Irradiation Attenuates Systemic Lupus Erythematosus-Like Morbidity in NZBWF1 Mice: Focusing on CD180-Negative Cells.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can induce systemic inflammation. Ultraviolet-A and X-ray irradiation have been reported to have therapeutic effects in patients with SLE. We previously demonstrated that CD180-negative cells, these are radiosensitive, contribute to the development of SLE-like morbidity in NZBWF1 mice. In this study, the effects of irradiation on SLE-like morbidity manifestations in NZBWF1 mice and on CD180-negative cells were investigated. Whole-body irradiation, excluding the head, attenuated SLE-like morbidity in vivo, as indicated by the prevention of the renal lesion development, inhibition of anti-dsDNA antibody production, reduction of urinary protein levels, and prolongation of the lifespan. Irradiation also reduced the proportion of CD180-negative cells in the spleen. Although other immune cells or molecules may be triggered because of the whole-body irradiation treatment, previous research, and the current results suggest a strong relationship between the radiation-induced decrease in CD180-negative cells and the amelioration of SLE-like morbidities. Clinical trials assessing CD180-negative cells as a therapeutic target for SLE have been hampered by the lack of validated cell markers; nonetheless, the present findings suggest that radiotherapy may be a new therapeutic strategy for managing SLE symptoms.

Primary Solitary Intracranial Malignant Melanoma: A Systematic Review of Literature.

INTRODUCTION: Primary solitary intracranial malignant melanoma (PIMM) is extremely rare. In 1992, an extensive review of 81 patients with PIMM was undertaken. Imaging studies, microsurgery, and adjuvant therapy have developed considerably over the last 25 years, and targeted therapy recently has been proven successful for metastatic melanoma. These factors could influence current and future clinical PIMM results. METHODS: We undertook a literature search of PIMM patients since 1992. RESULTS: We reviewed 49 cases of PIMM. The mean age was 45.8 years. No significant sex difference was found. Intracranial hypertension and focal neurologic deficits were commonly observed around 70% and 40%, respectively. There were no significant differences of survival period according to tumor sites. Surgeries were performed in 42 of 49 patients with PIMM reviewed (92%). The mean survival of the gross total removal group was significantly longer than that of surgical results (>22 months vs. 12 months (interquartile range: 5-22 months; P = 0.026). For adjuvant therapy, 9 patients underwent chemotherapy and 18 patients underwent radiotherapy postoperatively There was no significant difference in survival period between with and without adjuvant therapies. Leptomeningeal enhancement diagnosed in the initial MRI, was the worst prognostic factor. CONCLUSIONS: Gross total removal of the PIMM was the most promising treatment. Currently adjuvant therapy has not been associated with the survival period. To improve clinical outcome, immunotherapy and targeted therapies are likely to become more important.

Differences between gastric signet-ring cell carcinoma and poorly differentiated adenocarcinoma: A comparison of histopathologic features determined by mucin core protein and trefoil factor family peptide immunohistochemistry.

We investigated differences between the pathological features of gastric signet-ring cell carcinoma (sig) and poorly differentiated adenocarcinoma (por) by examining the expressions of the trefoil factor family peptides (TFFs) and mucin core proteins (MUCs). Ninety-seven tissues of 97 gastric cancer patients were selected for this study. After gastrectomy, the major histopathologic types were determined to be sig, solid-type poorly differentiated adenocarcinoma (por1), non-solid type poorly differentiated adenocarcinoma (por2), and well-differentiated tubular adenocarcinoma (tub1). We evaluated the prevalence of positive staining for MUCs (MUC5AC and MUC2) and TFFs (TFF1 and TFF3) and assessed the correlation between MUCs and TFFs in each histopathological type. The rate of MUC2 expression significantly differed between sig and por2 (50.0% vs 11.7%, P = 0.011). TFF3 expression in sig significantly differed from TFF3 expression in both por2 (100% vs 17.6%, P < 0.0001) and por1 (100% vs 33.3%, P = 0.0004). MUC5AC and TFF1 expressions were significantly correlated in por1 (r = 0.705, P = 0.002), por2 (r = 0.535, P = 0.0009), and tub1 (r = 0.470, P = 0.0034), while MUC2 and TFF3 expressions were significantly correlated only in sig (r = 0.593, P = 0.040). The expression and correlation patterns of the TFFs and MUCs suggest that the histopathologic features of gastric sig differ from those of por.

