bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II Study of Pemetrexed Plus Carboplatin in Malignant Pleural Mesothelioma
Authors: Ceresoli Giovanni L. , Zucali Paolo A. , Favaretto Adolfo G. , Grossi Francesco , Bidoli Paolo , Del Conte Guido , Ceribelli Anna , Bearz Alessandra , Morenghi Emanuela , Cavina Raffaele , Marangolo Maurizio , Parra Hector J. Soto , Santoro Armando
Published: March 2006

Purpose

This multicenter, phase II clinical study was conducted to evaluate the activity of the combination of pemetrexed and carboplatin in patients with malignant pleural mesothelioma (MPM).

Patients and Methods

Chemotherapy-naive patients with measurable disease and adequate organ function, who were not eligible for curative surgery, received pemetrexed 500 mg/m2and carboplatin area under the plasma concentration-time curve of 5 mg/mL/min, administered intravenously every 21 days. All patients received folic acid and vitamin B12supplementation. Pemetrexed was provided within the Expanded Access Program.

Results

A total of 102 patients were enrolled. An objective response was achieved in 19 patients (two complete and 17 partial responses), for a response rate of 18.6% (95% CI, 11.6% to 27.5%). Forty-eight patients (47.0%; 95% CI, 37.1% to 57.2%) had stable disease after treatment. Overall, 67 patients (65.7%) achieved disease control (95% CI, 55.6% to 74.8%). Median time to progression was 6.5 months; median overall survival time was 12.7 months. Compliance to treatment was excellent, with a relative dose-intensity of 97% for pemetrexed and 98% for carboplatin. Toxicity was mild, with grade 3 or 4 neutropenia occurring in 9.7% of total cycles and grade 3 or 4 anemia occurring in 3.5% of total cycles. Nonhematologic toxicity was negligible.

Conclusion

Treatment with pemetrexed and carboplatin was active and well tolerated in patients with MPM. Disease control rate, time to disease progression, and overall survival were similar to the results achieved with the standard regimen of pemetrexed and cisplatin, suggesting that the carboplatin combination could be an alternative option for these patients.
Phase III Study of Gemcitabine and Cisplatin With or Without Aprinocarsen, a Protein Kinase C-Alpha Antisense Oligonucleotide, in Patients With Advanced-Stage Non–Small-Cell Lung Cancer
Authors: Paz-Ares Luis , Douillard Jean-Yves , Koralewski Piotr , Manegold Christian , Smit Egbert F. , Reyes José Miguel , Chang Gee-Chen , John William J. , Peterson Patrick M. , Obasaju Coleman K. , Lahn Michael , Gandara David R.
Published: March 2006

Purpose

To determine whether aprinocarsen, an antisense oligonucleotide directed against protein kinase C-alpha, when added to the chemotherapy regimen of gemcitabine and cisplatin improved survival in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients with previously untreated stage IIIB/IV NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly assigned to either a control arm of gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1, or experimental arms consisting of the identical chemotherapy plus aprinocarsen 2 mg/kg/d as continuous infusion for 14 days, starting on either day 1 or 3 days before chemotherapy. Cycles were repeated every 21 days.

Results

A total of 670 patients were randomly assigned between the control (n = 328) and experimental arms (n = 342). Due to the results from another phase III study of aprinocarsen in NSCLC, further enrollment was stopped, and the study was terminated early. The median number of cycles was four on the control arm and three on the combined experimental arms. Median overall survival was not different between the two groups (control, 10.4 months [95% CI, 8.6 to 12.2]; experimental, 10.0 months [95% CI, 8.4 to 10.8]; P = .613; hazard ratio = 1.05 [95% CI, 0.88 to 1.25]). Response rates (control arm, 35.0%; experimental arms, 28.9%; P = .124) and other time-to-event measures were not significantly different. Grade 3 and 4 toxicities were significantly increased for thrombocytopenia (P < .0001), epistaxis, and thrombosis/embolism in the experimental arms.

Conclusion

Adding aprinocarsen to gemcitabine and cisplatin regimen did not enhance survival and other efficacy measures in patients with advanced NSCLC.
Missed Opportunities: Racial Disparities in Adjuvant Breast Cancer Treatment
Authors: Bickell Nina A. , Wang Jason J. , Oluwole Soji , Schrag Deborah , Godfrey Henry , Hiotis Karen , Mendez Jane , Guth Amber A.
Published: March 2006

Purpose

Underuse of adjuvant therapy is a potentially important and remediable explanation for the inferior survival of minority women with breast cancer. We sought to measure a racial disparity in the underuse of adjuvant treatments for early-stage breast cancer and to identify associated factors.

Methods

Cross-sectional study with review of all inpatient and outpatient medical records of 677 women treated surgically for a primary American Joint Committee on Cancer stage I or II breast cancer in 1999 to 2000. Underuse was defined as omissions of radiation therapy after breast-conserving surgery, adjuvant chemotherapy after resection of hormone-receptor-negative tumors ≥ 1 cm, or hormonal therapy for receptor-positive tumors ≥ 1 cm.

Results

One hundred forty-five (21%) of 677 women experienced underuse of appropriate adjuvant therapy: 16% in whites, 34% in blacks, and 23% in Hispanics (P < .001). Women referred to medical oncologists were less likely to experience underuse of necessary adjuvant treatments (relative risk [RR] for underuse = 0.2; 95% CI, 0.1 to 0.3). Women who were minorities (RR = 2.0; 95% CI, 1.3 to 3.1), had higher levels of comorbidity (RR = 1.4; 95% CI, 1.1 to 1.8) and lacked insurance (RR = 1.9; 95% CI, 0.9 to 4.0) were at greater risk for underuse.

