PPemd26, an anthraquinone derivative, suppresses angiogenesis via inhibiting VEGFR2 signalling.

BACKGROUND AND PURPOSE: Angiogenesis contributes to coronary heart disease, immune disorders and numerous malignancies. VEGF-A and its receptors (VEGFRs) play a pivotal role in regulating angiogenesis. In an effort to discover more effective inhibitors of tumour angiogenesis, we have analysed the actions of a novel anthraquinone derivative, PPemd26, and explored its anti-angiogenic mechanisms. EXPERIMENTAL APPROACH: The effects of PPemd26 were evaluated in vitro using HUVEC cultures to assess proliferation, migration, invasion and tube formation. Immunoblotting was used to analyse phosphorylation of signalling kinases. Effects in vivo were assayed using Matrigel plug and xenograft mouse models. KEY RESULTS: PPemd26 significantly inhibited VEGF-A-induced proliferation, migration, invasion and tube formation of HUVECs. PPemd26 also attenuated VEGF-A-induced microvessel sprouting from rat aortic rings ex vivo and suppressed formation of new blood vessels in implanted Matrigel plugs in models of angiogenesis in vivo. In addition, PPemd26 inhibited VEGF-A-induced phosphorylation of VEGFR2 and its downstream protein kinases including Akt, focal adhesion kinase, ERK and Src. Furthermore, systemic administration of PPemd26 suppressed the growth of s.c. xenografts of human colon carcinoma in vivo. Histochemical analysis of the xenografts revealed a marked reduction in stainingfor the vascular marker CD31 and proliferation marker Ki-67. CONCLUSIONS AND IMPLICATIONS: This study provides evidence that PPemd26 suppressed tumour angiogenesis through inhibiting VEGFR2 signalling pathways, suggesting that PPemd26 is a potential drug candidate for developing anti-angiogenic agents for the treatment of cancer and angiogenesis-related diseases.

Capsaicin mediates apoptosis in human nasopharyngeal carcinoma NPC-TW 039 cells through mitochondrial depolarization and endoplasmic reticulum stress.

Capsaicin, a pungent compound found in hot chili peppers, has been reported to have antitumor activities in many human cancer cell lines, but the induction of precise apoptosis signaling pathway in human nasopharyngeal carcinoma (NPC) cells is unclear. Here, we investigated the molecular mechanisms of capsaicin-induced apoptosis in human NPC, NPC-TW 039, cells. Effects of capsaicin involved endoplasmic reticulum (ER) stress, caspase-3 activation and mitochondrial depolarization. Capsaicin-induced cytotoxic effects (cell death) through G0/G1 phase arrest and induction of apoptosis of NPC-TW 039 cells in a dose-dependent manner. Capsaicin treatment triggered ER stress by promoting the production of reactive oxygen species (ROS), increasing levels of inositol-requiring 1 enzyme (IRE1), growth arrest and DNA-damage-inducible 153 (GADD153) and glucose-regulated protein 78 (GRP78). Other effects included an increase in cytosolic Ca(2+), loss of the mitochondrial transmembrane potential (ΔΨ(m)), releases of cytochrome c and apoptosis-inducing factor (AIF), and activation of caspase-9 and -3. Furthermore, capsaicin induced increases in the ratio of Bax/Bcl-2 and abundance of apoptosis-related protein levels. These results suggest that ER stress- and mitochondria-mediated cell death is involved in capsaicin-induced apoptosis in NPC-TW 039 cells.

Clinical manifestation of esophageal carcinosarcoma: a Taiwan experience.

Carcinosarcoma of the esophagus is a rare neoplasm with both carcinomatous and sarcomatous components. This study aimed to investigate its clinicopathologic features and endoscopic characteristics. The data of patients diagnosed to have esophageal carcinosarcoma pathologically in the past 30 years (January 1976-December 2007) were reviewed. Of 3318 cases of esophageal malignancy, 12 were diagnosed as esophageal carcinosarcoma, with an incidence of 0.36%. All of the cases were male with a mean age of 62.3 years. Of the 12 tumors, 8 were polypoid type, and 4 were ulcerative type. In the endoscopic ultrasonography examination, the tumors show heterogeneous hypoechoic lesions with irregular outer margins and internal multicystic components. Four patients (33.3%) had previous head and neck squamous cell carcinoma that occurred metachronously. This is the first report about the characteristics of esophageal carcinosarcoma under endoscopic ultrasonography examination. The relationship between esophageal carcinosarcomas and head and neck cancer needs further investigation.

