Histology and histopathology Vol.21, nº 7 (2006)

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http://hdl.handle.net/10201/177392

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Open Access
Altered patterns of RB expression define groups of soft tissue sarcoma patients with distinct biological and clinical behavior
(Murcia : F. Hernández, 2006) Polsky, D.; Mastorides, S.; Kim, D.; Dudas, M.; Leon, L.; Leung, D.; Woodruff, J.M.; Brennan, M.F.; Osman, I.; Cordon-Cardo, C.
Background: Function of the retinoblastoma tumor suppressor protein (pRB) may be compromised at a genetic level by gene loss or mutation or at a posttranslational level by hyperphosphorylation. In this study, we examined adult soft tissue sarcomas (ASTS) to determine if alterations of pRB were associated with distinct patterns of pRB expression and clinical outcome. Design: We investigated 86 ASTS patients using monoclonal antibodies that distinguish between hyperphosphorylated and underphosphorylated pRB products. We also used microsatellite analysis to investigate the genetic status of the RB locus. We correlated pRB alterations with proliferative activity, and with clinicopathological outcomes. Results: Altered patterns of pRB expression are common in ASTS occurring in 84% of cases, and it is significantly associated with proliferative activity (p<0.001). Patients whose tumors either lack expression of pRB, or express hyperphosphorylated forms of pRB, have poor survivals compared to patients whose tumors exhibit a normal, underphosphorylated pattern of pRB expression (p=0.03). In addition, 63% of cases lacking expression of pRB showed loss-of-heterozygosity at the locus Conclusions: Inactivation of pRB is common in adult STS, which may be due to either gene loss or posttranslational modification, namely hyperphosphorylation. Both mechanisms are associated with tumor cell proliferation and poor survival.
Open Access
Histological recovery of the hepatocytes is based on the redox system upregulation in the animal models of mutant superoxide dismutase (SOD)1-linked amyotrophic lateral sclerosis
(Murcia : F. Hernández, 2006) Kato, Massuo J.; Kato, S.; Abe, Y.; Nishino, T.; Ohama, E.; Aoki, M.; Itoyama, Y.
Histological rescue of superoxide dismutase1 (SOD1)-mutated hepatocytes from mutant SOD1 stress is investigated from the viewpoint of upregulation of the redox system [peroxiredoxin (Prx) and glutathione peroxidase (GPx)]. Histopathological and immunohistochemical studies using antibodies against PrxI/PrxII/GPxI were carried out on specimens from four different strains of animal models of mutant SOD1- linked familial amyotrophic lateral sclerosis (ALS). In the livers of the ALS animal models in the presymptomatic stage without motor neuron loss, both swollen and eosinophilic hepatocytes with vacuolation pathology were observed. After developing motor deficits, this swelling and vacuolation ceased to be apparent. In the terminal stage when severe motor neuron loss was observed, these hepatocytes recovered and appeared normal. In redox system-related immunohistochemical preparations, almost all of the normal hepatocytes expressed the redox system-related enzymes PrxI/PrxII/GPxI. In the presymptomatic stage, some hepatocytes did not express redox system-related enzymes. After clinical onset, over 75% of hepatocytes showed overexpression of PrxI/PrxII/GPxI, i. e., upregulation of the redox system. At the end stage, near normal PrxI/PrxII/GPxI expression was observed again in the hepatocytes. Redox system upregulation in SOD1- mutated hepatocytes rescues hepatocytes from the mutant SOD1 stress that leads to motor neuron death.
Open Access
Histone modifications in status epilepticus induced by Kainate
(Murcia : F. Hernández, 2006) Taniura, H.; Sng, J.C.G.; Yoneda, Y.
Animal models of epilepsy have allowed the determination of the basic molecular and cellular mechanisms of epileptogenesis. Generalized limbic seizures and subsequent status epilepticus can be induced by either pilocarpine, the muscarinic acetylcholine receptor agonist or kainate, the glutamate receptor agonist. There has been increasing interest that chromatin remodeling might play a critical role in gene regulation even in non-dividing cells such as neurons. One form of chromatin remodeling is histone aminoterminal modification that can generate synergistic or antagonistic affinities for the interactions of transcriptional factors, in turn causing changes in gene activity. Two widely studied histone modification processes are histone acetylation and phosphorylation. While histone hyperacetylation indicates an increase in gene activity, its hypoacetylation marks gene repression. Both states are controlled by a dynamic interplay of histone acetyltransferase (HAT) and histone deacetylase (HDAC). We have found the upregulation of acetylation and phosphorylation of histones, coupled with status epilepticus after kainate administration. c-fos and c-jun mRNA have been sequentially induced in response to kainate, in different hippocampal subpopulations starting from the dentate gyrus and spreading to the cornus ammonis regions well correlated with the spatiotemporal distribution of histone H4 hyperacetylation. Both histone modifications are associated with the c-fos gene promoter after kainate stimulation, while only histone acetylation with the c-jun gene. Pretreatment with curcumin, which has a HAT inhibitory activity specific for CBP/p300, attenuates histone modifications, IEGs expression and also the severity of status epilepticus after kainate treatment. Histone modifications may have a crucial role in the development of epilepsy induced by kainate.