Genetic-deletion of Cyclooxygenase-2 Downstream Prostacyclin Synthase Suppresses Inflammatory Reactions but Facilitates Carcinogenesis, unlike Deletion of Microsomal Prostaglandin E Synthase-1.

Prostacyclin synthase (PGIS) and microsomal prostaglandin E synthase-1 (mPGES-1) are prostaglandin (PG) terminal synthases that function downstream of inducible cyclooxygenase (COX)-2 in the PGI2 and PGE2 biosynthetic pathways, respectively. mPGES-1 has been shown to be involved in various COX-2-related diseases such as inflammatory diseases and cancers, but it is not yet known how PGIS is involved in these COX-2-related diseases. Here, to clarify the pathophysiological role of PGIS, we investigated the phenotypes of PGIS and mPGES-1 individual knockout (KO) or double KO (DKO) mice. The results indicate that a thioglycollate-induced exudation of leukocytes into the peritoneal cavity was suppressed by the genetic-deletion of PGIS. In the PGIS KO mice, lipopolysaccharide-primed pain nociception (as assessed by the acetic acid-induced writhing reaction) was also reduced. Both of these reactions were suppressed more effectively in the PGIS/mPGES-1 DKO mice than in the PGIS KO mice. On the other hand, unlike mPGES-1 deficiency (which suppressed azoxymethane-induced colon carcinogenesis), PGIS deficiency up-regulated both aberrant crypt foci formation at the early stage of carcinogenesis and polyp formation at the late stage. These results indicate that PGIS and mPGES-1 cooperatively exacerbate inflammatory reactions but have opposing effects on carcinogenesis, and that PGIS-derived PGI2 has anti-carcinogenic effects.

Antifibrotic response of cardiac fibroblasts in hypertensive hearts through enhanced TIMP-1 expression by basic fibroblast growth factor.

BACKGROUND: Cardiac fibroblasts (CFs) play a pivotal role in the development of myocardial fibrosis. We previously demonstrated that direct injection of basic fibroblast growth factor (bFGF) into the hypertensive Dahl salt-sensitive (DS) rat heart prevented systolic dysfunction and left ventricular dilation effectively. However, the precise role played by bFGF in fibrotic response of CFs remains unclear. We suggested potential effects of bFGF on the fibrotic response of CFs in vitro. METHODS AND RESULTS: Histopathologic assessment of cardiac fibrosis demonstrated a marked decline in the extent of perivascular and interstitial fibrosis in bFGF-injected hypertensive DS rat hearts. CFs harvested from the hearts of noninjected DS rats demonstrated a significantly increased messenger RNA (mRNA) expression of matrix metalloproteinase (MMP)-2, MMP-9, and both collagen I and III. In contrast, bFGF treatment in the CFs induced a marked increase in tissue inhibitor of MMP (TIMP)-1 expression and a marked decline in MMP-9 activation. bFGF also induced a decline in α-smooth muscle actin and collagen I and III mRNA expression in the CFs accompanied by inhibited differentiation of CFs into myofibroblasts. Small interfering RNA targeting FGF receptor 1 confirmed a specific interference of the mRNA expression changes elicited by bFGF. In vivo examination confirmed many TIMP-1-positive CFs in perivascular spaces of bFGF-injected hearts. CONCLUSIONS: Up-regulated TIMP-1 expression and down-regulated MMP-9 activation by bFGF in CFs could prevent excessive ECM degradation and collagen deposition in perivascular spaces effectively, leading to prevention of cardiac fibrosis during hypertensive heart failure. SUMMARY: Cardiac fibroblasts (CFs) play a pivotal role in myocardial fibrosis. The precise role of CFs in fibrotic response played by growth factors remains unclear. Our results indicates that basic fibroblast growth factor could up-regulate TIMP-1 expression and down-regulate MMP-9 activation in CFs in perivascular spaces, leading to inhibited progression of cardiac fibrosis during hypertensive heart failure.

Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators.

Resolution of inflammation is an active process that is mediated in part by antiinflammatory lipid mediators. Although phospholipase A2 (PLA2) enzymes have been implicated in the promotion of inflammation through mobilizing lipid mediators, the molecular entity of PLA2 subtypes acting upstream of antiinflammatory lipid mediators remains unknown. Herein, we show that secreted PLA2 group IID (PLA2G2D) is preferentially expressed in CD11c(+) dendritic cells (DCs) and macrophages and displays a pro-resolving function. In hapten-induced contact dermatitis, resolution, not propagation, of inflammation was compromised in skin and LNs of PLA2G2D-deficient mice (Pla2g2d(-/-)), in which the immune balance was shifted toward a proinflammatory state over an antiinflammatory state. Bone marrow-derived DCs from Pla2g2d(-/-) mice were hyperactivated and elicited skin inflammation after intravenous transfer into mice. Lipidomics analysis revealed that PLA2G2D in the LNs contributed to mobilization of a pool of polyunsaturated fatty acids that could serve as precursors for antiinflammatory/pro-resolving lipid mediators such as resolvin D1 and 15-deoxy-Δ(12,14)-prostaglandin J2, which reduced Th1 cytokine production and surface MHC class II expression in LN cells or DCs. Altogether, our results highlight PLA2G2D as a "resolving sPLA2" that ameliorates inflammation through mobilizing pro-resolving lipid mediators and points to a potential use of this enzyme for treatment of inflammatory disorders.

Placenta to cartilage: direct conversion of human placenta to chondrocytes with transformation by defined factors.

Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. We hypothesized that combinatorial expression of chondrocyte-specific transcription factors could directly convert human placental cells into chondrocytes. Starting from a pool of candidate genes, we identified a combination of only five genes (5F pool)-BCL6, T (also called BRACHYURY), c-MYC, MITF, and BAF60C (also called SMARCD3)-that rapidly and efficiently convert postnatal human chorion and decidual cells into chondrocytes. The cells generated expressed multiple cartilage-specific genes, such as Collagen type II α1, LINK PROTEIN-1, and AGGRECAN, and exhibited characteristics of cartilage both in vivo and in vitro. Expression of the endogenous genes for T and MITF was initiated, implying that the cell conversion is due to not only the forced expression of the transgenes, but also to cellular reprogramming by the transgenes. This direct conversion system from noncartilage tissue to cartilaginous tissue is a substantial advance toward understanding cartilage development, cell-based therapy, and oncogenesis of chondrocytes.

Trends in the prevalence of invasive fungal infections from an analysis of annual records of autopsy cases of Toho University.

Clinical diagnosis of invasive fungal infections (IFIs) is sometimes difficult, and obtaining an accurate assessment of trends concerning the prevalence of IFIs is a challenge. The aim of this study was to determine trends in the prevalence of IFIs from an autopsy survey. The retrospective review of autopsy records stored in Toho University was performed on all documented cases with fungal infection from 1955 to 2006. A total of 411 cases of IFIs were detected among 10 297 autopsies. The prevalence of candidiasis decreased from 3.6% (1981-93) to 2.0% (1994-2006), and that of aspergillosis increased throughout the 52-year period and reached 2.0% (1994-2006). The prevalence of IFIs in the patient group comprising haematological disorders was significantly higher (19.9%) than in other patient groups (2.9%), of which the odds ratio was 18.4 for mucormycosis and 10.0 for aspergillosis. The lung was the most common organ involved irrespective of major fungal species, and most cases with candidiasis showed multiple-organ infection. Results confirmed the increasing prevalence of aspergillosis and high risk of IFIs in the patient group with haematological disorders. IFIs were also detected in an immunocompromised state caused not only by primary disease but also by treatment with anti-tumour drugs and corticosteroids.

Histopathological predictors of regional lymph node metastasis at the invasive front in early colorectal cancer.

