The fifth epidermal growth factor-like region of thrombomodulin exerts cytoprotective function and prevents SOS in a murine model.

The present study found that the fifth epidermal growth factor-like domain of thrombomodulin (TME5) possesses the cytoprotective function in association with an increase in levels of anti-apoptotic myeloid cell leukemia-1 protein in an activated protein C-independent manner in human umbilical vein endothelial cells (HUVECs). Importantly, TME5 counteracted calcineurin inhibitor-induced vascular permeability and successfully prevented monocrotaline-induced sinusoidal obstruction syndrome (SOS) in a murine model. Taken together, TME5 may be useful for preventing or treating lethal complications that develop after hematopoietic stem cell transplantation such as SOS and thrombotic microangiopathy in which endothelial cell damage has a role.

Portal or superior mesenteric vein resection in pancreatoduodenectomy for pancreatic head carcinoma.

BACKGROUND: The aim of this study was to determine the added value of portal or superior mesenteric vein (PV/SMV) resection during pancreatoduodenectomy for pancreatic head carcinoma. METHODS: A multicentre observational study was conducted in patients with pancreatic head carcinoma who underwent pancreatoduodenectomy in seven Japanese hospitals between 2001 and 2012. Clinicopathological factors were compared between patients who did and did not undergo PV/SMV resection. Those with an impact on survival were identified by univariable and multivariable analysis. RESULTS: Of the 937 patients who underwent pancreatoduodenectomy, 435 (46·4 per cent) had PV/SMV resection, whereas the remaining 502 (53·6 per cent) did not. Some 71·5 and 63·9 per cent of patients with and without PV/SMV resection respectively had lymph node-positive disease. Patients who underwent PV/SMV resection had more advanced tumours. Perioperative mortality and morbidity rates did not differ between the two groups. Multivariable analysis revealed that PV/SMV resection was not an independent prognostic factor for overall survival (P = 0·268). Among the 435 patients in whom the PV/SMV was resected, borderline resectable tumours with arterial abutment (P = 0·021) and absence of adjuvant chemotherapy (P < 0·001) were independent predictors of poor survival in multivariable analysis. Patients with resectable or borderline resectable tumours with PV/SMV involvement had a median survival time with additional adjuvant chemotherapy of 43·7 and 29·7 months respectively. Median survival time in patients with borderline resectable tumours with arterial abutment was 18·6 months despite adjuvant chemotherapy. CONCLUSION: Pancreatoduodenectomy with PV/SMV resection and adjuvant chemotherapy in patients with pancreatic head carcinoma may provide good survival without increased mortality and morbidity.

Potential immunosuppressive and antiinflammatory activities of Malaysian medicinal plants characterized by reduced cell surface expression of cell adhesion molecules.

In the search for agents effective against immune-mediated disorders and inflammation, we have screened Malaysian medicinal plants for the ability to inhibit the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on the surface of murine endothelial cells (F-2), and mouse myeloid leukaemia cells (M1), respectively. Of 41 kinds (29 species, 24 genera, 16 families) of Malaysian plants tested, 10 and 19 plant samples significantly downregulated the expression of ICAM-1 and VCAM-1, respectively. Bioassay-directed fractionation of an extract prepared from the bark of Goniothalamus andersonii showed that its ingredients, goniothalamin (1) and goniodiol (2) inhibited the cell surface expression of both ICAM-1 and VCAM-1. The present results suggest that Malaysian medicinal plants may be abundant natural resources for immunosuppressive and antiinflammatory substances.

In vitro inhibitory effects of Daphne oleoides ssp. oleoides on inflammatory cytokines and activity-guided isolation of active constituents.

