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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DC) either induce T cell tolerance or contribute to the initiation and modulation of T and B cell responses. Since many of the variables determining the thresholds of naive T cell priming were defined in vitro using a homogeneously matured DC population, we here focused on partially mature DC which might reflect the occurrence of tumor-infiltrating and thymic DC. To predict how those DC regulate the induction of antigen-specific T cell proliferation and T cell tolerance, we co-cultured ovalbumin-pulsed murine DC at different ratios with antigen-specific DO11.10 transgenic T cells. Whereas partially mature DC at a DC/T cell ratio of 1:10 supported proliferation, a DC/T cell ratio of 1:2 induced proliferation arrest in naive CD4+ T cells. The acquisition of the NK cell inhibitory markers NK1.1 and KLRG on T cells exposed to high numbers of DC suggests a role for these molecules in the protection of antigen-responsive T cells from exhaustion by overstimulation. Mechanistically, abortive T cell proliferation upon encounter of high numbers of partially mature DC is caused by an apoptosis-related pathway, suggesting that excessive antigen density without sufficient costimulation results in activation-induced cell death.
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PMID:The ratio between dendritic cells and T cells determines the outcome of their encounter: proliferation versus deletion. 1618 Feb 53

The greatest risk factor for developing carcinoma of the prostate is advanced age. Potential molecular and physiologic contributors to the frequency of cancer occurrence in older individuals include the accumulation of somatic mutations through defects in genome maintenance, epigenetic gene silencing, oxidative stress, loss of immune surveillance, telomere dysfunction, chronic inflammation, and alterations in tissue microenvironment. In this context, the process of prostate carcinogenesis can be influenced through interactions between intrinsic cellular alterations and the extrinsic microenvironment and macroenvironment, both of which change substantially as a consequence of aging. In this study, we sought to characterize the molecular alterations that occur during the process of prostate fibroblast senescence to identify factors in the aged tissue microenvironment capable of promoting the proliferation and potentially the neoplastic progression of prostate epithelium. We evaluated three mechanisms leading to cell senescence: oxidative stress, DNA damage, and replicative exhaustion. We identified a consistent program of gene expression that includes a subset of paracrine factors capable of influencing adjacent prostate epithelial growth. Both direct coculture and conditioned medium from senescent prostate fibroblasts stimulated epithelial cell proliferation, 3-fold and 2-fold, respectively. The paracrine-acting proteins fibroblast growth factor 7, hepatocyte growth factor, and amphiregulin (AREG) were elevated in the extracellular environment of senescent prostate fibroblasts. Exogenous AREG alone stimulated prostate epithelial cell growth, and neutralizing antibodies and small interfering RNA targeting AREG attenuated, but did not completely abrogate the growth-promoting effects of senescent fibroblast conditioned medium. These results support the concept that aging-related changes in the prostate microenvironment may contribute to the progression of prostate neoplasia.
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PMID:The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. 1642 11

Dysregulated T-cell-mediated immunity contributes materially to the increased susceptibility to infectious disease, and possibly cancer, in the elderly. One hallmark of this state of "immunosenescence" in humans is the predominance of large clones of peripheral T cells with limited antigen receptor heterogeneity and a corresponding contraction of diversity in the T-cell antigen recognition repertoire. Surprisingly, a major driving force for these clonal expansions in humans is cytomegalovirus. The lifelong chronic antigenic stress caused by infection with this persistent activating virus results in clonal exhaustion of specific CD8 T cells, and their acquisition of a state of anergy and apoptosis resistance similar in many respects, and, the authors believe for similar reasons, to that commonly seen in the tumor-specific T cells of cancer patients. This excess of dysfunctional cells is indirectly immunosuppressive by filling the "immunologic space" and shrinking the T-cell repertoire for new antigens, as well as directly suppressive via cytokine secretion. It is associated with the "immunologic risk profile" predicting 2- and 4-year mortality in longitudinal studies of very old people. Therefore, it is hypothesized that deletion of such accumulations of dysfunctional cells would be beneficial to the individual. It may be possible to distinguish functional CMV-specific cells (which are essential to maintain immunosurveillance) from dysfunctional ones by their expression of certain surface molecules. This, coupled with methods directed at reinvigorating the thymus (e.g., use of interleukin 7), and targeting CMV by pharmacologic and immunotherapeutic interventions might result in a degree of "immunorejuvenation" sufficient to take elderly individuals out of the risk category and thereby extend healthy longevity.
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PMID:Immunorejuvenation in the elderly. 1660 7