Conclusion

Minority women with early-stage breast cancer have double the risk of white women for failing to receive necessary adjuvant treatments despite rates of oncologic consultation similar to those for white women. Oncology referrals are necessary to reduce treatment disparities but are not sufficient to ensure patients' receipt of efficacious adjuvant treatment.
Postradiotherapy Neck Dissection for Lymph Node–Positive Head and Neck Cancer: The Use of Computed Tomography to Manage the Neck
Authors: Liauw Stanley L. , Mancuso Anthony A. , Amdur Robert J. , Morris Christopher G. , Villaret Douglas B. , Werning John W. , Mendenhall William M.
Published: March 2006

Purpose

To determine how to use node response on computed tomography (CT) to indicate the need for neck dissection.

Patients and Methods

Five hundred fifty patients with lymph node–positive head and neck cancer were treated between 1990 and 2002 with radiotherapy (RT) at a median dose of 74.4 Gy; 24% of these patients (n = 133) were treated with chemotherapy. Three hundred forty-one patients (62%) underwent planned post-RT neck dissection. Physical examination and contrast-enhanced CT were performed 30 days after completion of RT. CT images were reviewed in 211 patients for lymph node size (largest axial dimension) and presence of a focal abnormality (lucency, enhancement, or calcification). By correlating post-RT CT to neck dissection pathology, criteria associated with a low likelihood of residual disease were identified. A subset of patients who fit these criteria of radiographic response who did not undergo post-RT neck dissection was observed for recurrence.

Results

Radiographic complete response (rCR) was defined as the absence of any large (> 1.5 cm) or focally abnormal lymph node. Correlation of response with neck dissection pathology indicated a negative predictive value of 77% for complete clinical response and 94% for rCR. In 32 patients (median follow-up time, 3.2 years) with rCR who did not undergo post-RT neck dissection, the 5-year ultimate neck control rate (100%) and cause-specific survival rate (72%) were not significantly different from the rates of patients with a negative post-RT neck dissection.

Conclusion

Patients with rCR 4 weeks after RT can be spared from a post-RT neck dissection regardless of initial node stage.
Can drug-bearing liposomes penetrate intact skin?
Authors: El Maghraby Gamal M M , Williams Adrian C , Barry Brian W
Published: March 2006

Using liposomes to deliver drugs to and through human skin is controversial, as their function varies with type and composition. Thus they may act as drug carriers controlling release of the medicinal agent. Alternatively, they may provide a localized depot in the skin so minimizing systemic effects or can be used for targeting delivery to skin appendages (hair follicles and sweat glands). Liposomes may also enhance transdermal drug delivery, increasing systemic drug concentrations. With such a multiplicity of functions, it is not surprising that mechanisms of liposomal delivery of therapeutic agents to and through the skin are unclear. Accordingly, this article provides an overview of the modes and mechanisms of action of different vesicles as drug delivery vectors in human skin. Our conclusion is that vesicles, depending on the composition and method of preparation, can vary with respect to size, lamellarity, charge, membrane fluidity or elasticity and drug entrapment. This variability allows for multiple functions ranging from local to transdermal effects. Application to dissimilar skins (animal or human) via diverse protocols may reveal different mechanisms of action with possible vesicle skin penetration reaching different depths, from surface assimilation to (rarely) the viable tissue and subsequent systemic absorption.
Significant and prolonged antisense effect of a multifunctional envelope-type nano device encapsulating antisense oligodeoxynucleotide
Authors: Nakamura Yoshio , Yamada Yuma , Kogure Kentaro , Harashima Hideyoshi , Futaki Shiroh
Published: March 2006

A multifunctional envelope-type nano device (MEND) was developed for use as an efficient non-viral system for the delivery of plasmid DNA (pDNA) using octaarginine (R8) as an internalizing ligand. Three types of R8-MENDs were prepared, co-encapsulating luciferase-encoding pDNA and antiluciferase oligodeoxynucleotide (ODN) condensed by three polycations, stearyl octaarginine (STR-R8), poly-l-lysine (PLL) and protamine, and the antisense effects of the ODN-encapsulated R8-MENDs (ODN-MEND) were analysed in-vitro. The ODN-MEND packaged using protamine as a condenser showed a 90% antisense effect 16 h after the transfection, and a persistent antisense effect of over 75% for up to 48 h, which was much more effective than that of LipofectAmine2000. On the other hand, the ODN-MENDs prepared using PLL and STR-R8 as condensers did not show any significant inhibition of luciferase activity. Although there was no specific relation between the physicochemical characteristics of the ODN-MENDs and their antisense effect, the pattern of the antisense effect among the ODN-MENDs was similar to that of the silencing effect of R8-MEND encapsulating plasmid DNA encoding siRNA. These results suggest that R8-MENDs are able to deliver encapsulated DNA to the cytosol as well as to the nucleus, and that protamine can also function as an efficient decondenser, not only in the nucleus but also in the cytosol. In conclusion, we successfully developed an ODN-MEND with a high antisense effect using protamine as a DNA condensing as well as a decondensing agent.
Evaluation of the immune response induced by a nasal anthrax vaccine based on the protective antigen protein in anaesthetized and non-anaesthetized mice
Authors: Sloat Brian R , Cui Zhengrong
Published: March 2006