AIMS: In early colorectal cancer (ECC), prediction of lymph node (LN) metastasis is vital for the decision of additional surgical treatment after endoscopic mucosal/submucosal resection. The aim of this study was to determine the relationship between LN metastasis and comprehensive histopathological findings including the cancer microenvironment in ECC. METHODS AND RESULTS: Using 111 ECC cases, including 36 cases with LN metastasis, histopathological observations and immunohistochemistry for lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), von Willebrand factor, matrix metalloproteinase-7 (MMP-7), CXC chemokine ligand-12 (CXCL12) and angiopoietin-like-4 (ANGPTL4) were conducted. Relationships between LN metastasis and growth pattern, status of muscularis mucosae, depth of cancer invasion, overall histopathological type, histopathological type at the invasive front, tumour budding, neutrophil infiltration in cancer cells (NIC), fibrotic cancer-stroma type, Crohn's-like lymphoid reaction, microscopic abscess formation and lymphatic invasion were determined. In addition, the expression of MMP-7, CXCL12 and ANGPTL4 in cancer cells at the invasive front were also considered in the context of LN metastasis. By multivariate analysis, lymphatic invasion, NIC and MMP-7 expression at the invasive front were independent predictors of LN metastasis. CONCLUSIONS: LN metastasis is regulated not only by the characteristics of cancer cells but also by microenvironmental factors of lymphatics and neutrophils, especially at the invasive front.

Adenomyoma of the small intestine in an adult: report of a case.

We report a case of adenomyoma in the small intestine, which is an extremely rare entity. An 81-year-old woman presented to our hospital with a history of three episodes of vomiting accompanied by abdominal pain. Upper gastrointestinal examination via a long tube found intestinal obstruction caused by a tumor of the small intestine. Laparotomy revealed a hard mass, 160 cm distal to the Treitz ligament. Pathological examinations of the resected tumor confirmed a diagnosis of adenomyoma originating in the small intestine. To our knowledge, this is only the second report of an adenomyoma of small intestine causing intestinal obstruction in an adult.

Malignant adrenal rest tumor of the retroperitoneum producing adrenocortical steroids.

We present a case of a malignant adrenal rest tumor arising from the retroperitoneum with Cushing's syndrome in a 31-year-old female. Her serum cortisol and dehydroepiandrosterone sulfate levels were elevated, while adrenocorticotropic hormone levels were low. Computed tomography scans and magnetic resonance imaging revealed a retroperitoneal tumor with no visible lesions in the adrenal glands and ovaries. From those results and the histopathologic findings following biopsy of an enlarged supraclavicular lymph node, the patient was diagnosed as a malignant adrenal rest tumor of the retroperitoneum. Despite chemotherapy, the patient died of rapid development of multiple metastases. Autopsy revealed a large tumor that extended around the abdominal aorta from the levels of the left kidney to the aortic bifurcation with generalized metastases. Tumor cells were characterized by clear and eosinophilic cytoplasm and atypical nuclei that exhibited frequent and atypical mitoses. Immunohistochemistry regarding steroidogenesis was performed and revealed that the tumor cells were immunopositive for adrenal 4 binding protein/steroidogenic factor-1, cholesterol side-chain cleavage enzyme, 17α-hydroxylase, and 21-hydroxylase. We thus elucidated the adrenocortical steroid production in the tumor cells causing Cushing's syndrome. This case report first demonstrates the steroidogenic capacity in a malignant adrenal rest tumor.

Solitary hepatic lymphangioma: report of a case.

A 52-year-old woman presented with upper abdominal pain. Abdominal ultrasonography showed a 4-cm well-defined mass containing solid and cystic components in segment IV of the liver, and contrast-enhanced T1-weighted magnetic resonance imaging revealed heterogeneous enhancement within the tumor, indicating a solid or fibrous component. There were no cystic lesions in any other organs. A partial hepatectomy was performed, based on a preoperative diagnosis of sclerosing hemangioma and biliary cystadenoma or cystadenocarcinoma. Pathologically, the tumor appeared to be a multilocular and cystic lesion lined by attenuated endothelial- like cells with no atypia. Immunohistochemistry demonstrated the endothelial-like cells to be positive for the lymphatic-specific markers D2-40, LYVE-1, and Prox-1, which proved helpful for confirming the diagnosis as solitary hepatic lymphangioma. This case is presented with details of the pathologic and radiologic findings, because solitary hepatic lymphangioma is an extremely rare tumor and no previous reports have provided details of the immunohistochemical characteristics.

