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Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention.

Free radicals have been implicated in over a hundred disease conditions in humans, including arthritis, hemorrhagic shock, atherosclerosis, advancing age, ischemia and reperfusion injury of many organs, Alzheimer and Parkinson's disease, gastrointestinal dysfunctions, tumor promotion and carcinogenesis, and AIDS. Antioxidants are potent scavengers of free radicals and serve as inhibitors of neoplastic processes. A large number of synthetic and natural antioxidants have been demonstrated to induce beneficial effects on human health and disease prevention. However, the structure-activity relationship, bioavailability and therapeutic efficacy of the antioxidants differ extensively. Oligomeric proanthocyanidins, naturally occurring antioxidants widely available in fruits, vegetables, nuts, seeds, flowers and bark, have been reported to possess a broad spectrum of biological, pharmacological and therapeutic activities against free radicals and oxidative stress. We have assessed the concentration- or dose-dependent free radical scavenging ability of a novel IH636 grape seed proanthocyanidin extract (GSPE) both in vitro and in vivo models, and compared the free radical scavenging ability of GSPE with vitamins C, E and beta-carotene. These experiments demonstrated that GSPE is highly bioavailable and provides significantly greater protection against free radicals and free radical-induced lipid peroxidation and DNA damage than vitamins C, E and beta-carotene. GSPE was also shown to demonstrate cytotoxicity towards human breast, lung and gastric adenocarcinoma cells, while enhancing the growth and viability of normal human gastric mucosal cells. The comparative protective effects of GSPE, vitamins C and E were examined on tobacco-induced oxidative stress and apoptotic cell death in human oral keratinocytes. Oxidative tissue damage was determined by lipid peroxidation and DNA fragmentation, while apoptotic cell death was assessed by flow cytometry. GSPE provided significantly better protection as compared to vitamins C and E, singly and in combination. GSPE also demonstrated excellent protection against acetaminophen overdose-induced liver and kidney damage by regulating bcl-X(L) gene, DNA damage and presumably by reducing oxidative stress. GSPE demonstrated excellent protection against myocardial ischemia-reperfusion injury and myocardial infarction in rats. GSPE was also shown to upregulate bcl(2) gene and downregulate the oncogene c-myc. Topical application of GSPE enhances sun protection factor in human volunteers, as well as supplementation of GSPE ameliorates chronic pancreatitis in humans. These results demonstrate that GSPE provides excellent protection against oxidative stress and free radical-mediated tissue injury.

Animals↗

Applicability of macro- and microradiography in diagnosis of malignant neoplasms infiltrating the jaw bones.

The subject of this paper is the evaluation of the applicability of structural jaw and mandible radiograms in diagnosing malignant neoplastic processes infiltrating the osseous tissue. The material studied comprised 20 patients treated surgically due to neoplasms of the faciocranium. The group investigated consisted of 17 males, aged 35--65 years and three females 45--60 years old. The most numerous group of neoplasms was composed of cancers: 18 patients; the remaining two were fibrosarcomas. For structural radiographs fine grained films and folialess cassettes were used, with soft X-rays being applied for irradiating the preparations. The radiograms were prepared by means of X-ray apparatus with a small focal lamp with a diameter of 0.3 mm, and with the point-focal apparatus. On the basis of analyses covering 24 macroradiograms and 71 microradiograms, criteria for estimating the malignant infiltration of the bone were established. The possibility of practical applicability of these investigations during intraoperative evaluation of the clinically suspicious bone segments has been emphasized.

Adult↗

[Efficacy of immunotherapy in the treatment of asthma].