To better protect against inhalational anthrax infection, a nasal anthrax vaccine based on the protective antigen (PA) protein of Bacillus anthracis could be an attractive alternative to the current Anthrax-Vaccine-Adsorbed (AVA), which was licensed for cutaneous anthrax prevention. Previously, we have demonstrated that an anti-PA immune response comparable with that in mice subcutaneously immunized with PA protein adjuvanted with aluminium hydroxide was induced in both the systemic compartment and the mucosal secretions of the nose and lung of anaesthetized mice when they were nasally immunized with PA protein incorporated into previously reported LPD (Liposome—Protamine—DNA) particles. In this study, we evaluated the anti-PA immune response induced by the nasal PA/LPD particles in non-anaesthetized mice and compared it with that in anaesthetized mice. Our data showed that the anti-PA antibody response and the anthrax lethal toxin-neutralization activity induced by the nasal PA/LPD in non-anaesthetized mice was relatively weaker than that in anaesthetized mice. However, the splenocytes isolated from the nasally immunized mice, anaesthetized and non-anaesthetized, proliferated comparably after in-vitro re-stimulation. By evaluating the uptake of fluorescence-labelled LPD particles by phagocytes in the nasal and broncho-alveolar lavages of mice after the nasal administration, we concluded that the relatively weaker anti-PA immune response in the non-anaesthetized mice might be partially attributed to the reduced retention of the PA/LPD particles in the nasal cavity of the non-anaesthetized mice. Data collected in this study are expected to be useful for future anthrax nasal vaccine studies when mice are used as a model.
Effects of enzyme inducers and inhibitors on the pharmacokinetics of intravenous ipriflavone in rats
Authors: Chung Hye J , Choi Young H , Lee Myung G , Kim So H
Published: March 2006

In order to find out what types of the hepatic microsomal cytochrome P450 (CYP) isozymes are involved in the metabolism of ipriflavone, ipriflavone at a dose of 20 mg kg−1 (or 15 mg kg−1) was infused in male Sprague—Dawley rats. In rats pretreated with SKF 525-A (a non-specific CYP isozyme inhibitor in rats), the total body clearance (CL) of ipriflavone was significantly slower (29.9% decrease) than that in control rats. This indicates that ipriflavone is metabolized via CYP isozymes in rats, hence various enzyme inducers and inhibitors were used in in-vitro or in-vivo studies in rats. In rats pretreated with 3-methylcholanthrene and phenobarbital (main inducers of CYP1A1/2 and 2B1/2 in rats, respectively), the CL values were significantly higher (153 and 67.2% increases, respectively). In rats pretreated with sulfaphenazole (a main inhibitor of CYP2C11 in rats), the CL was significantly slower (22.5% decrease) than that in control rats. On addition of furafylline (a main inhibitor of CYP1A2 in rats), the in-vitro intrinsic clearance for the disappearance of ipriflavone was significantly slower (50.8% decrease) than that without furafylline. However, the CL values were not significantly different in rats pretreated with orphenadrine and isoniazid (a main inducer of CYP2E1 in rats), and quinine and troleandomycin (main inhibitors of CYP2D1 and 3A23/2 in rats, respectively) compared to controls. These data suggest that ipriflavone could be metabolized mainly via CYP1A1/2, 2B1/2 and 2C11 in rats.
Ethinylestradiol-loaded ultraflexible liposomes: pharmacokinetics and pharmacodynamics
Authors: Garg Minakshi , Mishra Dinesh , Agashe Hrushikesh , Jain Narendra Kumar
Published: March 2006

This study aimed to develop ultraflexible liposomes as an alternative to the oral route, which would enhance the bioavailability and reduce the toxicity of ethinylestradiol. Ultraflexible liposomes of ethinylestradiol using an optimized concentration of surfactants were prepared and characterized in vitro. The effect of surfactant type under non-occlusive conditions on transdermal permeability was assessed. A histopathological study was performed to assess the action of ethinylestradiol on the uterus and ovaries. The pharmacokinetics of free ethinylestradiol (following single oral administration and one day of application to the skin), ultraflexible liposomal ethinylestradiol and non-flexible liposomal ethinylestradiol were studied in female Sprague—Dawley rats. Insignificant differences in size between the ultraflexible liposomal formulations containing optimized concentrations of different surfactants were observed. Ultraflexible liposomes can penetrate through pores much smaller than their own diameter. The transdermal permeability of lipophilic surfactant was greater than that of hydrophilic surfactant. The release of ethinylestradiol from the proposed formulation through rat skin was found to be constant. The histopathological study showed that the ultraflexible liposomal transdermal drug delivery system for ethinylestradiol provided effective contraception by follicular cell lysis, depletion of zona granulosa and ova, and by increasing the uterine mucosal and endometrial proliferation. Encapsulation of ethinylestradiol in ultraflexible liposomes modified the pharmacodynamics and pharmacokinetics of the contraceptive agent, resulting in a marked improvement in bioavailability and optimized therapy.
ATP participates in the regulation of microvessel permeability
Authors: Tanaka Naoko , Nejime Namie , Kagota Satomi , Kubota Yoko , Yudo Keiko , Nakamura Kazuki , Kunitomo Masaru , Shinozuka Kazumasa , Takahashi Koichi , Hashimoto Michio
Published: March 2006

We demonstrated previously that stimulation of the P2Y receptor enhanced the macromolecular permeability of cultured endothelial cell monolayers via the paracellular pathway. To determine whether the P2Y receptor participates in the regulation of permeability in intact microvessels, we have examined the effects of exogenous and endogenous ATP on the permeation of the surface tissue of perfused rat tail caudal artery using a fluorescein isothiocyanate-dextran (FD-4; MW 4400; 1.0 mg mL−1). The permeation of FD-4 was assessed by a confocal fluorescence imaging system. We found that 2-methylthioadenosine 5′-triphosphate, a P2Y receptor agonist, enhanced the fluorescence intensity of FD-4 in the surface of the rat caudal artery tissue and that it was inhibited by pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid, a P2 receptor antagonist. Also, noradrenaline, a sympathetic neurotransmitter, and bradykinin, an inflammatory autacoid, enhanced the fluorescence intensity of FD-4 in the surface tissue of the rat caudal artery. The enhancement by noradrenaline was significantly inhibited by the P2 receptor antagonist. In addition, noradrenaline and bradykinin caused the release of ATP, ADP, AMP and adenosine from the endothelium of the rat caudal artery. These results indicated that the exogenous and endogenous ATP increased the macromolecular permeability of blood capillaries via the P2Y receptor. Such purinergic regulation of endothelial permeability may function in physiological and pathophysiological conditions.
Induction of neutral endopeptidase (NEP) activity of SK-N-SH cells by natural compounds from green tea
Authors: Ayoub Shereen , Melzig Matthias F
Published: March 2006