Aerial parts of Daphne oleoides Schreber ssp. oleoides (Thymelaeaceae) are used to treat rheumatoid arthritis and lumbago in Turkish folk medicine. In order to evaluate folkloric utilization, in vitro inhibitory effects of the ethyl acetate extract and fractions obtained from this extract on interleukin 1 (IL-1alpha, IL-1beta) and tumour necrosis factor (TNF-alpha) biosynthesis were studied. Through chemical isolation techniques and activity-guided fractionation process, seventeen compounds were isolated and their structures were elucidated (numbered 1-17). Diterpenoids genkwadaphnin (3) and 1,2-dehydrodaphnetoxin (6) and a coumarin derivative daphnetin (9) showed potent inhibitory activity and were found to be the main active ingredients. Furthermore, gnidilatin (4), gnidilatin-20 palmitate (5), genkwadaphnin-20-palmitate (7) and gnidicin-20-palmitate (8), having diterpenoid structure, and eudesmine (12), wikstromol (13) and matairesinol (14), having lignan structure, were determined to possess moderate inhibitory activity and may have a contributory role in the effect of the remedy.

Influence of natural and synthetic compounds on cell surface expression of cell adhesion molecules, ICAM-1 and VCAM-1.

Various natural and synthetic compounds including alkaloids, terpenoids and phenolics were tested for inhibition of the cell surface expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), both of which are crucial in the regulation of immune response and inflammation. Of 40 compounds tested, two compounds significantly downregulated the expression of VCAM-1 on murine endothelial cells (F-2) and ten compounds that of ICAM-1 on mouse myeloid leukemia cells (M1). Sanguinarine chloride (5) and isoliquiritigenin (13) were capable of lowering the levels of both ICAM-1 and VCAM-1. The structure-activity relationships study on chalcone and flavone derivatives related to 13 suggested that the inhibitory activity of the chalcone derivatives is attributable to the 4-hydroxy group as well as the possible coplanarity between the phenyl ring and the adjacent conjugated ketone.

Clinicopathologic evaluation of hepatocellular carcinoma with bile duct thrombi.

BACKGROUND: The aim of this study was to evaluate the clinicopathologic characteristics of patients with hepatocellular carcinoma (HCC) and bile duct thrombi (BDT). PATIENTS: Seventeen patients with HCC and BDT among 671 patients with HCC who underwent hepatic resection were enrolled in this study. RESULTS: There were no significant differences in the survival rates between patients with and those without BDT, although the rate of stage IV or portal vein invasion was significantly higher in patients with HCC and BDT than in those with HCC but without BDT. In 9 of 17 patients with BDT, preoperative jaundice was observed. Five of the 17 patients underwent a bile duct resection combined with hepatic resection, and 12 patients underwent hepatic resection with removal of the BDT without bile duct resection. None of the patients had histopathologic evidence of direct tumor invasion into the bile duct wall or of any tumor recurrence related to the BDT. There were no significant differences in the survival rates between patients who underwent bile duct resection and those who did not. CONCLUSION: Hepatic resection and the removal of BDT without bile duct resection were sufficient surgical interventions to treat patients with HCC and BDT.

Inhibitory effects of rosmarinic acid on the proliferation of cultured murine mesangial cells.

BACKGROUND: Rosmarinic acid is a phenolic compound widely distributed in Labiatae herbs such as rosemary, sweet basil, and perilla, which are frequently used with meat and fish dishes in Western and Asian countries. In the present study we investigated the effects of rosmarinic acid on cultured murine mesangial cell proliferation. METHODS: Cultured murine mesangial cells were stimulated by growth factors with or without rosmarinic acid, and [(3)H]thymidine incorporation was measured in regard both to signal transduction and to cell cycle dependency. In other experiments, mRNA extracted from the cells was analysed by Northern blotting. RESULTS: Rosmarinic acid inhibited the cell proliferation induced by platelet-derived growth factor (PDGF) (P<0.01; IC(50) values, 1.4 microg/ml) or tumour necrosis factor-alpha (P<0.01; IC(50) values, 3. 8 microg/ml), and these effects involved both the G(0)/G(1) and G(1)/S phases of the cell cycle. Rosmarinic acid also suppressed the mRNA expressions of PDGF and c-myc in PDGF-stimulated mesangial cells. CONCLUSIONS: Rosmarinic acid inhibits cytokine-induced mesangial cell proliferation and suppresses PDGF and c-myc mRNA expression in PDGF-stimulated mesangial cells. Rosmarinic acid in Labiatae herbs might be a promising agent to prevent mesangial cell proliferation.

Coumarins and bicoumarin from Ferula sumbul: anti-HIV activity and inhibition of cytokine release.

