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.

[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.

[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.

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.

[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.

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.

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.

Dipole effects on molecular and electronic structures in a novel conjugate of oligo(phenyleneethynylene) and helical peptide.

A novel conjugate of a helical nonapeptide and an oligo(phenyleneethynylene) (OPE) having a nitro group at a molecular terminal was synthesized. Both components have a dipole. The peptide has a disulfide group at the N-terminal for immobilization on gold. In order to investigate the electric field effect of the helical peptide dipole on the OPE and molecular structure by the dipole-dipole interaction between the two components, the electronic structure of the OPE was spectroscopically studied in solution, the self-assembled monolayer on gold, and Langmuir-Blodgett (LB) layers on a fused quartz surface. The absorption maximum (lambda(max)) of the OPE component in chloroform is red-shifted by 4 nm from the reference OPE derivative without the helical peptide component. The red shifts of the OPE component are also observed in the LB monolayer and bilayer compared with that of the self-assembled monolayer. The observed dipole effect of the peptide on the OPE electronic structure was quantitatively discussed with ab initio calculations. Antiparallel orientation on the dipole directions of the peptide and the OPE components is considered to explain the red shifts via the dipole effect on the electronic structure of the OPE.

Electron transfer through a self-assembled monolayer of a double-helix peptide with linking the terminals by ferrocene.

A unique molecular structure, a double-helix peptide, was self-assembled on gold, and the electron transfer through the monolayer was studied. The double-helix peptide consists of two 9mer 3(10)-helical peptide chains having a disulfide group at each N terminal and being linked by a ferrocene dicarboxylic acid between the C terminals. Each helical peptide chain has three naphthyl groups in a linear arrangement along the helix. The monolayer properties and the electron transfer from the ferrocene unit to gold were studied with reference peptides with a similar double helix but without naphthyl groups, a single helix with a dicarboxylic ferrocene unit, and a single helix with a monocarboxylic ferrocene unit. It was demonstrated that the naphthyl groups on the side chains had no effect on electron transfer, and the electron-transfer rate in the double-helix monolayer was not promoted, despite the two electron pathways in the molecule. We propose that in the double-helix monolayer, molecular motions are suppressed, possibly by its rigid structure tethered by the two linkers on gold to cancel out acceleration effects of the 2-fold electron pathways and the ferrocene substitution number. The factors that affect the electron-transfer reaction across the helical peptide SAMs are discussed in depth.

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.

Second-harmonic generation from Langmuir-Blodgett film of cyclic peptide carrying two disperse red 1 on fused quartz surface.

Cyclic octapeptide carrying one or two nonlinear optical chromophores, disperse red 1 (DR-1), was synthesized and immobilized on a substrate to attain an active surface for second-harmonic generation (SHG). Each cyclic octapeptide was transferred on a fused quartz substrate by the Langmuir-Blodgett (LB) method to afford a uniform monolayer. Infrared reflection-absorption spectroscopy of the LB monolayer revealed that the cyclic skeleton lay roughly flat on the surface. The SHG intensity from the monolayer of the cyclic peptide with two DR-1 units was stronger than that from that with one DR-1 unit. The difference is discussed in terms of molecular orientation and surface density of the active chromophores. The cyclic peptide is shown here to be an effective scaffold to modify a substrate surface with functional groups of a monolayer with taking stability of the monolayer and orientation of the functional group into consideration.

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.

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.

Photoinduced electron transfer in thin layers composed of fullerene-cyclic peptide conjugate and pyrene derivative.

A bilayer structure was constructed on gold by Langmuir-Blodgett deposition of a fullerene (C 60)-cyclic peptide-poly(ethylene glycol) (PEG) conjugate and thereafter a pyrene derivative from the air/water interface. The cyclic peptide moiety acts as a scaffold to prevent the fullerenes from self-aggregation and accordingly makes the monolayer homogeneous and stable. In addition to this gold/C 60-cyclic peptide-PEG/pyrene bilayer, a pyrene monolayer, a gold/C 60-PEG conjugate/pyrene bilayer (lacking the peptide scaffold), and a gold/pyrene/C 60-cyclic peptide-PEG bilayer (with the opposite order of layers) were also prepared, and their anodic photocurrent generation were studied in an aqueous solution containing a sacrifice electron donor. The most efficient photocurrent generation was observed in the gold/C 60-cyclic peptide-PEG/pyrene bilayer. It is considered that the C 60 unit acts not only as sensitizer but also as an electron acceptor facilitating the electron transfer from the excited pyrene unit to gold, and that the fullerene layer suppresses quenching of the excited pyrene unit by energy transfer to gold. Furthermore, the cyclic peptide scaffold helps the fullerenes disperse without aggregation in the membrane and seems to protect their redox properties or inhibit self-quenching of their excited state. It is thus concluded that a bilayer structure with desired orientation of functional units is important for efficient photoinduced electron transfer and that a cyclic peptide scaffold is useful to locate hydrophobic functional groups properly in a thin layer.

Distance dependence of long-range electron transfer through helical peptides.

Helical peptides of 8mer, 16mer, and 24mer carrying a disulfide group at the N-terminal and a ferrocene moiety at the C-terminal were synthesized, and they were self-assembled on gold by a sulfur-gold linkage. Infrared reflection-absorption spectroscopy and ellipsometry confirmed that they formed a monolayer with upright orientation. Cyclic voltammetry showed that the electron transfer from the ferrocene moiety to gold occurred even with the longest 24mer peptide. Chronoamperometry and electrochemical impedance spectroscopy were carried out to determine the standard electron transfer rate constants. It was found that the dependence of the electron-transfer rates on the distance was significantly weak with the extension of the chain from 16mer to 24mer (decay constant beta = 0.02-0.04). This dependence on distance cannot be explained by an electron tunneling mechanism even if increased hydrogen-bonding cooperativity or molecular dynamics is considered. It is thus concluded that this long-range electron transfer is operated by an electron hopping mechanism.