Comprehensive evaluation of a novel nuclear factor-kappaB inhibitor, quinoclamine, by transcriptomic analysis.

BACKGROUND AND PURPOSE: The transcription factor nuclear factor-kappaB (NF-kappaB) has been linked to the cell growth, apoptosis and cell cycle progression. NF-kappaB blockade induces apoptosis of cancer cells. Therefore, NF-kappaB is suggested as a potential therapeutic target for cancer. Here, we have evaluated the anti-cancer potential of a novel NF-kappaB inhibitor, quinoclamine (2-amino-3-chloro-1,4-naphthoquinone). EXPERIMENTAL APPROACH: In a large-scale screening test, we found that quinoclamine was a novel NF-kappaB inhibitor. The global transcriptional profiling of quinoclamine in HepG2 cells was therefore analysed by transcriptomic tools in this study. KEY RESULTS: Quinoclamine suppressed endogenous NF-kappaB activity in HepG2 cells through the inhibition of IkappaB-alpha phosphorylation and p65 translocation. Quinoclamine also inhibited induced NF-kappaB activities in lung and breast cancer cell lines. Quinoclamine-regulated genes interacted with NF-kappaB or its downstream genes by network analysis. Quinoclamine affected the expression levels of genes involved in cell cycle or apoptosis, suggesting that quinoclamine exhibited anti-cancer potential. Furthermore, quinoclamine down-regulated the expressions of UDP glucuronosyltransferase genes involved in phase II drug metabolism, suggesting that quinoclamine might interfere with drug metabolism by slowing down the excretion of drugs. CONCLUSION AND IMPLICATIONS: This study provides a comprehensive evaluation of quinoclamine by transcriptomic analysis. Our findings suggest that quinoclamine is a novel NF-kappaB inhibitor with anti-cancer potential.

The effects of the modulated magnetic fields on electronic structures of graphene nanoribbons.

The low-energy magnetoelectronic structures of nanographene ribbons under a modulated magnetic field are investigated by the Peierls tight-binding model. They are dominated by the field strength, period, phase, the ribbon width, and edge structure. The modulated magnetic field could add state degeneracy, modify energy dispersions, alter subband spacings, affect carrier-density distributions, create additional band-edge states, and cause semiconductor-metal transitions. The main features of energy bands are directly reflected in density of states, such as the position, height, structure, and number of the prominent peaks. These results immensely differ from those in a uniform magnetic field. Significant differences between a 1D graphene ribbon and a 2D electron gas are also found.

Electronic properties of nanotube-ribbon hybrid systems.

In this work we use the tight-binding model to study the electronic properties of nanotube-ribbon hybrid systems. The nanotube-ribbon interactions will modify state energies, alter energy gaps, destroy state degeneracy, and create additional band-edge states. The bandstructures are asymmetric and symmetric about the Fermi energy when the interactions are turned on and off, respectively. The energy gap is found to vary sensitively with the nanotube location. Moreover, semiconductor-metal transition is predicted for nanotube-ribbon hybrid systems (I) and (III). For a zigzag ribbon, the partial flat bands at E(F) are almost unaffected by the nanotube-ribbon coupling although the bandstructures have been noticeably modified by such coupling; the energy gap of system (IV) is always zero. The effects of nanotube diameter and ribbon width on the energy gap and the density of states are also investigated. The semiconductor-metal transition can be accomplished by varying the nanotube location, the nanotube diameter or the ribbon width. The main features of the bandstructure are directly reflected in the density of states. The numbers, heights, and energies of the density of states peaks are strongly dependent on the nanotube-ribbon hoppings.

Extracorporal liver support with molecular adsorbents recirculating system in patients with hepatitis B-associated fulminant hepatic failure.