Deposition of amyloid β-peptide as senile plaques in the brain is one of the neuropathological hallmarks of Alzheimer's disease, which is the most prevalent progressive neurodegenerative disease leading to dementia. Neutral endopeptidase is one of the major β-amyloid-degrading enzymes in the brain. To examine the influence of different polyphenols and other natural products from green tea extract (from Camellia sinensis, Theaceae), we used the neuroblastoma cell line SK-N-SH and studied the changes in the specific cellular neutral endopeptidase activity after long-term treatment with these substances. We have shown that caffeine leads to an increase in specific cellular neutral endopeptidase activity more than theophylline, theobromine or theanine. We have also shown that the combination of epicatechin, epigallocatechin and epigallocatechingallate with caffeine, theobromine or theophylline induced cellular neutral endopeptidase activity. It is suggested that the enhancement of cellular neutral endopeptidase activity by green tea extract and its natural products might be correlated with an elevated level of intracellular cyclic adenosine monophosphate.
Rubiae Radix suppresses the activation of mast cells through the inhibition of Syk kinase for anti-allergic activity
Authors: Lee Jun Ho , Kim Nam Wook , Her Erk , Kim Bo Kyung , Choi Wahn Soo , Hwang Keum Hee , Choi Dong Kug , Lim Beong Ou , Han Jeung Whan , Kim Young Mi
Published: March 2006

The effect of extracts from various Oriental medicinal herbs on mast-cell-mediated allergic reactions was investigated in this study. Of these extracts, the medicinal herb Rubiae Radix exhibited the most potent activity in the cells, with an IC50 value (concentration necessary to obtain 50% inhibition of the response) of approximately 35±2.1 μg mL−1, and its inhibition of compound-48/80-induced systemic anaphylaxis by 48.6±8.5% at 300 mg kg−1 in mice. It also inhibited the expression of the pro-inflammatory mediator tumour necrosis factor-α (TNF-α). As for its mechanism of action, Rubiae Radix suppressed the activating phosphorylation of Syk, a key enzyme in mast-cell signalling processes, and that of Akt in a dose-dependent manner. It also inhibited the MAP kinase ERK1/2, which is critical for the production of inflammatory cytokines in mast cells, as indicated by the suppression of the activating phosphorylation of ERK1/2. These results suggest that Rubiae Radix suppresses the activation of mast cells through the inhibition of Syk for antiallergic activity.
Withania somnifera improves bone calcification in calcium-deficient ovariectomized rats
Authors: Nagareddy Prabhakara Reddy , Lakshmana M
Published: March 2006

Osteoporosis, characterized by reduction in bone density, is a significant source of mortality among the elderly, particularly in oestrogen-deficient women. We studied the effect of Withania somnifera (WS) root extract (ethanolic), which contains oestrogen-like withanolides for anti-osteoporotic activity. Female Sprague-Dawley rats were either sham operated (n = 12) or ovariectomized (n = 12) and treated with WS/vehicle (65 mg kg−1), orally for 16 weeks (n = 12). All rats were allowed free access to a calcium-deficient diet (0.04% Ca) and distilled water. At termination, urinary excretion of calcium (Ca) and phosphorus (P) and serum levels of Ca, P and alkaline phosphatase (ALP) were measured. Femur and tibia bones were processed for histological (histology), morphological (scanning electron microscopy, SEM), biomechanical strength (impact test) and mineral composition (ash) analysis. Ovariectomized (OVX) rats showed a significant increase in serum ALP levels and urinary Ca and P excretion. Histological findings revealed narrowed, and disappearance of, trabeculae with widened medullary spaces in the OVX group. Ash analysis showed a reduction in ash weight, percent ash, ash Ca, ash P and ash magnesium levels in the OVX group. Further, SEM examination revealed metaphyseal bone loss in femurs and impact test showed a reduction in biomechanical strength of tibias in OVX rats. WS treatment markedly prevented the above changes in OVX rats and thus may be a potential agent in the treatment of osteoporosis.
A polysaccharopeptide complex and a condensed tannin with antioxidant activity from dried rose (Rosa rugosa) flowers
Authors: Ng T B , Pi Z F , Fu M , Li L , Hou J , Shi L S , Chen R R , Jiang Y , Liu F , Yue H , Zhao L
Published: March 2006

In this study, the fraction (P) from an aqueous extract of dried rose (Rosa rugosa) flowers was obtained by ethanol precipitation. P was chromatographed on DEAE-cellulose. The components retained on DEAE-cellulose were eluted with a linear gradient of 0–2 m NaCl solution. Two fractions, eluted at concentrations of 0.5 m NaCl and 1 m NaCl, respectively, were obtained. These two components were designated as P1 and P2, respectively. P1 was further purified using gel filtration on Sephadex G-200. P1 yielded two peaks, and the two components were designated as P1-a and P1-b, respectively. P1-a was a polysaccharide-peptide complex, and P1-b exhibited chemical properties of a condensed tannin as revealed by FTIR and NMR assay of carbohydrate and protein contents and HPLC-ESI-MS. The molecular masses of P1-a and P1-b were 150kDa and 8kDa, respectively. Both P1-a and P1-b possessed antioxidant activity, with the activity of P1-b higher than that of P1-a. This study demonstrated that different components from rose flowers exhibited antioxidant activity.
Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats
Authors: Saad Sherif Y , Alkharfy Khalid M , Arafah Maha M
Published: March 2006

