[Clinical efficacy of low-dose CDDP and CPT-11 therapy as second- or third-line chemotherapy for advanced and recurrent gastric cancer].

We retrospectively studied the clinical efficacy and safety of the combination therapy with low-dose cis-diamminedichloroplatinum ( CDDP) and irinotecan hydrochloride(CPT-11)as a second- or third-line chemotherapy in 41 patients with advanced and recurrent gastric cancer. Low-dose CDDP (20mg/m²) and CPT-11 (80 mg/m²) were administered intravenously once every 2 or 3 weeks. The patients comprised 31 men and 10 women, with ages ranging from 42 to 81 years (mean, 67.4 years). The overall treatment response rate was 12%, including 5 partial responses but no complete response. The mean survival time was 8 months, and the disease-free survival time was 3.7 months from the start of the regimen. The median number of treatment cycles was 7.1 (range, 1.0-26.0). The most common grade 3/4 toxicity was neutropenia (2 cases), followed by dehydration (1 case) and allergy (1 case). Our data suggest that the combination of low-dose CDDP and CPT-11 has mild therapeutic toxicities and may effectively prolong the median survival time in patients with advanced and recurrent gastric cancer.

Photocurrent generation by helical peptide monolayers integrating light harvesting and charge-transport functions.

In this study, we construct photoenergy-conversion systems with chromophores located with molecular precision to facilitate efficient light harvesting and charge transport. 3(10) -Helical peptides carrying a disulfide group at the N-terminal, linearly arranged six naphthyl groups at the side chains, and an energy acceptor (anthryl, pyrenyl, or N-ethylcarbazolyl group) at the C-terminal were immobilized on a gold surface via a gold-sulfur linkage to form a well-defined self-assembled monolayer with vertical orientation. The monolayer composed of helical peptides terminated with a naphthyl group instead of an energy acceptor was used as control. Upon photoexcitation of the naphthyl groups of the monolayers in solutions containing an electron donor, all the monolayers generated an anodic photocurrent. The photocurrent generation by the monolayers with an acceptor is composed of the following three steps: (1) photon capture by the side-chain naphthyl groups and energy transfer to the terminal acceptor (light harvesting), (2) electron donation from the aqueous donor to the excited acceptor (electron generation), and (3) electron transport from the terminal to gold via the side-chain naphthyl groups (electron hopping). Unfortunately, it was found that introduction of an energy acceptor facilitates the light-harvesting step but suppresses the electron-generation and electron-hopping steps, resulting in slight reduction of the efficiency of photocurrent generation compared to the control system. Further detailed discussion on photoenergy and electron transport processes shows a prospect to realize efficient photocurrent generation systems taking advantages of both light harvesting and charge-transport functions in future.

Molecular direction dependence of single-molecule conductance of a helical peptide in molecular junction.

The helix-peptide dipole effect on single-molecule conductance was analysed experimentally and theoretically with a single 8mer helical peptide. The helical peptide was immobilized on a gold surface in two opposite directions of the helix dipole. Single-molecule conductance of the helical peptide was determined to be 2.4 × 10(-5) G(0) by scanning tunneling microscopy (STM) break-junction measurements under the condition of applied bias voltage parallel to the dipole, which was about 1.2-fold larger than that in the anti-parallel direction. Theoretical calculation also supports that the helix dipole influences the electron transport reaction depending on parallel or anti-parallel orientation of the dipole against the applied electric field.

[A case of consciousness disorder induced by the syndrome of inappropriate secretion of antidiuretic hormone following cisplatin and 5-fluorouracil chemotherapy in a patient with esophageal cancer].

We report a case of consciousness disorder following the fourth course of chemotherapy with cisplatin (CDDP) and 5- fluorouracil (5-FU) in a patient with esophageal cancer. A 74-year-old man was admitted to our hospital to receive chemotherapy for esophageal cancer. Six days after chemotherapy, the patient showed impaired consciousness and his serum sodium concentration was found to be 125 mEq/L, but no edema or dehydration was noted. This hyponatremic state was diagnosed as CDDP-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) on the basis of serum and urine hypo-osmolality. Accordingly, fluid intake was restricted and sodium supplements were administered, resulting in an appropriate increase in the serum sodium concentration to 132 mEq/L in 4 days.

[Pathological complete response in 2 patients with cT4 esophageal cancer treated with neoadjuvant chemoradiation therapy].