The methanol extract of the dried roots of Ferula sumbul afforded two furanocoumarin esters, fesumtuorin A, B, one bicoumarin, fesumtuorin C, five spirobicoumarins, fesumtuorin D, E, F, G and H, along with nineteen known coumarins. Their structures were established on the basis of spectroscopic studies. Some of the isolated compounds showed anti-HIV activity and very weak inhibition of cytokine release.

Right hepatic lobectomy for hepatocellular carcinoma which developed in primary biliary cirrhosis: report of a case.

The case of a 74-year-old female patient who underwent a right hepatic lobectomy for hepatocellular carcinoma (HCC) which developed in primary biliary cirrhosis (PBC) is reported herein. During a follow-up examination for Parkinson's disease, an elevation of hepatobiliary tract-related enzymes and alpha-fetoprotein was uncovered. Diagnostic imagings showed a hypervascular, solitary, and encapsulated tumor measuring about 7 cm in diameter located mainly in the posterior segment. Positive antimitochondrial and antinuclear antibodies and a preoperative liver biopsy strongly suggested well differentiated HCC developed in PBC (Scheuer's classification stage II). Since the natural prognosis of PBC estimated by the Mayo risk score was fairly good and the liver function indicated sufficient tolerance for major hepatic resection, and preoperative computed tomography (CT) volumetry showed the atrophy of the right hepatic lobe, a right hepatic lobectomy was performed. A pathological examination revealed well encapsulated, moderately differentiated HCC with, in part, well-differentiated HCC in the tumor and stage II PBC in the noncancerous region. CT volumetry performed at postoperative day 14 showed a 146% enlargement of the remnant liver. An early detection of HCC and PBC by strict screening would prevent a limitation of surgical therapy due to a deteriorated liver function.

Effect of Perilla frutescens extract on nitric oxide production by cultured murine mesangial cells.

The effects of a water extract of perilla (Perilla frutescens Britton) leaves on nitric oxide (NO) production by cultured murine mesangial cells were investigated. Perilla extract significantly induced NO production from mesangial cells, which was enormously augmented without cytotoxity by combination with interferon (IFN)-gamma or tumor necrosis factor-alpha. On the other hand, perilla extract suppressed a large amount of NO production induced by IFN-gamma combined with lipopolysaccharide. Northern blot analysis revealed that such effects of perilla extract were dependent on inducible NO synthase mRNA expression. Perilla extract exhibited an inhibitory effect on cytokine-induced mesangial cell proliferation, and this effect was significantly decreased upon combination with N(G)-monomethyl-L-arginine (L-NMMA), a non-specific NO synthase inhibitor, suggesting that perilla extract inhibits mesangial cell proliferation partially through the induction of NO production. Such results indicate that perilla may be a promising agent for the prevention of the progression of glomerulonephritis.

Management of adrenal metastasis of hepatocellular carcinoma by asynchronous resection of bilateral adrenal glands.

We report on a 65-year-old man who received asynchronous bilateral adrenalectomy for adrenal metastasis of hepatocellular carcinoma. Fifteen months after curative resection of right hepatic lobe for hepatocellular carcinoma, a metastatic lesion of the left adrenal gland was detected and left adrenalectomy was performed. Ten months after the second operation, a metastatic lesion in the right adrenal gland, associated with tumor thrombus in the inferior vena cava, was revealed. Transcatheter arterial embolization of the arteries feeding the metastatic tumor was performed, but its effects were incomplete. As there was the tumor thrombus in the inferior vena cava and no other intrahepatic recurrence or extrahepatic metastasis was found, resection of the right adrenal gland with tumor thrombus, without the employment of veno-venous bypass, was performed, followed by postoperative hormonal supplementation. Changes in the patient's alpha-fetoprotein level were clinically useful for the detection of the metastatic lesions and the evaluation of therapeutic effects. Metastasis to adrenal gland from hepatocellular carcinoma should be actively managed, and the appropriate surgical treatment selected, if intrahepatic recurrence and/or other extrahepatic metastasis are controlled. To achieve higher curability and better outcome in patients with bilateral adrenal metastasis of hepatocellular carcinoma, bilateral total adrenalectomy is indicated, accompanied by effective postoperative hormonal supplementation.