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg−1 intraperitoneally and 30 mg kg−1 orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.
Isl1Cre reveals a common Bmp pathway in heart and limb development
Authors: Yang Lei , Cai Chen-Leng , Lin Lizhu , Qyang Yibing , Chung Christine , Monteiro Rui M. , Mummery Christine L. , Fishman Glenn I. , Cogen Anna , Evans Sylvia
Published: March 2006

A number of human congenital disorders present with both heart and limb defects, consistent with common genetic pathways. We have recently shown that the LIM homeodomain transcription factor islet 1 (Isl1) marks a subset of cardiac progenitors. Here, we perform lineage studies with an Isl1Cre mouse line to demonstrate that Isl1 also marks a subset of limb progenitors. In both cardiac and limb progenitors, Isl1 expression is downregulated as progenitors migrate in to form either heart or limb. To investigate common heart-limb pathways in Isl1-expressing progenitors, we ablated the Type I Bmp receptor,Bmpr1a utilizing Isl1Cre/+. Analysis of consequent heart and limb phenotypes has revealed novel requirements for Bmp signaling. Additionally, we find that Bmp signaling in Isl1-expressing progenitors is required for expression of T-box transcription factors Tbx2 and Tbx3 in heart and limb. Tbx3 is required for heart and limb formation, and is mutated in ulnar-mammary syndrome. We provide evidence that the Tbx3 promoter is directly regulated by Bmp Smads in vivo.
The TGFβ activated kinase TAK1 regulates vascular development in vivo
Authors: Jadrich Joy L. , O'Connor Michael B. , Coucouvanis Electra
Published: March 2006

TGFβ activated kinase 1 (TAK1) is a MAPKKK that in cell culture systems has been shown to act downstream of a variety of signaling molecules,including TGFβ. Its role during vertebrate development, however, has not been examined by true loss-of-function studies. In this report, we describe the phenotype of mouse embryos in which the Tak1 gene has been inactivated by a genetrap insertion. Tak1 mutant embryos exhibit defects in the developing vasculature of the embryo proper and yolk sac. These defects include dilation and misbranching of vessels, as well as an absence of vascular smooth muscle. The phenotype of Tak1 mutant embryos is strikingly similar to that exhibited by loss-of-function mutations in the TGFβ type I receptor Alk1 and the type III receptor endoglin,suggesting that TAK1 may be a major effector of TGFβ signals during vascular development. Consistent with this view, we find that in zebrafish,morpholinos to TAK1 and ALK1 synergize to enhance the Alk1 vascular phenotype. Moreover, we show that overexpression of TAK1 is able to rescue the vascular defect produced by morpholino knockdown of ALK1. Taken together,these results suggest that TAK1 is probably an important downstream component of the TGFβ signal transduction pathway that regulates vertebrate vascular development. In addition, as heterozygosity for mutations in endoglin and ALK1 lead to the human syndromes known as hereditary hemorrhagic telangiectasia 1 and 2, respectively, our results raise the possibility that mutations in human TAK1 might contribute to this disease.
Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates
Authors: Adams Dany S. , Robinson Kenneth R. , Fukumoto Takahiro , Yuan Shipeng , Albertson R. Craig , Yelick Pamela , Kuo Lindsay , McSweeney Megan , Levin Michael
Published: March 2006

Biased left-right asymmetry is a fascinating and medically important phenomenon. We provide molecular genetic and physiological characterization of a novel, conserved, early, biophysical event that is crucial for correct asymmetry: H+ flux. A pharmacological screen implicated the H+-pump H+-V-ATPase in Xenopus asymmetry, where it acts upstream of early asymmetric markers. Immunohistochemistry revealed an actin-dependent asymmetry of H+-V-ATPase subunits during the first three cleavages. H+-flux across plasma membranes is also asymmetric at the four- and eight-cell stages, and this asymmetry requires H+-V-ATPase activity. Abolishing the asymmetry in H+flux, using a dominant-negative subunit of the H+-V-ATPase or an ectopic H+ pump, randomized embryonic situs without causing any other defects. To understand the mechanism of action of H+-V-ATPase, we isolated its two physiological functions,cytoplasmic pH and membrane voltage (Vmem) regulation. Varying either pH or Vmem, independently of direct manipulation of H+-V-ATPase, caused disruptions of normal asymmetry, suggesting roles for both functions. V-ATPase inhibition also abolished the normal early localization of serotonin, functionally linking these two early asymmetry pathways. The involvement of H+-V-ATPase in asymmetry is conserved to chick and zebrafish. Inhibition of the H+-V-ATPase induces heterotaxia in both species; in chick, H+-V-ATPase activity is upstream of Shh; in fish, it is upstream of Kupffer's vesicle and Spaw expression. Our data implicate H+-V-ATPase activity in patterning the LR axis of vertebrates and reveal mechanisms upstream and downstream of its activity. We propose a pH- and Vmem-dependent model of the early physiology of LR patterning.
Conversion of CO2 to Dimethylether and Methanol over Hybrid Catalysts
Authors: Dubois Jean-Luc , Sayama Kazuhiro , Arakawa Hironori
Published: March 2006

Combination of a CH3OH synthesis catalyst (Cu-ZnO-Al2O3) with a solid acid, which promotes CH3OCH3 formation, creates a strong driving force for CO2 conversion. At equilibrium higher yields and selectivities can be achieved: 24.3% yield in DME + CH3OH with hybrid catalyst, compared to 11.6% with CH3OH synthesis catalyst only, at 240 °C and 3 MPa. Zeolites were proved to be very efficient, with a yield of 17%.
SmI2 Promoted Coupling Reaction of Isocyanates to Oxamides
Authors: Liu Yun-Shan , Bei Mei-Zhi , Zhou Zhi-Hua , Takaki Ken , Fujiwara Yuzo
Published: March 2006