We report the cases of 2 patients with clinical T4( cT4) esophageal cancer who achieved pathological complete response on treatment with neoadjuvant chemoradiation therapy. Case 1 involved a 68-year-old woman who was diagnosed as having cT4 advanced esophageal cancer( with involvement of the aorta and left pulmonary vein). Neoadjuvant chemoradiation therapy with 5-fluorouraci(l 5-FU)( 800 mg/m2, days 1-5 and days 29-33), cisplatin( CDDP 80 mg/m2, days 1 and 29), and radiation (39.6 Gy/22 Fr) was administered, and the tumor showed a partial response (PR). Case 2 involved a 69-year-old man who was diagnosed as having cT4 advanced esophageal cancer( with involvement of the main bronchus). Neoadjuvant chemoradiation therapy with 5-FU( 800 mg/m2, days 1-5 and days 29-33), CDDP( 80 mg/m2, days 1 and 29), and radiation( 39.6 Gy/22 Fr) was administered, and the tumor showed a clinical PR. After tumor response was noted, curative esophagectomy was performed in both cases, without any complications, and a pathological complete response was achieved in both patients.

The hammock effect of wheelchair cushion covers: persistent redness over the ischial tuberosities in a patient with spinal cord injury - a case report.

We report a case of a 28-year-old man with a complete C5 level spinal cord injury who developed persistent redness over his ischial tuberosities due to his wheelchair cushion cover's hammock effect. He had purchased wheelchairs and cushions in 2004 and 2008. Persistent redness occurred over his ischial tuberosities when using the second cushion purchased in 2008. Pressure mapping did not detect any differences in pressure over the ischial tuberosities with different cushions. When comparing cushions without their covers, we noticed that the first cushion had a greater air volume than the second cushion. We exchanged the cushion covers to evaluate the hammock effect due to different covers. We found that the redness occurred at any time the second cushion cover was used. After the patient's family changed the top of the second cushion cover to a more elastic material, the redness resolved. As we were unable to detect the influence of the hammock effect using pressure mapping, it would be useful to develop an alternative method to evaluate this phenomenon. It would also be valuable to find a readily available solution for other patients experiencing this problem.

Ultra-long-range electron transfer through a self-assembled monolayer on gold composed of 120-Å-long α-helices.

Electron transfer through α-helices has attracted much attention from the viewpoints of their contributions to efficient long-range electron transfer occurring in biological systems and their utility as molecular-electronics elements. In this study, we synthesized a long 80mer helical peptide carrying a redox-active ferrocene unit at the terminal and immobilized the helical peptide on a gold surface. The molecular length is calculated to be 134 Å, in which the helix accounts for 120 Å. The preparation conditions of the self-assembled monolayers were intentionally changed to obtain monolayers with different physical states to study the correlation between molecular motions and electron transfer. Ellipsometry and infrared spectroscopy showed that the helical peptide forms a self-assembled monolayer with vertical orientation. Electrochemical measurements revealed that an electron is transferred from the ferrocene unit to gold through the monolayer composed of this long helical peptide, and the experimental data are well explained by theoretical results calculated under the assumption that electron transfer occurs by a unique hopping mechanism with the amide groups as hopping sites. Furthermore, we have observed a unique dependence of electron transfer on the monolayer packing, suggesting the importance of structural fluctuations of peptides on the electron transfer controlled by the hopping mechanism.

Analysis of gene expression profiles in fatal hepatic failure after hepatectomy in mice.

BACKGROUND: We developed 90%-hepatectomized mice that were the fatal model, and analyzed the gene expression profiles using a complementary DNA (cDNA) microarray to clarify the mechanisms of hepatic failure after excessive hepatectomy. MATERIALS AND METHODS: Ribonucleic acid (RNA)s from the remnant hepatic tissue of 70%- and 90%-hepatectomized mice were labeled with fluorescent dyes, and hybridized to the Riken set of 39,168 full-length enriched mouse cDNA arrays. The gene expression profiles in 90%- and 70%-hepatectomized mice were analyzed by scanning date for fluorescent dye signals. RESULTS: The down-regulated genes in 90%-hepatectomized mice were genes activating extracellular matrix (ECM) remodeling (matrix metalloproteinases, laminins, and integrins), genes related to cytokines (tumor necrosis factor α converting enzyme, and Janus kinase 3) that were related to the priming, genes related to growth factor (heparin-binding epidermal growth factor-like growth factor and others), and genes promoting cell cycle progression (cyclin D1, D2, and E2) that were related to the progression of hepatocytes. The up-regulated genes were genes inhibiting ECM remodeling [plasminogen activator inhibitors (PAIs)]. CONCLUSIONS: Hepatic failure after hepatectomy was characterized by the inhibition of hepatic cell cycle priming and progression both induced by ECM remodeling in liver regeneration. Particularly, the overexpression of PAIs was thought to play the major role in the first step of inhibition of ECM remodeling.

