PMID:The role of hormonal treatment in prostate cancer. 1743 62

Gene transfer into hematopoietic stem cells (HSC) provides a potential means of correcting monogenic defects and altering drug sensitivity of normal bone marrow to cytotoxic agents. These applications have significant therapeutic potential but the translation of successful murine studies into human therapies has been hindered by low gene transfer in large animals (including humans), and recent serious side effects in a human immunodeficiency trial related to insertional mutagenesis. The latter trial, along with other subsequent trials, while bringing into focus the potential risks of integrating vector systems, also clearly demonstrate the potential usefulness of in vivo selection as it relates to inefficient stem cell transduction. Developing from initial studies by our group and other investigators in which drug resistance was utilized to demonstrate the feasibility of using gene transfer to effect protection from myelotoxicity of chemotherapeutic agents, expression of mutant forms of O(6)-methyguanine-DNA-methytransferase (MGMT) coupled with the simultaneous use of pharmacologic inhibitors and chemotherapeutic agents has been shown to provide a powerful method to select HSC in vivo. While stem and progenitor cell protection and resulting selection in vivo has potential applications for the treatment of selected cancers (allowing dose escalation) and for correction of monogenic disease (allowing an iatrogenic survival advantage of transduced cells in vivo), such an in vivo selection may have untoward effects on stem cell behavior. These deleterious effects may include stem cell exhaustion; lineage skewing; accumulation of genotoxic lesions; and clonal dominance driven towards a pro-leukemic phenotype. Knowledge of the likelihood of such deleterious events occurring as well as their potential implications will be critical to future clinical applications and may also enhance our understanding of both normal stem cell behavior and the evolution of hematopoietic malignancies.
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PMID:Live and let die: in vivo selection of gene-modified hematopoietic stem cells via MGMT-mediated chemoprotection. 1748 93

The enzyme telomerase counteracts telomere loss in proliferating cells and extends their capacity for replication. The importance of telomerase is highlighted by the award of the 2006 Albert Lasker Prize for Basic Medical Research for its discovery. Malignant cells subvert telomerase induction to their advantage, and up-regulation of this enzyme confers these populations with unlimited proliferative potential with obvious detrimental consequences. However this enzyme is also essential for the lifelong maintenance of normal cell populations that have a high rate of turnover. Thymic involution in early adulthood dictates that memory T cell populations have to be maintained by continuous proliferation. This highlights the inherent paradox that telomerase down-regulation in T cells may protect against malignancy yet also lead to replicative exhaustion of repeatedly activated memory T cells. In this article, we review the data on telomerase regulation in T lymphocytes and the implications this has for the maintenance of T cell memory.
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PMID:Telomerase in T lymphocytes: use it and lose it? 1751 11

Recent empirical studies revealed that fostering patients' perception of meaning in their life is an essential task for palliative care clinicians. However, few studies have reported the effects of training programs for nurses specifically aimed at improving skills to relieve the meaninglessness of terminally ill cancer patients, and we have had no specific measurement instruments. The primary aims of this study were 1) to validate measurement tools to quantify nurses' self-reported practice and attitudes toward caring for terminally ill cancer patients feeling meaninglessness and 2) to explore the effects of the five-hour educational workshop focusing on meaninglessness on nurses' self-reported practice, attitudes toward caring for such patients, confidence, burnout, death anxiety, and meaning of life. A quasi-experimental pre-post questionnaire survey was performed on 147 nurses. The questionnaire was distributed before the intervention workshop and one and six months after. The workshop consisted of lecture, role-play, and the exercise of assessment and care planning based on two vignette verbatim records. First, using the first questionnaire sample and an additional sample of 20 nurses for the test-retest examination, we validated a six-item Self-Reported Practice scale, and an eight-item Attitudes Toward Caring for Patients Feeling Meaninglessness scale with three subscales (Willingness to Help, Positive Appraisal, and Helplessness). The nurses also completed a scale to assess confidence in caring for terminally ill patients with meaninglessness, the Maslach Burnout Inventory, the Death Attitude Inventory, the Frommelt Attitudes Toward Care of the Dying scale, the Self-Reported Practice Score in General Communication, and the three pain-related items from the Palliative Care Quiz for Nursing. For the Self-Reported Practice scale and the subscales of the Attitudes Toward Caring for Patients Feeling Meaninglessness scale, the Cronbach's alpha coefficients were 0.63-0.91, and the intra-class correlations were 0.89-0.94. The Self-Reported Practice scale significantly, but moderately, correlated with the Self-Reported Practice Score in General Communication (P=0.41). The Willingness to Help and Helplessness subscales significantly but weakly correlated with the Frommelt scale (P=-0.27, 0.21). Both scales did not correlate or minimally correlated with the Palliative Care Quiz for Nursing (P<0.20). The construct validity was confirmed using factor analysis. At the follow-up, of 147 nurses who participated in this workshop, 91 (62%) and 80 (54%) nurses responded. Self-reported practice and confidence significantly improved, whereas helplessness, emotional exhaustion, and death anxiety significantly decreased. The percentages of nurses who evaluated this program as "useful" or "very useful" were 79% (to understand the conceptual framework in caring for terminally ill patients with meaninglessness), 73% (to help in self-disclosing nurses' personal beliefs, values, and life goals), and 80% (to help in learning how to provide care for patients with meaninglessness). The Self-Reported Practice scale and the Attitudes Toward Caring for Patients Feeling Meaninglessness scale are reliable and valid tools to specifically quantify nurses' self-reported practice and attitudes toward caring for terminally ill cancer patients feeling meaninglessness of life. The five-hour workshop appeared to have a modest but significant beneficial effect on nurse-reported practice, attitudes, and confidence in providing care for terminally ill cancer patients feeling meaninglessness. Further educational intervention trials with control groups are promising.
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PMID:Meaninglessness in terminally ill cancer patients: a validation study and nurse education intervention trial. 1754 50


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