Open Access
Cytokeratin-positive subserosal myofibroblasts in gastroduodenal ulcer; another type of myofibroblasts
(Murcia : F. Hernández, 2006) Guo, L.; Kuroda, Naoto; Nakayama, Hiroyuki; Miyazaki, E.; Hayashi, Yoshihiro; Toi, M.; Hiroi, Makoto; Enzan, H.
To investigate the distribution and origin of alpha-smooth muscle actin (ASMA)-positive stromal cells in the perforation of human gastroduodenal ulcers. Perforative lesions of 24 surgically resected gastroduodenal ulcers were examined immunohistochemically for ASMA, HCD, CD34, CD31, CAM5.2 and HMW-CK, and double staining of ASMA and CAM5.2 was also performed. In addition, to determine the cell source of collagen, in situ hybridization of collagen I mRNA was performed. In the normal gastroduodenal wall, the reticular network of CD34-positive stromal cells was identified in the muscularis mucosa, submucosa, muscular propria, and subserosa. In the subepithelial area, many myofibroblasts were observed, whereas no CD34- positive stromal cells were seen. In areas neighboring ulcerative lesions, no CD34-positive stromal cells were observed, but a significant number of myofibroblasts were present there. In the deep layer of ulceration, numerous fusiform or stellate stromal cells strongly positive for ASMA and CAM5.2 were observed in the subserosal area around the perforation. In the same site, many cells co-expressing ASMA and CAM5.2 were identified by double staining. In contrast, in the surface layer of ulceration, stromal cells expressing only ASMA were observed. The cytokeratin-positive subserosal myofibroblastic cell in human gastroduodenal ulcer is a novel type of myofibroblast.
Open Access
Topoisomerase 1A, HER,2neu and Ki67 expression in paired primary and relapse ovarian cancer tissue samples
(Murcia : F. Hernández, 2006) Surowiak, P.; Materna, V.; Kaplenko, I.; Spaczynski, M.; Dietel, Manfred; Lage, H.; Zabel, M.
In the present study we examined prognostic value of immunohistochemical estimation of topoisomerase 1A (TOP 1A) and HER-2/neu expression in ovarian cancers treated with platinum-based drugs but not with topotecan and the relation between expression of these proteins on the one hand and intensity of proliferation (Ki67) on the other. The analyses were performed on 73 samples of ovarian carcinoma originating from 43 first-look laparotomies (FLL) and, in 30 cases, from secondary cytoreductions (SCR)(after chemotherapy) from the same patients. In paraffin sections immunohistochemical reactions were performed using antibodies directed to HER-2/neu, TOP 1A and Ki67. Kaplan-Meier’s analysis disclosed a shorter overall survival time in cases with augmented expression of TOP 1A at FLL and with higher expression of Ki67 at SCR. A shorter progression-free time was detected in cases with higher proportion of Ki67 positive cells at FLL. No relationship could be disclosed between HER- 2/neu expression and the studied clinicopathological parameters. The studies confirmed high value of Ki67 estimation. The augmented expression of TOP 1A was demonstrated to represent an unfavourable prognostic factor. Thus, in cases with elevated expression of TOP 1A application of topotecan-based therapeutic schemes should be considered.
Open Access
Cardiac natriuretic peptides: hormones with anticancer effects that localize to nucleus, cytoplasm, endothelium, and fibroblasts of human cancers
(Murcia : F. Hernández, 2006) Saba, S.R.; Vesely, D.L.