First-line Gemcitabine Versus Treatment of Physician's Choice for Metastatic Breast Cancer: A Prospective Cohort Study.

BACKGROUND/AIM: This study aimed to investigate the efficacy of first-line gemcitabine monotherapy for metastatic breast cancer (MBC) and its effect on health-related quality of life (HRQoL) compared with treatment of physician's choice (TPC). PATIENTS AND METHODS: We enrolled 96 patients into the first-line gemcitabine group (n=47) or other treatment of physician's choice (TPC) group (n=49) from May 2010 to April 2013. HRQoL was evaluated every 4 weeks. RESULTS: There was no significant difference in the median time to treatment failure (5.3 vs. 4.6 months, hazard ratio=0.87, p=0.546) and the incidence rates of grade 3/4 haematological toxicity (10.6% vs. 8.1%, p=0.677) and grade 3/4 non-haematological toxicity (4.2% vs. 8.1%, p=0.429) between the gemcitabine and TPC groups. Changes in HRQoL from baseline to 12 weeks were not significantly different. CONCLUSION: Gemcitabine achieves similar efficacy and HRQoL benefit to other chemotherapy and can be used as first-line treatment for MBC.

Linker effects on monolayer formation and long-range electron transfer in helical peptide monolayers.

Helical peptides carrying a ferrocene unit at the C-terminus were immobilized on gold at the N-terminus via three different linkers to form self-assembled monolayers, and the long-range electron transfer from the ferrocene unit to gold was electrochemically studied. The linkers are 4-thiobenzoic acid, 3-fluoro-4-thiobenzoic acid, and 2-methoxy-4-thiobenzoic acid. All the peptides formed a monolayer with vertical orientation but some differences in monolayer packing and ferrocene surface density as they formed. However, the treatment with dodecanethiol in a gas phase uniformed to show similar monolayer physical parameters, and the electron-transfer rate constants were reproducibly obtained as well. These three peptide monolayers exhibited the same electron-transfer rate constants despite three linkers with different oxidation potentials. On the other hand, the electron transfer was decelerated seemingly by reducing the ferrocene surface density. Theoretical calculations with simple models demonstrated that the experimental result supports a hopping mechanism rather than electron tunneling though it cannot be fully excluded.

Gene expression during liver regeneration after partial hepatectomy in mice lacking type 1 tumor necrosis factor receptor.

BACKGROUND: To investigate the function of tumor necrosis factor-alpha (TNF-alpha) during hepatocyte proliferation, we studied liver regeneration following partial hepatectomy in mice lacking type 1 TNF receptor (TNFR-1). MATERIALS AND METHODS: TNFR-1 knockout (KO) and wild-type mice were subjected to partial (two-thirds) hepatectomy. Liver regeneration was evaluated by assessing liver weights and Ki67 immunohistochemistry. Riken complementary DNA microarray analysis was performed for liver samples from mice undergoing partial hepatectomy to better compare different mouse partial hepatectomy models (TNFR-1 KO mice, KO group; and wild-type mice, W group). RESULTS: Liver weight was regained after 14 days in the KO group, and after 7 days in the W group. Genes including lipopolysaccharide, toll-like receptor 4 precursor, mitogen-activated protein kinase kinase kinase 4, mitogen-activated protein kinase kinase kinase kinase 4, and mitogen-activated protein kinase 8-interacting protein were up-regulated in the KO group. As for the cell-cycle-regulated genes, the levels of cyclin D1, nuclear factor-kappa B light chain, and TNF receptor super family membrane 1a were down-regulated in the KO group. Microarray analysis showed decreased activities of the hexokinase- and phospho-fructokinase-related glycolytic pathways in the KO group. CONCLUSIONS: These results contribute to the better understanding of the mechanisms of liver regeneration after partial hepatectomy in TNFR-1 KO mice.

Reduction-induced switching of single-molecule conductance of fullerene derivatives.