A spontaneous case of renal tumor was observed in a 7-year-old ovariectomized female pet ferret (Mustela putorius furo). Clinical signs included exhaustion, emaciation, anorexia, and stooping position. At necropsy, a solid and cystic mass replaced the left kidney and adrenal gland. The tumor was composed of pleomorphic epithelial cells with a large number of giant cells. Metastases were recognized in the lung, liver, greater omentum, right renal pelvis, and systemic lymph nodes. Immunohistochemical stains revealed that the tumor cells were positive for CD10, cytokeratin (CAM 5.2), and Ki-67 (MIB-1). On the basis of morphologic and immunohistochemical features, the tumor was diagnosed as a pleomorphic renal adenocarcinoma. This type of neoplasm is very rare in all species and has never been reported in a ferret.
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PMID:Renal adenocarcinoma in a ferret. 1667 82

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

Cerebral edema is a life-threatening condition that develops as a result of an inflammatory reaction. Most frequently, this is the consequence of cerebral trauma, massive cerebral infarction, hemorrhages, abscess, tumor, allergy, sepsis, hypoxia, and other toxic or metabolic factors. At present, the following types of cerebral edema are differentiated: the vasogenic cerebral edema resulting from an increased permeability of the endothelium of cerebral capillaries to albumin and other plasma proteins; the cytotoxic cerebral edema resulting from the exhaustion of the energy potential of cell membranes without damage to the barrier; the hydrostatic cerebral edema resulting from disturbance of the autoregulation of cerebral blood circulation; the osmotic cerebral edema resulting from dilution of blood; and the interstitial cerebral edema resulting from acute hydrocephaly. Some authors also differentiate ischemic cerebral edema. At present, when various traumas and traumatic cerebral injuries are frequent causes of death in young people, treatment strategy for cerebral edema is of utmost importance. Monitoring of the patient's condition in the intensive care unit is a necessity. It is important to ensure proper positioning of the patient--the head should be tilted at 30 degrees in order to optimize the cerebral perfusion pressure and control of the increase in intracranial pressure. Hyperventilation should be applied. Controlled hypothermia decreases the rate of metabolism in the brain. Slightly positive fluid balance should be maintained using crystalloid or colloid (hypertonic-hyperoncotic) solutions, at the same time maintaining cerebral perfusion pressure exceeding 70 mmHg. The treatment includes administration of antihypertensive medications, nonsteroidal antiinflammatory drugs, and barbiturates. Steroids decrease the permeability of capillaries and the hemato-encephalic barrier, promoting the movement of Na(+)/K(+) ions and water through the main endothelial membrane, and therefore they are used in the treatment of vasogenic cerebral edema as well as edema caused by a cerebral tumor. Glutamate and N-methyl-D-aspartate receptor antagonists improve cerebral microcirculation and metabolism. Trometamol corrects cerebral acidosis. Extended cerebral edema is treated surgically via a bilateral decompressive craniotomy, sometimes including craniotomy of lateral and posterior fossae. The treatment of cerebral edema is complex, and positive results may be expected only if the diagnosis and the provision of assistance are timely.
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PMID:[Cerebral edema and its treatment]. 1732 53

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

Excessive telomere shortening has been demonstrated in inherited and acquired blood disorders, including aplastic anemia and myelodysplastic syndromes. It is possible that replicative exhaustion, owing to critical telomere shortening in hematopoietic progenitor cells (HPCs), contributes to the development of cytopenias in these disorders. However to date, a direct link between the telomere length (TL) of human HPCs and their proliferative potential has not been demonstrated. In the present investigation, the TL and level of telomerase enzyme activity (TA) detected in cord blood (CB)-derived HPCs was found to predict erythroid expansion (P<0.01 and P=0.01 respectively). These results were corroborated by a correlation between proliferation of erythroid cells and telomere loss (P=0.01). In contrast, no correlations were found between initial TL, telomere loss or TA and the expansion of other myeloid lineage-committed cells. There was also no correlation between TL or TA and the number of clonogenic progenitors, including primitive progenitors derived from long-term culture. Our investigations revealed upregulation of telomerase to tumor cell levels in CD34- cells undergoing erythroid differentiation. Together, these results provide new insight into the regulation of TL and TA during myeloid cell expansion and demonstrate that TL is an important determinant of CB-derived erythroid cell proliferation.
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PMID:Telomere length of cord blood-derived CD34(+) progenitors predicts erythroid proliferative potential. 1734 14

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.
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PMID:Purging of the neuroblastoma stem cell compartment and tumor regression on exposure to hypoxia or cytotoxic treatment. 1736 56

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.
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PMID:The role of hormonal treatment in prostate cancer. 1743 62


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