Prognostic value of LYVE-1-positive lymphatic vessel in tongue squamous cell carcinomas.

The density of lymphatic vessels in 52 cases of human tongue squamous cell carcinoma (TSCC) and normal portions was analyzed. TSCC specimens were immunostained with antibodies against lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin monoclonal antibody (D2-40). The significance of the LYVE-1-positive vessel density (LVD) was calculated in 6 topographic areas and investigated on the basis of specific clinical and histo-pathological parameters. LYVE-1 positivity was more evident in the muscular area than the submucosal area, while small D2-40-positive lymphatic vessels were not demonstrable in muscular endomysium. The LVD in peri-tumoral submucosal and peri-tumoral muscular areas was lower than in normal counterparts (p<0.01). LVD was higher in the tumor invasion front as compared to tumor-associated stroma (p<0.01). Low LVD in invasion front and peri-tumoral submucosal area was significantly related to regional lymph node metastasis (p<0.05 and p<0.01, respectively). The decrease of LYVE-1-positive lymphatic vessels in the invasion front and peri-tumoral submucosal area would seem to predict cervical lymph node metastasis in TSCC.

The mechanisms underlying fibroblast apoptosis regulated by growth factors during wound healing.

While investigating the mechanisms underlying cell death during wound healing processes, we uncovered the pro-apoptotic effects of basic fibroblast growth factor (bFGF) on granulation tissue fibroblasts following pretreatment with transforming growth factor (TGF)-beta1 in vitro. bFGF induced caspase-3 activation and apoptosis in TGF-beta1-pretreated granulation tissue-derived fibroblasts (GF-1) following bFGF treatment for 48 and 96 h. In contrast, fibroblasts that had been treated in the same manner and that originated from the uninjured dermis did not display apoptosis, indicating that the mechanisms underlying apoptosis events in fibroblasts that originate from normal dermal and wound tissues differ. In this process, we also found that bFGF inhibited Akt phosphorylation at serine 473 and induced a rapid loss of phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 in pretreated GF-1 cells, an event that coincided with the dissociation of phosphorylated FAK from the focal adhesions. Therefore, inhibition of survival signals relayed via the disrupted focal adhesion structures and inactivated Akt following bFGF treatment may lead to apoptosis in GF-1 cells pretreated with TGF-beta1. Pretreatment of GF-1 with TGF-beta1 followed by the addition of bFGF resulted in significantly greater inhibition of phosphorylation of Akt and FAK compared to treatment with TGF-beta1 or bFGF alone. The combinatorial treatment also led to proteolysis of FAK and inhibition of FAK and Akt protein expression in GF-1 cells. These findings demonstrated a significant role for the two cytokines in apoptosis of granulation tissue fibroblasts during wound healing. In vivo studies also confirmed a marked decline in phosphorylation and protein expression of Akt and FAK in bFGF-injected skin wounds. These results led to the hypothesis that temporal activation of TGF-beta1 and bFGF at the injury site promotes apoptosis in granulation tissue fibroblasts, an event that is critical for the termination of proliferative granulation tissue formation.

Distribution of smooth muscle cells and macrophages expressing scavenger receptor BI/II in atherosclerosis.