Specific immunotherapy consists of the administration of allergen extracts to patients with allergic disease to achieve clinical tolerance to the causative allergens. Currently, it is the only etiologic treatment for respiratory allergy. A World Health Organization opinion paper published in 1997 defines immunotherapy as "the only form of treatment able to modify the natural course of allergic diseases". In patients with allergic rhinitis, several studies suggest that immunotherapy can modify the natural history of respiratory allergy by preventing the development of asthma in children with this disease. Numerous studies demonstrate its efficacy in IgE-mediated asthma and particularly in mild-to-moderate asthma. When complete avoidance of the allergen cannot be achieved with measures that allow the patient to lead a normal life, pharmacological treatment can help to control symptoms, but symptoms immediately return when treatment is interrupted. However, asthma care can be improved by allergen-specific treatment; immunotherapy may shift the immune response from an allergic pattern toward a more protective response, producing persistent improvement with reduction of symptoms and the need for pharmacological treatment. Numerous comparative studies with specific immunotherapy vs. placebo or pharmacological treatment have demonstrated the efficacy of this treatment and its advantages in control of the disease. Specific immunotherapy induces favorable clinical, biological and functional modifications in the course of allergic asthma. Significant improvement in clinical manifestations has been demonstrated, even with levels of allergen exposure higher than those at the beginning of treatment. This improvement is associated with a reduced need for antiinflammatory and bronchodilator treatment. Moreover, specific bronchial reactivity shows a clear improvement with disappearance of delayed response and a clear increase in the threshold for immediate response to the allergen. Reduction in nonspecific bronchial hyperreactivity and improvement in exercise-induced asthma are also observed. Several studies recommend an optimal duration of specific immunotherapy for allergic asthma of between 3 and 5 years to achieve maximal therapeutic efficacy. A direct relationship between treatment duration and the persistence of its effects has been observed. Moreover, the treatment is more effective when started early. The possible adverse effects related to systemic reactions should be borne in mind. Although these effects are infrequent, maximal precautions should be taken when administering this treatment. Immunotherapy is contraindicated in cases of severe asthma, heart disease, autoimmune disease and associated severe neoplastic processes. However, all the beneficial effects of immunotherapy are conditioned by an accurate and early etiological diagnosis confirming the causative allergen. The availability of high-quality allergen extracts is essential to obtain the desired effect. Inappropriate patient selection for this treatment is the main cause of its failure. The integral treatment of allergic asthma includes environmental measures, patient education, pharmacological treatment and, whenever possible, immunotherapy.

Adult↗

Nitroxides and malignant human tissues: electron spin resonance in colorectal neoplastic and healthy tissues.

Healthy and neoplastic colorectal human tissues of as many as 12 patients have been studied, immediately after surgery, by electron spin resonance (ESR) of stable nitroxides at physiological temperature. Cells were maintained in a living state using the McCoy's 5A culture medium. The very low concentration changes of hydrophilic and lipophilic nitroxides allowed us to establish that the response to the oxidative stress induced by the occurrence of nitroxides in healthy and tumor cells was very weak, thus suggesting these compounds are good candidates for contrast enhancement agents in magnetic resonance imaging of colorectal tumor. The analysis of the computed ESR line shape of lipophilic nitroxides in both healthy and malignant cells of the same patient agreed for an unmodified physical status of the membranes where they were mainly localized. The results reported here proved that the comparison between ESR results must be made in tissues from the same patient and that the physical status of the membranes depended more on the patient history than on changes in the colorectal cell membrane fluidity induced by the neoplastic process.

Aged↗

Immunohistochemical analysis of the distribution of a breast tumor associated antigen recognized by a monoclonal antibody.