Oxamides were obtained in moderate to good yields by the reaction of isocyanates with the SmI2/HMPA/THF system under mild conditions. The system also caused desulfurization of isothiocyanates to give isocyanides in good yields.
Novel 1,6-Anhydro-β-lactose Derivatives for Rapid and Efficient Syntheses of Oligosaccharide Sequences Containing N-Acetyllactosamine
Authors: Nishimura Shin-Ichiro , Murayama Sadao , Kurita Keisuke , Kuzuhara Hiroyoshi
Published: March 2006

Fully functionalized glycosyl acceptors for the efficient syntheses of cell-surface carbohydrate determinants containing N-acetyllactosamine have been systematically prepared by the regioselective manipulations of a readily available 1,6-anhydro-6′-O-trityl-β-lactose as a key starting material. Versatility of the standardized intermediates having an unprotected hydroxyl group C-3 or C-2′ position are also preliminarily demonstrated by the glycoside formation with the known fucose derivatives.
A Useful Palladium Catalyst for Addition of Ge–Ge Bonds to Alkynes
Authors: Mochida Kunio , Hodota Chikako , Yamashita Hiroshi , Tanaka Masato
Published: March 2006

Germanium-germanium bonds of digermanes, octamethyltrigermane, and decamethyltetragermane add readily to alkynes in the presence of Pd(dba)2–2P(OCH2)3CEt (dba = dibenzylideneacetone).
DNA Strand Scissions by Hydroxamic Acids-Copper(II) Ion under Aerobic Conditions
Authors: Hashimoto Shigeki , Yamashita Rinichi , Nakamura Yushin
Published: March 2006

Carbazolyloxyacetohydroxamic acid (1), 9,9′-decamethylene-bis-carbazolyloxyacetohydroxamic acid (2), benzohydroxamic acid (3) and acetohydroxamic acid (4) without reducing agent under aerobic conditions induced Col E1 DNA strand scissions with increasing of the activities in the order of 4 > 3 > 2 > 1. Inhibition experiments indicated that hydrogen peroxide and superoxide participated in the reactions, but hydroxyl radical or singlet oxygen did not.
The Origin of the ESR Signal of C60 Seen in the Powder and in Benzene Solution. The Indication of the Reaction of C60 with Oxygen Induced by Photoexcitation
Authors: Kawata Satoshi , Yamauchi Kotaro , Suzuki Shinzo , Kikuchi Koichi , Shiromaru Haruo , Katada Motomi , Saito Kazuya , Ikemoto Isao , Achiba Yohji
Published: March 2006

ESR signals were obtained for the C60 sample in powder and in benzene solution, by irradiation with Xe lamp in an atmosphere of oxygen. It was shown that the ESR signal with g-value of 2.0026 and a derivative peak-to-peak width of about 0.175 mT was clearly enhanced by the irradiation. This fact indicates that C60 is reactive with oxygen by irradiation of light and produces the radical which gives the ESR signal.
Syntheses of Naphthoquinone Methide-type Near-IR Color Formers
Authors: Kubo Yuji , Kotani Kyoichi , Yoshida Katsuhira
Published: March 2006

New naphthoquinone methide-type near-IR color formers have been synthesized, which immediately exhibited intense absorption in the near-IR region on oxidation. The color development has been investigated using the stopped-flow technique.
Extraordinary Monomer-Dimer Transition of Methylene Blue Induced by the Phase Transition of Telomer-Bilayer Membranes Formed from Dialkyl L-Glutamate Amphiphiles with Oligo-Acrylic Acid-Head Group
Authors: Hachisako Hiroshi , Motozato Yoshiaki , Murakami Ryoichi , Yamada Kimiho
Published: March 2006

Novel anionic telomer-bilayers formed from dialkyl L-glutamates with oligo-acrylic acid-head group were prepared. Methylene Blue interacted with these bilayers to form both monomeric and dimeric species. These monomeric species were converted to the dimeric species due to the gel-to-liquid crystalline phase transition of bilayer matrix. A similar phenomenon was observed even in the case of Acridine Orange.
A Facile Synthesis of 5-Thio-l-fucose and 3-O-Allyl-l-fucose Triacetate from d-Arabinose
Authors: Hashimoto Hironobu , Izumi Masayuki
Published: March 2006

5-Thio-l-fucose and 3-O-allyl-l-fucose triacetate were synthesized from d-arabinose via  d-arabino-pentodialdo-1,4-furanose derivative.
Structures and Absolute Configurations of New Lobane Diterpenoids from the Okinawan Soft Coral Sinularia flexibilis
Authors: Hamada Toshiyuki , Kusumi Takenori , Ishitsuka Midori O , Kakisawa Hiroshi
Published: March 2006

Three new diterpenoids possessing lobane skeleton have been isolated from the Okinawan soft coral of Sinularia flexibilis. Their structures and absolute configurations have been established by chemical transformations as well as spectroscopic analysis.
Conformational Properties of [n.2.2]- and [n.3.3]Metacyclophanes
Authors: Tsuge Akihiko , Sawada Tsuyoshi , Mataka Shuntaro , Tashiro Masashi
Published: March 2006

Metacyclophanes having three aromatic rings in their skeleton were prepared. Their conformational properties were estimated by the 1H NMR spectra and the X-ray analysis. It was proved that they assume a “folded inwards” or an “alternate” conformation depending on a slight difference in the structure of the internal substituent.
Specific Intermolecular Association between NAD+ and Rh(terpy)23+
Authors: Umeda Keisuke , Ikeda Hiroshi , Nakamura Asao , Toda Fujio
Published: March 2006