AIM: Scavenger receptors type I and II (SRBI/II) have dual roles in both atherogenic and antiatherogenic functions through interactions with lipoproteins and their expression in macrophages; how-ever, the distribution and density of SRBI/II-positive macrophages and smooth muscle cells (SMCs) as well as their association with lipid metabolism-related proteins in atherosclerotic intima of the human aorta remain unclear. METHODS: Autopsied aortic tissues were double-immunostained with SRBI/BII and smooth muscle actin or macrophage-specific antibodies. The density of SRBI/BII-positive SMCs and macrophages in intimal lesion was measured. They were also immunostained with antibodies against four apolipoproteins, four phospholipase A2s, and CETP. RESULTS: SRBI/II was expressed in both macrophages and SMCs distributed in various intimal lesions. The density of SRBI/II-positive SMCs in intimal lesions significantly decreased with the advance of atherosclerosis, whereas the density of SRBI/II-positive macrophages significantly increased with atherosclerotic development. In addition, functional proteins, such as apolipoproteins, secretory phospholipase A2s, and CETP, were distributed in the intimal stroma around SRBI/II-positive cells in all lesion types. CONCLUSION: The results indicated that SMCs are involved in lipid metabolism via SRBI/II expression mainly in the early stages of atherosclerosis evolution, and that SRBI/II-positive macrophages are mainly involved in advanced stages.

Microsomal prostaglandin E synthase-1 in both cancer cells and hosts contributes to tumour growth, invasion and metastasis.

mPGES-1 (microsomal prostaglandin E synthase-1) is a stimulus-inducible enzyme that functions downstream of COX (cyclo-oxygenase)-2 in the PGE2 (prostaglandin E2)-biosynthesis pathway. Although COX-2-derived PGE2 is known to play a role in the development of various tumours, the involvement of mPGES-1 in carcinogenesis has not yet been fully understood. In the present study, we used LLC (Lewis lung carcinoma) cells with mPGES-1 knockdown or overexpression, as well as mPGES-1-deficient mice to examine the roles of cancer cell- and host-associated mPGES-1 in the processes of tumorigenesis in vitro and in vivo. We found that siRNA (small interfering RNA) silencing of mPGES-1 in LLC cells decreased PGE2 synthesis markedly, accompanied by reduced cell proliferation, attenuated Matrigel invasiveness and increased extracellular matrix adhesion. Conversely, mPGES-1-overexpressing LLC cells showed increased proliferating and invasive capacities. When implanted subcutaneously into wild-type mice, mPGES-1-silenced cells formed smaller xenograft tumours than did control cells. Furthermore, LLC tumours grafted subcutaneously into mPGES-1-knockout mice grew more slowly than did those grafted into littermate wild-type mice, with concomitant decreases in the density of microvascular networks, the expression of pro-angiogenic vascular endothelial growth factor, and the activity of matrix metalloproteinase-2. Lung metastasis of intravenously injected LLC cells was also significantly less obvious in mPGES-1-null mice than in wild-type mice. Thus our present approaches provide unequivocal evidence for critical roles of the mPGES-1-dependent PGE2 biosynthetic pathway in both cancer cells and host microenvironments in tumour growth and metastasis.

Improvement of radiation-induced healing delay by etanercept treatment in rat arteries.

Surgical treatment often causes difficulty in the irradiated field because of delayed wound healing, which is mainly due to vascular dysfunction. To overcome this difficulty, we attempted to accelerate the recovery from clamp injury in irradiated superficial epigastric arteries of rats as a model. Etanercept, a soluble receptor of tumor necrosis factor-alpha, was administered four times to rats with irradiated arteries before and after clamp injury. Loss of endothelial cells and necrosis of the media in the irradiated arteries continued for more than 1 week after the injury; however, in the rats treated with etanercept, the endothelial cells recovered in the intima, and alpha-smooth muscle actin-positive smooth muscle cells recovered in the injured and irradiated arteries. After clamp injury of common carotid arteries that had previously been irradiated, the blood flow in these arteries was visualized by magnetic resonance (MR) angiography. The time-of-flight signal was weakened in the injured and irradiated arteries. This time-of-flight signal was recovered by the etanercept treatment. These findings suggest that etanercept improves the radiation-impaired healing of arteries in rats.

Significance of lymphatic invasion and cancer invasion-related proteins on lymph node metastasis in gastric cancer.