Hepatitis B virus (HBV) infection is the most prevalent cause of fulminant hepatic failure (FHF) in the Far East. HBV-associated FHF is characterised by rapidly progressive end organ dysfunction/failure and a very poor prognosis. To investigate how molecular adsorbent recirculating system (MARS) treatment impacts multiple organ system function in HBV-associated FHF. Ten consecutive patients were treated with MARS in a period of 12 months. Clinical, biochemical and haemodynamic parameters were assessed before and after MARS. Various disease severity scoring systems including model for end-stage liver disease, APACHE II, APACHE III, sequential organ failure assessment and organ system failure scores were also assessed. There were significant improvements in hepatic encephalopathy grading (p < 0.001), mean arterial pressure (p < 0.001), plasma renin activity (p = 0.027), bilirubin (p < 0.001), ammonia (p = 0.001) and creatinine levels (p < 0.001). There were also significant improvements in all the scoring systems evaluated. Meanwhile, platelet count was significantly decreased (p < 0.001). One patient was successfully bridged to liver transplantation. Three patients were alive at 3 months of follow-up. MARS can improve multiple organ functions in HBV-associated FHF. On the basis of these findings, randomised controlled studies are indicated and justified.

Synthesis of 1-benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole analogues as novel antiplatelet agents.

1-Benzyl-3-(5'-hydroxymethyl-2'-furyl)indazole (28, YC-1) was selected as the lead compound for systemic structural modification. After screening for antiplatelet activity, SARs of YC-1 analogues were established. Among these potent active derivatives, compounds 29, 30, 31, 44, and 45 functioned as potent activators of sGC and inhibitors of PDE5 with potency comparable to that of YC-1. In addition, compound 58 was found to be a selective and potent inhibitor of protease-activated receptor type 4 (PAR4)-dependent platelet activation.

Angiomyolipoma of the liver: case report.

Hepatic angiomyolipoma is a rare benign mesenchymal tumor of the liver. Most multiple hepatic angiomyolipomas have appeared in patients with renal angiomyolipoma and tuberous sclerosis. A 38-year-old female patient without chronic hepatitis B or C was hospitalized because of epigastric fullness for 2 months. Radiologic studies showed a large solid tumor with a small daughter nodule in the right hepatic lobe. Upon intravenous bolus injection of contrast medium, both tumors showed weak heterogeneous enhancement in the delayed phase. Although hepatocellular carcinoma was suspected by the findings of computed tomography, percutaneous transhepatic ultrasound-guided biopsy was performed for the large tumor. The histopathology showed many mature fat cells intermingled with thick-walled blood vessels, and epithelioid cells with eosinophilic cytoplasm; the epithelioid cells stained positively for HMB-45 and smooth muscle actin. Angiomyolipoma of the liver was confirmed. The main tumor enlarged considerably during a follow-up period of 3 years. Surgical resection was performed due to persistent symptoms. She had an uneventful postoperative recovery and was well when followed up 10 months after surgery. We should be aware that a hepatic angiomyolipoma can change in size during its natural course, and this finding does not necessarily indicate malignancy.

Acute jejunogastric intussusception: report of five cases.

The purpose of this study was to investigate the clinical manifestations and diagnosis of patients with acute jejunogastric intussusception. From May 1986 to June 1999, a total of 5 men (54-76 years old) were collected. Their initial presentations included epigastralgia (4), coffee-ground vomitus (3), frank hematemesis (1), and tarry stool (1). All patients had gastric surgeries 10-30 years previously. Radiograph of the abdomen showed a soft tissue density at the left upper quadrant in one patient. Panendoscopies were done in 4 patients. An obstructed efferent loop with a distended hyperemic small bowel protruding into the remnant of stomach was found in 3 cases, gangrenous change of the bowel wall in one of them. Stump cancer was diagnosed initially in the other patient. Barium study (3/5) showed efferent loop obstruction with "coil spring sing" and a central defect in the stomach. All 5 patients underwent segmental resection and end-to-end anastomosis between the 2nd to 6th hospital day. Operative findings were type II jejunogastric intussusception with retrograde invagination of a segment of efferent loop (30-100 cm in length) into the stomach. In conclusion, acute jejunogastric intussusception is an emergent condition. Early and accurate diagnosis is important. A high susception must be kept in mind in patients having a history of gastrojejunostomy with severe abdominal pain or upper gastrointestinal bleeding.