The effect of electrochemical reduction on the single-molecule conductance of fullerene C60 derivatives was studied by scanning tunneling microscopy. Three types of C60 derivatives were synthesized, a monoadduct having an amino-terminated linker and two bisadducts having two linkers at different positions (trans2 and trans3). Each C60 derivative was immobilized on a gold surface by an amino-gold linkage, confirmed by infrared reflection-absorption spectroscopy. The immobilized C60 derivatives showed reversible and multiple reduction peaks in the cyclic voltammogram in dimethylformamide (DMF) at almost the same potentials as those in solution, showing the redox properties of the molecules are intact on gold. Single-molecule conductances of the bisadducts, which can span between a scanning tunneling microscopy (STM) tip made of gold and substrate with the two linkers, were determined by the STM break-junction measurements in water and DMF. The conductances were 6.1+/-4.5 nS in water and 4.9+/-1.7 nS in DMF for the trans2 bisadduct and 8.4+/-3.4 nS in water and 7.9 nS+/-2.8 in DMF for the trans3 bisadduct. By using a potential-controlled STM setup, the tunneling current through a single molecule was recorded with sweeping the potentials of the tip and substrate. The trans2 bisadduct showed significant changes in the current when the reductions of the C60 moiety occur. Some current curves showed multiple peaks, and the other curves showed stepwise increase and decrease at the C60 reduction and subsequent reoxidation. Statistical analysis afforded stepwise switching of the conductance as the average behavior and suggested that the electron tunneling through the C60 derivative is enhanced as it accepts electrons.

Effects of monolayer structures on long-range electron transfer in helical peptide monolayer.

Self-assembled monolayers of alpha-helical peptides were prepared on gold, and the effects of the monolayer structures (kind of constituent amino acid, molecular orientation, and molecular packing) on long-range electron transfer through the helical peptides were studied. The helical peptides were 16mer peptides having a thiophenyl linker at the N-terminal for immobilization on gold and a redox active ferrocene moiety at the C-terminal as an electron-transfer probe. The peptides were immobilized on gold by a gold-sulfur linkage and the electron transfer from the ferrocene moiety to gold was studied by electrochemical methods. When two types of the peptides, one with the repeating unit of Leu-Aib (Aib represents 2-aminoisobutyric acid) and the other with that of Ala-Aib, were compared, the electron transfer was found one order slower in the Leu-Aib peptide monolayer than that in the Ala-Aib peptide monolayer. The self-assembled monolayers of the Ala-Aib peptide with mixing of three different lengths of the peptides, 8mer, 12mer, and 16mer without a ferrocene moiety, were also prepared. The monolayer regularity in terms of molecular orientation and packing was higher roughly in the order of the monolayers mixed with 16mer > 12mer > no additive > 8mer, but the electron transfer became faster in the opposite order. The logarithms of the standard rate constants showed a nearly linear relationship with the direct distances between the ferrocene moiety and gold (beta = 0.32 A (-1)). Some data deviated from this linear relationship, but the deviations could be explained from the difference in the molecular packing, which was evaluated from the monolayer capacitance. It is thus concluded that an electron is transferred along a few molecules along the surface normal so that the vertical orientation or the increase of the interchain backbone separation slows down the electron transfer. Further, it is demonstrated that a tightly packed monolayer, where vibrational mode is restricted, suppresses the electron transfer. Three models are proposed to account for the observed molecular dynamics effects on the basis of either electron-transfer mechanism of electron tunneling or sequential hopping.

Histopathological and immunohistochemical findings in a case of glycogen-rich clear cell carcinoma of the breast.

Glycogen-rich clear cell carcinoma (GRCC) of the breast is a rare variant of primary breast carcinoma that was first described by Hull et al. in 1981, and is characterized by carcinoma cells containing an optically clear cytoplasm and intracytoplasmic glycogen. The present case involved a 33-year-old female. She had noticed a lump in the inner quadrant of the left breast. The tumor obtained by enucleation biopsy had an irregular shape. The tumor cells exhibited sharply defined borders, polygonal contours, a clear or finely granular cytoplasm, and moderate nuclear atypia. The tumor cells showed a positive reaction with periodic acid Schiff, eliminated by diastase digestion. The tumor was diagnosed as GRCC. There was no nodal metastasis. Immunohistochemically, the tumor cells were positive for cytokeratin, epithelial membrane antigen, HER2, and p53, but negative for estrogen receptor (ER) and progesterone receptor (PR). Although the biological behavior of GRCC is difficult to predict in view of the very limited number of case reports, the prognosis of GRCC may be associated with not only histopathological subtype but also other clinicopathological factors, such as size, status of invasion, status of nodal metastasis, nuclear grade, ER, PR, HER-2, p53 and so on. To clarify the pathogenesis of mammary GRCC, the systematic study of additional well-documented cases with long-term follow up will be necessary.