BACKGROUND AND AIMS: Cancer invasion and metastasis are critical events for patient prognosis; however, the most important step in the whole process of lymph node (LN) metastasis in gastric cancer remains obscure. In this study, the significance of cancer cell behaviors, such as cell detachment, stromal invasion and lymphatic invasion on regional LN metastasis in gastric cancer was investigated by comprehensive immunohistochemistry. METHODS: A total of 210 cases with gastric cancer were selected. These consisted of 105 cases with regional LN metastasis (LN[+] group) and 105 cases without LN metastasis (LN[-] group). Both groups exhibited the same depth of invasion. Cancer tissues were subjected to immunohistochemistry with antibodies against claudin-3, claudin-4, beta-catenin, matrix metalloproteinase (MMP)-1, and MMP-2, as well as endothelial markers of lymphatic vessel endothelial hyaluronan receptor-1 and von Willebrand factor for the objective discrimination between lymphatics and blood vessels. The expression of each protein as well as the histopathological parameters were compared between LN(+) and LN(-) groups. RESULTS: Along with lymphatic invasion by cancer cells and gross tumor size, MMP-1 expression in cancer cells at the invasive front of the primary tumor was a significant, independent predictor of LN metastasis. The expression of claudins and beta-catenin was associated with the histopathological type of cancer, but not with LN status. CONCLUSION: Among the cancer invasion-related proteins examined, MMP-1 plays a vital role in LN metastasis of gastric cancer. Tumor size, lymphatic invasion and MMP-1 expression level at the invasive front were the predictive factors of LN metastasis of gastric cancer.

Histopathological predictor for regional lymph node metastasis in gastric cancer.

Regional lymph node metastasis in gastric cancer is a definitive indicator of the patient's prognosis. The goal of this study was to identify the predictors for lymph node metastasis among all the possible histopathological parameters, especially by conducting an objective discrimination of the lymphatic and blood vessels. A total of 210 resected primary gastric cancers with or without lymph node metastasis were evaluated based on the conventional histopathological parameters together with immunohistochemistry using antisera-recognizing lymphatic endothelial hyaluronan receptor-1 (LYVE-1), von Willebrand factor, and lymphangiogenesis promoter vascular endothelial growth factor-C (VEGF-C) antibodies. A multivariate regression analyses of the results indicated that only lymphatic invasion was a significant independent predictor of lymph node metastasis at any stage of cancer invasion. VEGF-C expression was partially related to lymph node metastasis in early gastric cancer. The identification of lymphatic invasion by LYVE-1 antibody is therefore useful to predict regional lymph node metastasis in gastric cancer.

Basic fibroblast growth factor inhibits ventricular remodeling in Dahl salt-sensitive hypertensive rats.

OBJECTIVE: Basic fibroblast growth factor (bFGF) inhibits the progression of ventricular remodeling in ischemic and hypertensive heart diseases (HHDs). Recent studies have revealed that bFGF induces the transition from myofibroblasts to fibroblasts with decreased expression of alpha-smooth muscle actin (alpha-SMA). To clarify the mechanisms underlying the reduced ventricular remodeling in hypertensive heart diseases caused by bFGF, we examined the degree of interstitial fibrosis associated with alpha-smooth muscle actin expression and matrix metalloproteinase activity in hypertensive heart diseases. METHODS: Dahl salt-sensitive rats were fed with a high-salt diet from 6 to 18 weeks of age and injected with a single dose of bFGF (100 microg) into the left myocardium at 15 weeks. Others were administered PBS without bFGF. Control age-matched Dahl salt-sensitive rats were fed with a low-salt diet. RESULTS: Cardiac systolic function was well preserved and decompensation of heart failure was prevented at 18 weeks in the rats treated with bFGF at 15 weeks. The bFGF-treated rats had significantly fewer interstitial alpha-SMA-positive myofibroblasts and significantly decreased prolyl 4-hydroxylase expression. Increased matrix metalloproteinase-9 gelatinase activity correlated with the downregulation of transforming growth factor-beta1 by bFGF, suggesting that inhibited extracellular matrix deposition is associated with a decreased number of myofibroblasts induced by bFGF. CONCLUSION: bFGF can inhibit the progression of ventricular remodeling by inhibiting interstitial fibrosis and promoting angiogenesis without decreasing blood pressure in hypertensive heart disease.