A new monoclonal antibody (MoAb), MM 1-80, recognizing a tumor associated epitope of a breast high molecular weight mucin molecule was tested, using the avidin biotin immunoperoxidase method on normal and pathological mammary tissues. The normal mammary ducts and lobules were negative. Fibroadenomas showed a strong intracytoplasmic staining. In apocrine metaplasia, adenosis, and papillomatosis, scattered cells showed intracytoplasmic, luminal border or secretion reactivity. In lobular and ductal hyperplasia the cells showed intracytoplasmic immunoreactivity which, however, became more intense and homogeneous in atypical lesions, i.e. lobular and ductal in-situ carcinomas. The infiltrating carcinomas of different histotype expressed positivity on 98% of the cases (113/115) and axillary metastatic lymph nodes were always positive (20/20). The MoAb was tested on 175 human neoplasias of different origin which were in the majority of the cases negative with the exception of adenocarcinomas of the lung, ovary and bladder. MM1-80 appears to react preferentially with mammary cells undergoing hyperplastic, metaplastic and neoplastic processes. The 1-80 epitope distribution is different in these lesions starting with a predominant luminal expression in benign lesions and becoming strong and cytoplasmic in the malignant breast cell.

Adult↗

Stages in the evolution of squamous cell carcinoma of the uterine cervix: a critique of the concepts of "dysplasia" and "cancer".

A clinically detectable, frankly invasive, squamous cell carcinoma of the uterine cervix evolves through a series of step-like stages, at any one of which, except the last, its progress can be arrested. These stages are intraepithelial neoplasia, early stromal invasion, microcarcinoma and, eventually and irreversibly, invasive squamous cell carcinoma. Crucial to this concept of a series of plateaus in tumour development is the recognition that "dysplasia" is a differentiated intraepithelial neoplasm and the discarding of the term "cancer" in favour of the less emotionally loaded expression "neoplastic process".

Carcinoma, Squamous Cell↗

Hodgkin and non-Hodgkin lymphoma involving bone marrow.

The role of bone marrow examination in diagnosis and staging of patients with Hodgkin lymphoma, B-non-Hodgkin lymphoma, and T-non-Hodgkin lymphoma is reviewed. Optimal routine and specialized bone marrow examination techniques are discussed. The salient morphologic, immunophenotypic, and genetic features of mature and immature B, T neoplasms and classic Hodgkin lymphoma in bone marrow are delineated, along with recommendations to distinguish these overt neoplasms from non-neoplastic processes.

Biopsy↗

Diseases of the abdomen.

Because the abdomen of the adult horse is too thick to obtain good-quality radiographs, diagnostic ultrasound is a particularly valuable imaging modality in the diagnosis of abdominal disease. The size, shape, position, and texture of the liver, spleen, kidneys, urinary bladder, gravid uterus, and gut wall can be determined by scanning the abdominal surface. The presence or absence of abdominal fluid can be determined efficiently. Gut motility as well as ileus secondary to peritonitis or obstruction can be assessed. Suspected adhesions of the bowel can often be documented, and primary or secondary neoplastic processes can be identified and biopsied.

Abdomen↗

Environment, genome and cancer.

Cancer is one of the most serious diseases that threaten human being today. To some degree, it is a genetic disease but environmental and other nongenetic factors clearly play a role in many stages of neoplastic process. Genetic factors by themselves are thought to explain only about 5% of all cancer. The remainder can be attributed to external, 'environment' factors that act in conjunction with both genetic and acquired susceptibility. Of note, part of the susceptibility is owing to the variety of human genome. So, environment, human genome and cancer have much to do with each other. Combining all of the information from epidemiology and from research works in laboratory with policy-making and clinical works, purifying the environment, giving special protection to the high risk population, the mortality of cancer may decrease gradually in the future.

Carcinogens, Environmental↗

Imaging of the olfactory system.

The olfactory system consists of the primary olfactory nerves in the nasal cavity, the olfactory bulbs and tracts, and numerous intracranial connections and pathways. Diseases affecting the sense of smell can be located both extracranially and intracranially. Many sinonasal inflammatory and neoplastic processes may affect olfaction. Intracranially congenital, traumatic, and neurodegenerative disorders are usually to blame for olfactory dysfunction. The breadth of diseases that affect the sense of smell is astounding, yet the imaging ramifications have barely been explored.

Acquired Immunodeficiency Syndrome↗

Magnetic resonance imaging of the pancreas and biliary tree.