MFL-P Chemotherapy for Pretreated Metastatic Breast Cancer Patients: A Regimen with Triple Biochemical Modulation by MTX-5FU, LV-5FU and 5FU-CDDP.

BACKGROUND: Chemotherapeutic regimens, such as cyclophosphamide + doxorubicin + 5FU (CAF) or cyclophosphamide + methotrexate + 5FU (CMF), are sometimes used in combination with endocrine or radiotherapy as a standard first line of treatment for recurrent or metastatic breast cancer. However, many cases are, or become, refractory to these treatments. METHODS: Twenty-one women with recurrent or metastatic breast cancer who previously underwent treatment were administered our original regimen of combinationchemotherapy, MFL-P: Day 1, bolus methotrexate (MTX) 50 mg/body (median dose, 33 mg/m(2); range, 29-35 mg/m(2)) and 4 hours later 5-fluorouracil (5FU) 750 mg/body/h (median dose, 497 mg/m(2)/h; range, 441-528 mg/m(2) /h); Days 2-3, bolus leucovorin(LV) 15 mg/body every 8 h x 3; Days 2-5, 72 hours continuous 5FU 750 mg/body/24h; Day 6, cisplatin (CDDP) 50 mg/body/h (median dose, 33 mg/m(2)/h; range, 29-35 mg/m(2) /h) with sufficient hydration. The subjects ranged in age from 26 to 63 years (mean age, 51.3 years). RESULTS: One complete and 9 partial responses were achieved among the 20 patients (response rate, 50%). In 1 patient, diffuse liver metastasis was not measurable. Among various metastatic sites, a higher response rate was observed especially for soft tissue lesions (skin, chest wall and lymph nodes; 9 responders among 11 lesions). On the other hand, in visceral or skeletal metastases, the response rate was poor. The adverse effects were tolerable in all patients, except for common low-grade stomatitis or anorexia. CONCLUSION: MFL-P is useful as a second or third line of therapy for patients with refractory, recurrent or metastatic breast cancer with soft tissues lesions.

Nine-year survivor after resection of cholangiocellular carcinoma with tumor thrombi in the main portal trunk.

We report a patient with cholangiocellular carcinoma with tumor thrombi in the main portal trunk who has survived for 9.5 years after hepatic resection. A 57-year-old woman underwent an extended left lobectomy, and resection of the caudate lobe plus the main portal trunk for a liver tumor that had a portal tumor thrombus in the main portal trunk. The portal vein was reconstructed with an autologous vein graft obtained from the external iliac vein. Histological examination of the resected specimen revealed moderately differentiated tubular adenocarcinoma compatible with cholangiocellular carcinoma. Factors contributing to the patient's long-term survival are discussed. Aggressive surgical resection can be effective even for such an advanced case of cholangiocellular carcinoma.

Inhibitory effect of Perilla frutescens and its phenolic constituents on cultured murine mesangial cell proliferation.

The inhibitory effects of Perilla frutescens and its phenolic constituents on cytokine-induced proliferation of murine cultured mesangial cells were investigated. DNA synthesis of mesangial cells stimulated by platelet derived growth factor (PDGF, 10 ng/ml) or tumor necrosis factor (TNF)-alpha (100 U/ml) was inhibited by the extract of P. frutescens (IC50 values, 3.3 and 1.4 micrograms/ml, respectively). The strength of the anti-proliferative activity was nearly equal in various chemotypes of P. frutescens. Caffeic acid, methyl caffeate, rosmarinic acid, and luteolin 7-O-glucuronide-6"-methyl ester were isolated as active constituents from the extract of the typical strain of P. frutescens, and their IC50 values for PDGF-induced mesangial cell proliferation were estimated as 26 microM, 2.6 microM, 1.8 microM, and 4.1 microM, respectively. We also compared the activities of related flavonoids previously isolated from P. frutescens, and luteolin had the highest anti-proliferative activity.

Inhibitory effects of Turkish folk remedies on inflammatory cytokines: interleukin-1alpha, interleukin-1beta and tumor necrosis factor alpha.