Synthesis of 4-alkoxy-2-phenylquinoline derivatives as potent antiplatelet agents.

In our continuing search for novel antiplatelet agents, 4-alkoxy derivatives of 2-phenylquinoline as well as related compounds were prepared. Through biological screening, a preliminary structure antiplatelet activity relationship was established. Compounds 5-ethyl-4-methoxy-2-phenylquinoline (8), 4-ethoxy-5-ethyl-2-phenylquinoline (9), 4-ethoxycarbonylmethoxy-5-ethyl-2-phenylquinoline (10), 4-ethoxycarbonylbutoxy-5-ethyl-2-phenylquinoline (12) and 5-ethyl-4-(N-ethylcarboxido)methoxy-2-phenylquinoline (17) all demonstrated potent antiplatelet activity. Among them, compound 8 was the most potent with an IC50 value of 0.08 microM and was about 3-fold more active than indomethacin. The mechanism of antiplatelet action of 8 is possibly through its inhibition on cyclooxygenase or thromboxane synthetase.

Hemosuccus pancreaticus from a traumatic gastroduodenal pseudoaneurysm: an unusual cause of upper gastrointestinal bleeding.

Hemosuccus pancreaticus, blood entering the gastrointestinal tract through the pancreatic duct, is a rare and elusive form of gastrointestinal bleeding with diagnostic difficulties. We report a 37-year-old man who had recurrent gastrointestinal bleeding from erosion of a pseudoaneurysm of the gastroduodenal artery into the pancreatic duct. The lack of history of pancreatitis, associated symptoms, equivocal endoscopic findings, and the rarity of this entity resulted in a delay in diagnosis. Pancreatic duct stenosis detected during surgery suggested the lesion might have been caused by blunt abdominal trauma. A nearly total pancreatectomy and splenectomy were performed. The patient remained symptom-free 8 months after the operation. This obscure cause of gastrointestinal bleeding should be considered when common causes of bleeding have been ruled out, even in the absence of pancreatitis.

Vector competence of Culex pipiens molestus (Diptera: Culicidae) from Taiwan for a sympatric strain of Japanese encephalitis virus.

Laboratory strains of Culex pipiens molestus Forskal and Culex tritaeniorhynchus Giles from northern Taiwan were compared for their susceptibility to the Sanhsia MQ1-2 (SH) strain of Japanese encephalitis (JE) virus isolated from Taiwan. After feeding on a sweetened blood-virus mixture, viral titers in Cx. p. molestus during the 14-d incubation period ranged from a minimum of 2.9 log10PFU (plaque forming units) per mosquito on day 3 after ingestion to a maximum of 4.65 log10PFU at day 8 and in Cx. tritaeniorhynchus from 2.6 on day 10-5.18 log10PFU per mosquito on day 13. Although virus titer in Cx. p. molestus was lower than in Cx. tritaeniorhynchus at the end of the experiment, this difference was not statistically significant. The median infective dose (ID50) for Cx. p. molestus was 2.83 log10PFU and for Cx. tritaeniorhynchus was 1.02 log10PFU per mosquito, and this difference also was not significant. There also was no significant difference between the median infective dose for transmission (TID50) per mosquito for Cx. p. molestus (5.34 log10PFU) and Cx. tritaeniorhynchus (4.59 log10PFU). We concluded that Cx. p. molestus is an effective laboratory vector of JE virus.

Mutational analysis of the p27(kip1) gene in hepatocellular carcinoma.

p27(Kip1) is an inhibitor of cyclin-dependent kinase. It has been reported that reduced p27(Kip1) expression is present in human hepatocellular carcinoma. To determine the role of p27(Kip1) in hepatocarcinogenesis, 46 cases with hepatocellular carcinomas were studied. p27(Kip1) mutation was first screened by single strand conformation polymorphism, and direct DNA sequencing was then performed on those cases with mobility shifts. Two polymorphism sites were found. One is a previously described polymorphism at codon 109 (GTC-->GGC) which was found in two cases. The second polymorphism was identified at codon 55 (GCG-->GCA) in six of the 46 cases. However, the polymorphism at codon 55 was also present in seven of 93 healthy controls (7.5%), indicating that it is not associated with a predisposition for development of hepatocellular carcinoma (Fisher's exact test, 0.05). These results show that p27(Kip1) mutation is not a frequent event in human hepatocellular carcinoma, and suggest that it may be inactivated predominantly by transcriptional and/or posttranscriptional regulation rather than genomic aberrations.