Four cardiac peptide hormones, i.e., vessel dilator, long acting natriuretic peptide (LANP), kaliuretic peptide, and atrial natriuretic peptide (ANP) synthesized by the same gene decrease within 24 hours up to 97% the number of human breast, colon, pancreatic, and prostate adenocarcinoma cells as well as human small-cell and squamous carcinomas of the lung cells. These peptide hormones completely inhibit the growth of human pancreatic adenocarcinomas growing in athymic mice. Immunocytochemical investigations have revealed that LANP, vessel dilator, kaliuretic peptide and ANP localize to the nucleus and cytoplasm of human pancreatic adenocarcinomas, which is consistent with their ability to decrease DNA synthesis in the nucleus of this cancer mediated by the intracellular messenger cyclic GMP. These peptide hormones also localize to the endothelium of capillaries and fibroblasts within these cancers. These are the first growth-inhibiting peptide hormones ever demonstrated to localize to the nucleus. Their ability to decrease the activation of growth promoting substances such as Extracellular Receptor Kinase (ERK)-1/2 and Nuclear Factor Kappa Beta (NFkB) suggests that in addition to inhibiting DNA synthesis their ability to decrease the activation of growth promoting substances helps to mediate their ability to inhibit the growth of human cancers.
Open Access
Comparison of MR images and histochemical localization of intra-arterially administered microglia surrounding ß-amyloid deposits in the rat brain
(Murcia : F. Hernández, 2006) Song, Y.; Morikawa, S.; Morita, M.; Inubushi, T.; Takada, T.; Torii, R.; Kitamura, Y.; Taniguchi, T.; Tooyama, I.
The therapeutic use of microglial cells has recently received some attention for the treatment of Alzheimer disease (AD), but few non-invasive techniques exist for monitoring the cells after administration. Here we present a magnetic resonance imaging (MRI) technique for tracking microglia injected intra-arterially in vivo. We micro-injected Aß42 into the left hippocampus and saline into the right hippocampus of rats. We then administered microglia, which were labeled with enhanced green fluorescent protein (EGFP) gene and Resovist, into the carotid artery. After monitoring exogenously administered microglia using MRI, we compared the MR images and the histochemical localization of administered microglia. MRI revealed clear signal changes attributable to Resovist-containing microglia in Aß-injected areas. Histochemistry demonstrated that EGFP-positive microglia accumulated around Aß deposits and internalized the peptide. This study demonstrates the usefulness of MRI for non-invasive monitoring of exogenous microglia, and suggests a promising future for microglia/macrophages as therapeutic tools for AD.
Open Access
Perioperative IFN-a to avoid surgically induced immune suppression in colorectal cancer patients
(Murcia : F. Hernández, 2006) Oosterling, S.J.; van der Bij, G.J.; Mels, A.K.; Beelen, R.H.J.; Meijer, S.; van Egmond, M.; van Leeuwen, P.A.M.
Surgical treatment of colorectal cancer is associated with postoperative immunosuppression, which might facilitate dissemination of tumor cells and outgrowth of minimal residual disease/(micro) metastases. Minimal residual disease has been shown to be of prognostic relevance in colorectal cancer. Therefore, stimulation of (anti-tumor) immune responses may be beneficial in the prevention of metastases formation. Important anti-tumor effector cells, which serve this function, are natural killer (NK) cells, CD8+ lymphocytes (CTL), dendritic cells (DC) and macrophages. In this review the immunomodulating properties of IFN-a are discussed, with a particular focus on perioperative stimulation of immune function in cancer patients. IFN-a is known to enhance innate immune functions such as stimulation of NK cells, transition from innate to adaptive responses (activation of DC) and regulating of CD8+ CTL activity and memory. Moreover, it exerts direct antitumor effects by regulating apoptosis and cell cycle. In several clinical trials, perioperative administration of IFN-a has indeed been shown to improve T cell responsiveness, prevent impairment of NK cell cytotoxicity and increase expression of activation markers on NK, T and NKT cells. In a clinical pilot study we showed in colorectal cancer patients that received perioperative IFN-a enhanced activation markers on T cells and NK cells, combined with betterpreserved T cell function as indicated by phytohemaggluttinin skin tests. In the liver of these patients significantly more CD8+ T cells were found. In conclusion, IFN-a provides an effective adjuvant in several forms of cancer and improves several postoperative immune functions in perioperative administration. However, larger clinical trials are necessary to investigate effects on disease-free and overall survival.
Open Access
Toll like receptor-4 expression in lipopolysaccharide induced lung inflammation
(Murcia : F. Hernández, 2006) Janardhan, K.; McIsaac, M.; Fowlie, J.; Shrivastav, A.; Caldwell, S.; Sharma, R.K.; Singh, B.