MRI of the pancreas and bile ducts is becoming more widely used due to recent advances in surface coils, breath-hold imaging techniques, and magnetic resonance cholangiopancreatography (MRCP). MRI provides a comprehensive and accurate examination for the detection, staging, and characterization of a variety of developmental, inflammatory, and neoplastic processes that involve the pancreas.

Biliary Tract↗

Candidate tumor suppressor genes at FRA7G are coamplified with MET and do not suppress malignancy in a gastric cancer.

Common fragile sites predispose to specific chromosomal breakage associated with deletion, amplification, and/or translocation in certain forms of cancer. Chromosomal fragile sites not only are susceptible to DNA instability in cancer cells, but may also be associated with genes that contribute to the neoplastic process. FRA7G is a common fragile site containing the candidate tumor suppressor genes CAV1, CAV2, and TESTIN (TES). The human gastric cancer cell line GTL-16 has an amplification of this genomic region and was used to seek evidence for the suppressor candidacy of one of these genes. Our results demonstrate that CAV1, CAV2, and TESTIN are coamplified with the MET oncogene and overexpressed in GTL-16. Somatic mutation was not detected in the coding regions of these genes, although they were each overexpressed. The results show that CAV1, CAV2, and TESTIN are not tumor suppressor genes in this gastric cancer.

Chromosome Fragility↗

Effect of 2 episodes of cryosurgery on carcinogen-treated hamster cheek pouch.

Hamster cheek pouches were treated with the topical carcinogen DMBA for 8 weeks. 2 episodes of cryosurgery, located within the area of previous carcinogen application enhanced the neoplastic process by comparison with matched controls. Comparison with previous studies suggests that the 2 episodes of cryosurgery may have a greater effect in provoking overt malignancy than a single episode of cryosurgery.

9,10-Dimethyl-1,2-benzanthracene↗

The synthesis of ACTH and related peptides by tumours.

Despite all we have learned, the reason why certain tumours and particularly non-pituitary tumours synthesize ACTH remains an enigma. There is no clear theory which links the neoplastic process with the expression of peptide hormones but it is interesting to speculate that the amplification of certain oncogenes may be linked to de-repression of hormone genes. Once the gene has been switched on, there should be some mechanism for preventing continuous expression and in the pituitary the POMC gene is normally inhibited by glucocorticoids. Therefore it is crucial to investigate the role of glucocorticoids in non-pituitary tumours and this requires an understanding of the molecular mechanisms involved in glucocorticoid inhibition of the normal POMC gene in the pituitary. The evidence presented in this chapter describing the glucocorticoid receptor binding site in the promoter region of the POMC gene in rat pituitary gives an exciting insight into the regulatory mechanisms and their potential for aberrant control. Taken with the presence of pituitary-specific regions regulating the POMC gene promoter there appear to be multiple approaches to dissecting out the differences in non-pituitary tumours. Thus in a relatively short period of time there has been a marked increase in our understanding of the molecular mechanisms underlying POMC gene expression. At the level of the peptides, progress has been slower. We are now aware that secretion of ACTH implies that a number of other peptides will be found in the circulation, even though there is limited evidence for a specific role for any of the co-secreted peptides. However, it is hard to understand the conflicting reports that N-POC is synthesized by non-small cell and small cell carcinoma of the lung when ACTH, which we assume to be co-secreted, is thought to be synthesized only by small cell carcinoma. The most likely explanation for this is the difficult nature of the radio-immunoassays for these hormones and the problems associated with studying large groups of clearly defined patients. Development of very simple methods for measuring the ACTH precursors has demonstrated that they are released into the circulation in normal subjects and that the levels are markedly elevated in non-pituitary tumours, suggesting that they are the major circulating forms in the ectopic ACTH syndrome. This implies that these tumours cannot process the precursor molecules suggesting that the processing enzymes are lacking.(ABSTRACT TRUNCATED AT 400 WORDS)

ACTH Syndrome, Ectopic↗

Histone acetylation and cancer.