In this study, in vitro inhibitory effects of 55 extracts or fractions obtained from 10 plant species on interleukin-1 (IL-1alpha, IL-1beta) and tumor necrosis factor (TNF-alpha) biosynthesis were studied. The following plant materials from Turkish folk medicine for the treatment of various diseases which are thought to be inflammatory in nature e.g. rheumatism, fever, infections, edemas or related inflammatory diseases were selected as the subject of this study: Cistus laurifolius leaves, Clematis flammna flowering herbs, Crataegus orientalis roots, Daphne oleoides ssp. oleoides whole plant, Ecbalium elaterium roots, Rosa canina roots, Rubus discolor roots, Rubus hirtus roots, Sambucus ebulus flowers and leaves, Sambucus nigra flowers and leaves. All plants showed inhibitory activity against at least one of these models in various percentages depending upon the concentration, thus supporting the folkloric utilization. Daphne oleoides was found to be the most active plant against the test models.

cDNA cloning, characterization, and functional expression of 4S-(-)-limonene synthase from Perilla frutescens.

A molecular biological study on limonene synthase that catalyzes the cyclization of geranyldiphosphate to yield the olefin 4(S)-limonene, an intermediate in the biosynthesis of a monoterpenoid, perillaldehyde, in Perilla frutescens Britton has been carried out. We isolated and characterized 10 cDNAs homologous to spearmint limonene synthase cDNA from an expression library constructed from cotyledons of a Perilla strain homozygous for two pairs of dominant genes, G and H, which are responsible for the formation of 4(S)-limonene. Two of these cDNA clones were functionally expressed in Escherichia coli, yielding enzymes which were catalytically active in generating 4(S)-limonene from geranyldiphosphate. The longest open reading frame in the representative cDNA clone PFLC1 consisted of 1812 nucleotides corresponding to 603 amino acids. Its identity to the ORFs of spearmint limonene synthase, tobacco 5-epi-aristolochene synthase, and castor bean casbene synthase were 65, 35, and 30%, respectively. Genomic Southern blot analyses of various genotypes (GGHH, GGhh, ggHH, and gghh) of P. frutescens suggested that more than one copy of the PFLC1 DNA exists in strains having the HH genotype. In contrast, no PFLC1 DNA sequences were found in the genomes of strains with the hh genotype that are incapable of producing cyclohexanoid monoterpenes for lack of limonene synthase activity. Northern blot analysis, using a PFLC1 3'-flanking region as a hybridization probe, showed that PFLC1 mRNA accumulated in all the aerial parts of the GGHH plants, particularly in the leaves. In the ggHH plants, on the other hand, PFLC1 mRNA was detected only in minute amounts in the stem and calyx.

Musculoskeletal neoplasm: perineoplastic edema versus tumor on dynamic postcontrast MR images with spatial mapping of instantaneous enhancement rates.

PURPOSE: To evaluate the utility of fast, contrast-enhanced, sequential magnetic resonance (MR) imaging in differentiating between extraosseous tumor and perineoplastic edema. MATERIALS AND METHODS: Fourteen patients underwent sequential MR imaging (3.5 seconds per image) after bolus administration of gadopentetate dimeglumine. Initial rates of enhancement (initial slope) were calculated on a pixel-by-pixel basis and displayed as a "slope image"' in which pixel intensity reflected the slope value. Close correlation with wedge biopsy specimens was performed. RESULTS: Mean initial slope values were viable extraosseous tumor, 9.33 (standard deviation, 2.23); infiltrated muscle, 9.07 (2.31); edematous muscle without tumor infiltration, 5.48 (1.27); normal muscle, 1.11 (0.65). Differences in initial slope between all neoplastic and nonneoplastic tissues were statistically significant. Within individual patients, initial slope of edematous muscle was always 20% or more lower than that of neoplastic tissue. Slope images highlighted areas of viable extraosseous tumor and infiltrated muscle against edematous and normal tissues. CONCLUSION: Computer-generated slope images derived from sequential postcontrast MR images allow differentiation between tumor and nonneoplastic edema and may thereby guide the surgeon in planning limb-sparing procedures.