The intermolecular association of NAD+ and Rh(terpy)23+ was confirmed with NMR spectroscopy. The protons of adenine in NAD+ was shifted to upfield by the addition of Rh(terpy)23+. ROESY spectrum showed intermolecular NOE between aromatic protons of those compounds. From these observations, the structures of complex of Rh(terpy)23+ and NAD+ were proposed.
A New Polymer Electrolyte Composed of Poly(N-vinylacetamide), Poly(ethylene glycol), and Lithium Trifluoromethanesulfonate
Authors: Iwatsuki Shouji , Kubo Masataka , Ohtake Makoto
Published: March 2006

A new solid composite of poly(N-vinylacetamide), lithium trifluoromethanesulfonate, and poly(ethylene glycol) was prepared and characterized as a polymer electrolyte with high conductivity.
Does Reduction of Organic Peroxides by Iodide Ions Really Proceed via Single Electron Transfer?
Authors: Tokumaru Katsumi
Published: March 2006

The mechanism for reactions of diaroyl peroxides with I− commonly utilized for their determination is reexamined in terms of single electron transfer (SET) theory and is regarded not as an SET mechanism as has been supposed but an SN2 mechanism.
Crystal Structure of (Ph4As)2[Fe4S4(SAd)4] and Stabilization of [Fe4S4(SAd)4]− State in Aqueous Media
Authors: Kambayashi Hide , Nakamoto Masami , Peng Shie-Ming , Nagao Hirotaka , Tanaka Koji
Published: March 2006

Stability of superoxidized form of [Fe4S4(SAd)4]2− (AdS−: 1-adamantanethiolate) in DMF, H2O/DMF, and aqueous poly[2-(dimethylamino)hexanamide] (PDAH) solutions is discussed in connection with the crystal structure of (Ph4As)2[Fe4S4(SAd)4].
The Carboxylation of Active Methylene Compounds with Carbon Dioxide in the Presence of 18-Crown-6 and Potassium Carbonate
Authors: Chiba Koji , Tagaya Hideyuki , Miura Syunji , Karasu Masa
Published: March 2006

Active methylene compounds were carboxylated with the reagent system, 18-crown-6, potassium carbonate and carbon dioxide, in dimethyl sulfoxide at room temperature and atmospheric presssure. The concentration of the carbonate ion is important for carboxylation.
Laser-Induced Electrodeposition of Polyaniline on a Gold Electrode
Authors: Jin Ji-Ye , Teramae Norio , Haraguchi Hiroki
Published: March 2006

Maskless local electrodeposition of polyaniline (PANi) on a gold electrode has been achieved by electropolymerization of aniline in a neutral electrolytic solution with an aid of laser irradiation. It was found that PANi can be deposited on the laser irradiated sites even at relatively lower anodic potential.
Observation of an Excited Singlet Charge-Transfer Complex (or a Singlet Ion Pair) Produced by Excitation of a Ground-State Complex of 1,8-Dichloroanthraquinone with 2,5-Dimethylhexa-2,4-diene
Authors: Hamanoue Kumao , Nakayama Toshihiro , Sasaki Hideyuki , Asada Satoshi
Published: March 2006

1,8-dichloroanthraquinone forms a weak ground-state complex with 2,5-dimethylhexa-2,4-diene, and its selective excitation by the picosecond 435-nm light pulse generates an excited singlet charge-transfer complex (or a singlet ion pair) with a lifetime of 100 ps.
Synthesis and Properties of Optically Active α-Trifluoromethylbenzyl Derivatives as New Chiral Dopants for Ferroelectric Liquid Crystals
Authors: Aoki Yoshio , Nohira Hiroyuki
Published: March 2006

Optically active α-trifluoromethylbenzyl derivatives as new chiral dopants for ferroelectric liquid crystals (FLCs) were synthesized utilizing optically active 4,4,4-trifluoro-3-(4-methoxyphenyl)butanoic acid prepared by optical resolution procedures. The magnitudes of spontaneous polarization (Ps) and the response time depended on the type of the linkage between the optically active block and core blocks.
Novel exo-nido-Cupracarborane with an Unusual Solution Fluxionality. Synthesis and Structure of [9,10-exo-{Cu(PPh3)2}-9,10-(μ-H)2-7,8-nido-C2B9H10]
Authors: Park Young-Whan , Kim Jinkwon , Kim Sangsoo , Do Youngkyu
Published: March 2006

Synthetic routes to [9,10-exo-{Cu(PPh3)2}-9,10-(μ-H)2-7,8-nido-C2B9H10] which displays an unusual solution dynamic property have been devised. The molecular structure and composition of the novel d10  exo-nido-cupracarborane, established by single-crystal X-ray analysis and 11B NMR spectroscopy, reveal the η2-hapticity of nido-C2B9 cage toward an exo-Cu(PPh3)2 moiety as well as the presence of the 12th H atom.
Metastable Solution Structures of Spirobenzoselenazolinobenzopyrans and Their Negative Photochromic Properties
Authors: Nakano Shinji , Miyashita Akira , Nohira Hiroyuki
Published: March 2006

A series of photochromic 6′-nitro-3-octadecylspirobenzoselenazolinobenzopyrans have been newly prepared and their solution structures of the colored form have been confirmed as 3-octadecylbenzoselenazolenium-2-trans-1′-cis-(5′-nitrostyryl-2′-oxide) by selective partial deuteration and NMR techniques. Photochromic repetition of these compounds for 50% fatigue attained the number more than ca. 800 times.
Synthesis of C-Aromatic Taxinine Derivatives
Authors: Seto Masaki , Morihira Koichiro , Katagiri Setsuo , Furukawa Takashi , Horiguchi Yoshiaki , Kuwajima Isao
Published: March 2006