Molecular rectification of a helical peptide with a redox group in the metal-molecule-metal junction.

A helical hexadecapeptide immobilized on gold via a thiophenyl group at the N-terminal was analyzed by scanning tunneling microscopy under ultrahigh vacuum to obtain the I-V response at a molecular level. The attenuation factor of the electron transfer through the hexadecapeptide was determined by applying the Simons model to the I-V response to show better molecular conductance of the hexadecapeptide than dodecanethiol. Chemical modification at the C-terminal of the hexadecapeptide with a ferrocene unit, on the other hand, brought about significant changes in the I-V response, where the helical peptide became more conductive at the negative bias voltage. The molecular rectification behavior is due to the ferrocene unit regulating the direction of the electron transfer at the metal-molecule junction.

Effects of dipole moment, linkers, and chromophores at side chains on long-range electron transfer through helical peptides.

Octadecapeptides carrying a ferrocene moiety at the molecular terminal were self-assembled on gold, and long-range electron transfer from the ferrocene moiety to gold was investigated by electrochemical methods. Effects on electron transfer of dipole moment of helical peptides, linkers connecting the peptide to gold, and chromophores introduced into the side chains were discussed. Cyclic voltammetry of the monolayers in an aqueous solution revealed that long-range electron transfer over 40 A occurred along the peptide molecule. Chronoamperometry showed that the long-range electron transfer should be ascribed to a hopping mechanism with use of amide groups as hopping sites. Electron transfer through the long peptide was not significantly accelerated by the dipole moment. However, the linker remarkably affected electron transfer depending on whether it was a methylene chain or a phenylene group, suggesting that local electron transfer between gold and the peptides should be the slowest step to determine the overall rate. Pyrenyl groups introduced into the side chains in the middle of the peptide molecule did not noticeably change electron transfer, probably because pyrenyl groups were too distant to allow direct electron transfer between them. Electrostatic potential profiles across the peptide monolayers were also calculated to explain reasonably the several interesting features in the present peptide systems.

Pharmacologic preconditioning effects: prostaglandin E1 induces heat-shock proteins immediately after ischemia/reperfusion of the mouse liver.

Prostaglandin E1 (PGE1) has several potential therapeutic effects, including cytoprotection, vasodilation, and inhibition of platelet aggregation. This study investigates the protective action of PGE1 against hepatic ischemia/reperfusion injury in vivo using a complementary DNA microarray. PGE1 or saline was continuously administered intravenously to mice in which the left lobe of the liver was made ischemic for 30 minutes and then reperfused. Livers were harvested 0, 10, and 30 minutes postreperfusion. Messenger RNA was extracted, and the samples were labeled with two different fluorescent dyes and hybridized to the RIKEN set of 18,816 full-length enriched mouse complementary DNA microarrays. Serum alanine aminotransferase and aspartate aminotransferase levels at 180 minutes postreperfusion were significantly lower in the PGE1-treated group than in the saline-treated group. The cDNA microarray analysis revealed that the genes encoding heat-shock protein (HSP) 70, glucose-regulated protein 78, HSP86, and glutathione S-transferase were upregulated at the end of the ischemic period (0 minutes postreperfusion) in the PGE1 group. Our results suggested that PGE1 induces HSPs immediately after ischemia reperfusion. HSPs might therefore play an important role in the protective effects of PGE1 against ischemia/reperfusion injury of the liver.

Formation of gold nanoparticles in microreactor composed of helical peptide assembly in water.

A novel microreactor was prepared by self-assembly of an amphiphilic block copolymer composed of a hydrophobic helical peptide unit with a naphthyl group at the C terminal and a hydrophilic poly(ethylene glycol) unit. The copolymer formed a self-assembly in water, taking a vesicular structure. Noticeably, when the copolymer was dispersed in an Au(3+) aqueous solution, gold nanoparticles were formed without addition of any reducing reagent. The naphthyl groups, which are located at the inner surface of the vesicular assembly, promoted the reduction of Au(3+) ions with accompanying pH decrease.

NiCl2(PMe3)(2)-catalyzed borylation of aryl chlorides.

The cross-coupling of aryl chlorides and bis(pinacolato)diboron was achieved using NiCl(2)(PMe(3))(2) catalyst in the presence of metal 2,2,2-trifluoroethoxide. The catalyst smoothly provided the desired products regardless of a variety of functional groups and substituted positions.