Tumoral calcinosis: radiologic-pathologic correlation.

OBJECTIVE: Tumoral calcinosis is a frequently misdiagnosed disorder. This study details the radiologic and pathologic characteristics of tumoral calcinosis that distinguish it from most other entities. DESIGN: Radiologic and pathologic findings, and medical records of 12 patients with tumoral calcinosis were reviewed and compared with equivalent information about 5 patients with other calcified lesions. PATIENTS: The 12 patients ranged in age from 15 months to 62 years. Six had idiopathic tumoral calcinosis and 6 had secondary tumoral calcinosis. RESULTS AND CONCLUSIONS: A consistent radiologic finding for tumoral calcinosis was a dense calcified mass that was homogeneous except for a "chicken wire" pattern of lucencies, which correlated histologically with thin fibrous septae. Other characteristics of tumoral calcinosis included fluid-calcium levels, demonstrated in four patients, and smooth osseous erosions adjacent to the mass, demonstrated in three patients. Five cases of tumoral calcinosis were originally confused with other calcified lesions; however, the radiologic findings were characteristic of tumoral calcinosis in retrospect.

Genetic analysis of essential oil variants in Perilla frutescens.

A new chemotype (C type) of Perilla frutescens (Labiatae) that accumulates trans-citral as a main component of the essential oil in the leaf was crossed with five other chemotypes containing perillaldehyde (PA), elsholtziaketone (EK), perillaketone (PK), perillene (PL), and phenylpropanoid (PP) as their respective major components for comparison of genetic differences. The analyses of F1 and F2 progenies showed that trans-citral is accumulated when its metabolism is blocked in the simultaneous absence of a dominant gene N, which is involved in the conversion of trans-citral into naginataketone via cis-citral, and two polymeric genes Fr1 and Fr2, which are involved in the conversion of trans-citral into perillene. On the basis of new data obtained from various intercrosses involving the C type as one of the parents, the genotypes of different chemotypes as well as the sites of action of several genes controlling reaction steps in the biosynthesis of monoterpenes in Perilla have been revised.

Primary bone tumors: value of MR angiography for preoperative planning and monitoring response to chemotherapy.

OBJECTIVE: The purposes of our study were to investigate the use of MR angiography with two- (2D) and three-dimensional (3D) displays in evaluating vascular morphology of musculoskeletal neoplasms for preoperative planning of limb-salvage surgery and to assess the use of MR angiography for monitoring changes in neovascularity and evaluating response to chemotherapy. SUBJECTS AND METHODS: We used MR angiography (2D time-of-flight) to study 13 patients with primary bone tumors (nine osteogenic sarcomas, two Ewing's sarcomas, and two primary lymphomas of bone) at the time of initial presentation. Eight patients (all of whom had osteogenic sarcoma) also underwent MR angiography following chemotherapy before limb-salvage surgery. Two-dimensional maximum intensity projections were obtained. Three-dimensional reconstructions of vascular structures were created from the angiographic source images and were displayed simultaneously with 3D reconstructions of tumor and normal bone generated from conventional MR images. RESULTS: Two-dimensional maximum intensity projections were useful for evaluating small vessel neovascularity; 3D displays demonstrated spatial relationships of tumor, feeder vessels, and normal vascular structures. Tumor encroachment onto or encasement of normal vascular structures was shown in four patients on 2D maximum intensity projections and on 3D displays. The eight patients with osteogenic sarcoma who had follow-up imaging showed marked neovascularity prior to chemotherapy. Five patients responded to chemotherapy (> or = 90% tumor necrosis at histology); MR angiography showed marked reduction in tumor neovascularity in these patients. Three patients did not respond to chemotherapy; MR angiography showed unchanged neovascularity in one and increased neovascularity in two of these patients. CONCLUSION: MR angiography provides good visualization of peripheral vascular branches and tumor neovascularity in patients with primary bone tumors. MR angiography demonstrates encroachment onto and encasement of major vessels by the tumor mass and appears to be useful for assessing response to chemotherapy in osteogenic sarcoma and possibly other primary bone tumors by detecting treatment-induced changes in tumor neovascularity.