An oxygenated substituent at the 2-position (taxane numbering) plays a critical role to determine the endo/exo cyclization into the 8-membered ring system involved in the taxane skeleton, and the aromatic taxinine derivative was prepared from the corresponding 2α,9β,10α–exo cyclized compound through thermal exo-to-endo isomerization and a Lewis acid induced inversion on the C-9 and C-10 sites.
Atomic Layer-by-Layer Deposition of La-Sr-Cu-O Films
Authors: Terui Toshifumi , Fleming R J , Maruyama Yusei
Published: March 2006

La-Sr-Cu-O films have been prepared as-deposited condition by an atomic layer-by-layer deposition technique in a high vacuum evaporation system with multi-electron-beam-gun sources. The film quality is crucially dependent on the substrate temperature, oxidation gas, and source material. It is found that the layer-by-layer successive deposition of the three elements is superior to the simultaneous deposition.
An NMR Study of the Formation of N-Silylacetonitrilium Ions by Using Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate as Counteranion
Authors: Kira Mitsuo , Hino Takakazu , Sakurai Hideki
Published: March 2006

The formation of adducts of silicenium ions with acetonitrile (N-silylacetonitrilium ions) was elucidated by means of NMR spectroscopy during the hydride abstraction from hydrosilanes by trityl TFPB in CD2Cl2 in the presence of excess acetonitrile. The results indicate that acetonitrile is not a non-nucleophilic solvent suitable for formation of free silicenium ions, but stabilizes the ions by complexation giving tetracoordinate silicon species in solution.
Synthesis of 1,2-Phenylene-Bridged Diporphyrin Linked with Porphyrin Monomer and Its Intramolecular Singlet-Singlet Excitation Energy Transfer
Authors: Osuka Atsuhiro , Kobayashi Fumikazu , Nakajima Satoshi , Maruyama Kazuhiro , Yamazaki Iwao , Nishimura Yoshinobu
Published: March 2006

A new photosynthetic model, in which 1,2-phenylene-bridged diporphyrin is connected with monomeric porphyrin through strapped chain, was synthesized by acid-catalyzed intramolecular cyclization reaction. Picosecond time-resolved fluorescence spectroscopy has revealed the efficient unidirectional singlet-singlet energy transfer from the monomeric porphyrin to the diporphyrin.
Substrate-Specific Rearrangement and Acetonidation of Epoxy-Ethers Catalyzed by Tetracyanoethylene
Authors: Masaki Yukio , Miura Tsuyoshi , Ochiai Masahito
Published: March 2006

Rearrangement of epoxy-ethers providing carbonyl compounds was catalyzed by tetracyanoethylene (TCNE) in acetonitrile under the preferential anchimetric assistance of intramolecular etheric oxygen function in the 5-exo mode for the 1,2-disubstituted epoxide unit and in the quaternary 5-exo, 5-endo, and 6-endo mode for the trisubstituted type. In acetone, epoxy-ethers favored by neighboring group participation were led to carbonyl compounds and the other epoxides furnished acetonides.
Total Synthesis of Trehalase Inhibitor, Trehazolin
Authors: Ogawa Seiichiro , Uchida Chikara
Published: March 2006

The total synthesis of trehalase inhibitor, trehazolin has been accomplished by coupling the optically active aminocyclopentanepentaol with α-d-glucopyranosylisothiocyanate derivative, followed by subsequent oxazoline-ring formation and removal of the protecting groups, thereby confirming its absolute configuration.
Electrochemical Oxidation of α,β-Unsaturated Ketones
Authors: Takahashi Tohru , Nakagawa Tetsuji , Sakai Naomi , Sono Masakazu , Shizuri Yoshikazu
Published: March 2006

α,β-Unsaturated ketones were successfully oxidized by using electrochemical method. In this oxidation reaction, allylic methyl or methylene groups were converted into acetoxylmethyl group or methoxy carbonyl group. In contrast, these unsaturated ketones were stable to Sharpless’s method (a combination of selenium dioxide and t butyl hydroperoxide).
Spectroscopy and Electrochemistry of a Monomer and Sandwich Dimer of Lutetium Tetra-tert-Butylpyrazinoporphyrazine
Authors: Kobayashi Nagao , Rizhen Jin , Nakajima Shin-ichiro , Osa Tetsuo , Hino Hiroaki
Published: March 2006

A monomer and sandwich dimer (so-called “blue form”) of lutetium tetra-tert-butylpyrazinoporphyrazine have been synthesized and characterized by electronic absorption and magnetic circular dichroism spectroscopy (MCD), together with cyclic- and differential-pulse-voltammetry. A-term MCD dispersions appear in the Q and B bands, especially corresponding in each of the split Q bands of the dimer. The potential difference between the 1st-oxidation and -reduction of the monomer is 1.98 V and that between the 1st- and 2nd-reduction is 0.72 V in o-dichlorobenzene (DCB). The dimer shows 7 redox couples.
Structures of Cassumunin A, B, and C, New Potent Antioxidants from Zingiber cassumunar
Authors: Masuda Toshiya , Jitoe Akiko , Nakatani Nobuji
Published: March 2006

Three new potent antioxidants have been isolated from the rhizomes of Zingiber cassumunar. Their structures have been established from spectral data. These compounds also showed inhibitory activity against inflammation induced by a tumor promoter, TPA.
Isolation of
l
-N-[2-(3-Pyridyl)ethyl]-glutamic Acid from the Poisonous Mushroom Clitocybe acromelalga. A Possible Intermediate in the Biogenesis of Acromelic Acids
Authors: Yamano Kimiaki , Shirahama Haruhisa
Published: March 2006

A new amino acid, l-N-[2-(3-pyridyl)ethyl]-glutamic acid, was isolated from the poisonous mushroom Clitocybe acromelalga and the structure confirmed by synthesis. Its occurrence in this fungus supports the previously proposed biogenesis of acromelic acids.