In the past year, several papers have been published which implicate a link between alterations in chromatin structure and the development of cancer. Both histone hyperacetylation and hypoacetylation appear to be important in the neoplastic process, depending on the target gene involved. In the case of colon cancer, induction of the p21 gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis.

Acetylation↗

Serum levels of intercellular adhesion molecule 1 (ICAM-1) in patients with colorectal cancer: inhibitory effect on cytotoxicity.

A positive correlation between the level of ICAM-1 in serum and the stage of neoplastic processes has been demonstrated. We studied ICAM-1 serum concentration in 27 colorectal cancer patients and investigated the effect of this molecule on cellular aggregation and toxicity. ICAM-1 serum concentration in the group of patients was significantly higher (P < 0.01) than in normal controls and was related to tumour stage. Patient sera inhibited both the formation of cellular aggregates and the percentage of specific lysis, the effect being lost when the serum was depleted of ICAM-1. These results suggest that the release of soluble ICAM-1 may represent a mechanism of tumour escape.

Aged↗

An experimental model of diabetes and cancer in rats.

The aim of this study was to develop an experimental model for the study of cancer associated with diabetes. For diabetes induction, Sprague-Dawley rats were given streptozotocin (STZ, 90 mg/kg body weight (BW), by intraperitoneal injection on the second day of life. For mammary tumour induction, rats were injected with 50 mg/kg BW of N-nitroso-N-methylurea (NMU) at 50, 80 and 110 days old. The neoplastic process and the effect of tamoxifen treatment was examined in non-diabetic and diabetic rats. The latency period, NMU-induced tumour incidence and the number of tumours per rat in diabetic rats versus controls were 117 +/- 7 days versus 79 +/- 9 days (P < 0.001); 93% versus 95% (NS); and 5.2 +/- 1.6 versus 2.7 +/- 0.5 (P < 0.02). A more benign histological pattern for tumours in diabetic animals was observed. Mammary tumours in diabetic rats grew more slowly than in controls. Tamoxifen (1 mg/kg/day) treated diabetic rats showed tumour regression in 67% of NMU-induced mammary tumours versus 53% in controls (NS). Our results show that tumour progression seems to be affected by diabetes in this experimental model. We suggest this is the result of changes to insulin-like growth factors and their receptors, which occur in diabetics, and our future research will examine this hypothesis.

Animals↗

The importance of glucose transport activity as the rate-limiting step of 2-deoxyglucose uptake in tumor cells in vitro.

Glucose transporter (GLUT) expression and hexokinase activity are thought to be related to high [18F]-fluorodeoxyglucose (FDG) uptake in tumor cells, but their relative importance is still unknown. To determine which is the predominant factor in FDG uptake in tumor cells, cultured tumor cell lines and a normal cell line were studied in vitro with respect to 2-deoxyglucose (DG) uptake, hexokinase activity, and the initial uptake rate of 3-O-methylglucose (3-O-MG) transport, which is generally accepted as indicating the amount of GLUT expressed on the plasma membrane. In 16 types of tumor cells and one fibroblast cell line, DG uptake was assessed for 60 min, the initial uptake rate of 3-O-MG transport was measured for 1 min, and total hexokinase activity, including that in the mitochondrial fraction, was determined. Across all 16 tumor cell lines, there was a significant correlation between DG uptake and 3-O-MG transport (p = 0.0012, F test), but not between DG uptake and hexokinase activity. Hexokinase activity of the tumor cells was comparable to that of the human fibroblast cells in the exponential growth phase. Most tumor cells showed higher DG uptake and 3-O-MG transport than the human fibroblast cells. The results suggest that DG uptake of cultured tumor cells is governed by GLUT expression, which may be a distinct characteristic of the neoplastic process.

3-O-Methylglucose↗