Bacterial lipopolysaccharides (LPS) initiate immune response through Toll-like receptor 4 (TLR4). Because many a times host is confronted with secondary bacterial challenges, it is critical to understand TLR4 expression following initial provocation. We studied TLR4 expression in rats at various times after intratracheal instillation of LPS. Although TLR4 mRNA was undetectable in normal lungs, it increased at 6h and 12h and declined at 36h post-LPS treatment. Western blots showed TLR4 protein at all time points. Immunohistochemistry localized TLR4 in alveolar septal cells, bronchial epithelium, macrophages and endothelium of large and peribronchial blood vessels. Dual label immunoelectron microscopy showed colocalization of TLR4 and LPS in the cytoplasm and nucleus of various lung and inflammatory cells. Nuclear localization of TLR4 was confirmed with Western blots on lung nuclear extracts. We conclude that TLR4 expression in lung is sustained up to 36 hours and that TLR4 and LPS are localized in the cytoplasm and nuclei of lung cells
Open Access
Quantitative cell-cycle protein expression in oral cancer assessed by computer-assisted system
(Murcia : F. Hernández, 2006) Soares, C.P.; Zuanon, J.A.S.; Teresa, D.B.; Fregonezi, P.A.; Neto, C.B.; Oliveira, M.R.B.; Donadi, E.A.; Martinelli-Kläy, C.P.; Soares, E.G.
The knowledge of cell-cycle control has shown that the capacity of malignant growth is acquired by the stepwise accumulation of defects in specific genes regulating cell growth. Histologic diagnosis might be improved by a quantitative evaluation of more specific diagnosis biomarkers, which could help to precisely identify pre-malignant and malignant oral lesions. The aim of the present study is to evaluate whether computer-based quantitative assessment of p53, PCNA and Ki-67 immunohistochemical expression, could be used clinically to foresee the risk of oral malignant transformation. This retrospective study was carried out in ninety-five oral biopsies, 27 were classified as fibrous inflammatory hyperplasia, 40 as leukoplakia and 28 as oral squamous cell carcinoma. Sixteen out of the 40 leukoplakia were diagnosed as non-dysplastic leukoplakia, the other 24 being dysplastic leukoplakia, of which 50.0% were classified as moderate to severe dysplasia. Comparison of the four groups of oral tissues showed significant rises in p53 and Ki-67 positivity index, which increased steadily in the order benign, premalignant, and malignant. In contrast, it was not possible to relate higher PCNA levels with pre-malignant and malignant oral lesions. We therefore conclude that PCNA immunohistochemistry expression is probably an inappropriate marker to identify oral carcinogenesis, whereas joint quantitative evaluation of p53 and Ki-67, appears to be useful as a tumor marker, providing a prediagnostic estimate of the potential for cell-cycle deregulation of the oral proliferate status.
Open Access
Do chondrocytes undergo "activation" and "transdifferentiation" during the pathogenesis of osteoarthritis? A review of the ultrastructural and immunohistochemical evidence
(Murcia : F. Hernández, 2006) Kourí, J.B.; Lavalle, C.
Chondrocytes, which are the only cell type in the articular cartilage, show substantial morphological and functional differences, depending on their location within the tissue. In OA cartilage, outstanding modifications have been reported concerning their structure and functions. Based on the principle that both structure and function run in a parallel manner, new concepts are arising related to morphological observations. Observations on OA chondrocytes, such as cytoskeleton disruption, development of the secretory machinery (rough endoplasmic reticulum and Golgi complex), and cell death by apoptosis, among others, certainly must be related to the role of chondrocytes in OA pathogenesis. In this degradative process, it has been acknowledged that cell death, matrix degradation and subchondral bone remodelling are the main causes of cartilage breakdown in osteoarthritis. The aim of this review was to correlate and integrate in a logical manner the modifications of chondrocytes with cartilage breakdown during osteoarthritis pathogenesis. Furthermore, we intend to open a debate on cell cycle and mitosis, as well as on signalling molecules that might be involved in the morphofunctional changes in OA chondrocytes, which we propose to name “activation” and “transdifferentiation” of chondrocytes. We expect this analysis to be useful for studying OA pathogenesis in depth, with the aim of finding new strategies for the early diagnosis and therapeutic procedures for this invalidating disease, which is already an important public health problem.
Open Access
Role of WNT signaling in normal and malignant hematopoiesis
(Murcia : F. Hernández, 2006) Khan, N.I.; Bendall, L.
The WNT pathway is a powerful signaling pathway that plays a crucial role in cell fate determination, survival, proliferation and movement in variety of tissues. Abnormalities in the WNT signaling pathway have been implicated in a number of diseases, most notably cancer. Recent exciting evidence suggests that WNT signaling also plays an important role in hematopoietic stem cell self-renewal and progenitor development. In this review we discuss current state of knowledge on WNT signaling in hematopoiesis and extend our focus on aberrant WNT signaling in hematological malignancies.

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