Endocrine effects of the podophyllotoxine derivative drug CPH 82 (Reumacon) in patients with rheumatoid arthritis.

CPH 82 is a non-steroid antirheumatic drug containing two benzylidenated podophyllotoxin glucosides with no affinity for the glucocorticoid receptor. Treatment with CPH 82 as single drug therapy significantly decreased serum and urinary cortisol and cortisol metabolites, serum adrenal androgens and urinary androgen metabolites, plasma ACTH and serum interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), and increased serum levels of sex hormone-binding globulin (SHBG). Significant positive correlations were found between serum TNF-alpha and plasma ACTH and between serum IL-6 and TNF-alpha on the one hand and serum and urinary cortisol and cortisol metabolites on the other. The initial action of CPH 82 on adrenal steroidogenesis may be a reduction in cytokine levels due to the drugs' antiinflammatory effect. This causes decreased ACTH stimulation, resulting in a reduced adrenocortical steroid secretion. Accumulation of the drug in the adrenal cortex may also affect adrenal steroidogenesis. The elevated SHBG levels may be caused by a weak estrogenic activity of the drug.

Tissue-engineered valved conduits in the pulmonary circulation.

OBJECTIVE: Bioprosthetic and mechanical valves and valved conduits are unable to grow, repair, or remodel. In an attempt to overcome these shortcomings, we have evaluated the feasibility of creating 3-leaflet, valved, pulmonary conduits from autologous ovine vascular cells and biodegradable polymers with tissue-engineering techniques. METHODS: Endothelial cells and vascular medial cells were harvested from ovine carotid arteries. Composite scaffolds of polyglycolic acid and polyhydroxyoctanoates were formed into a conduit, and 3 leaflets (polyhydroxyoctanoates) were sewn into the conduit. These constructs were seeded with autologous medial cells on 4 consecutive days and coated once with autologous endothelial cells. Thirty-one days (+/-3 days) after cell harvesting, 8 seeded and 1 unseeded control constructs were implanted to replace the pulmonary valve and main pulmonary artery on cardiopulmonary bypass. No postoperative anticoagulation was given. Valve function was assessed by means of echocardiography. The constructs were explanted after 1, 2, 4, 6, 8, 12, 16, and 24 weeks and evaluated macroscopically, histologically, and biochemically. RESULTS: Postoperative echocardiography of the seeded constructs demonstrated no thrombus formation with mild, nonprogressive, valvular regurgitation up to 24 weeks after implantation. Histologic examination showed organized and viable tissue without thrombus. Biochemical assays revealed increasing cellular and extracellular matrix contents. The unseeded construct developed thrombus formation on all 3 leaflets after 4 weeks. CONCLUSION: This experimental study showed that valved conduits constructed from autologous cells and biodegradable matrix can function in the pulmonary circulation. The progressive cellular and extracellular matrix formation indicates that the remodeling of the tissue-engineered structure continues for at least 6 months.

Combined endoscopic and surgical treatment for the polyposis of Peutz-Jeghers syndrome.

Repeated laparotomy with extensive small bowel resectioning and eventual short-bowel syndrome is a major problem in Peutz-Jeghers syndrome (PJS) patients. This problem is caused by gastrointestinal polyposis with intussusception. A combined surgical and endoscopic approach can assess the extent of the polyposis, and small polyps can be removed by snare polypectomy. This can avert multiple enterotomies and decrease bowel resection segments. We applied an intraoperative colonscope via the enterotomy route in an 20-year-old PJS woman, and successfully removed the other 10 polyps distributed in the whole small bowel. As part of an aggressive approach to the management of polyposis in PJS, complete polypectomy can provide a longer symptom-free interval and remove potentially premaligment polyps.