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Our aim was to investigate the efficacy and safety of initial neoadjuvant endocrine therapy with exemestane alone followed by tailored treatment, either continued exemestane monotherapy or exemestane plus docetaxel–cyclophosphamide (TC) combination therapy, in postmenopausal patients with primary invasive estrogen receptor–positive, human epidermal growth factor receptor 2–negative, stage I‐IIIA breast cancer and Ki67 labeling index ≤30%. In this open‐label phase II study, patients initially received exemestane 25 mg/d for 12 weeks. Responders were defined as patients who achieved complete response (CR), partial response (PR) with Ki67 labeling index ≤5% after treatment, or stable disease with Ki67 labeling index ≤5% both before and after treatment. For the subsequent 12 weeks, exemestane monotherapy was continued for responders (group A), whereas nonresponders received exemestane plus four cycles of TC (docetaxel 75 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks) (group B). Clinical response rate (ie the proportion of patients with CR or PR) at 24 weeks was the primary endpoint. Of 64 patients provisionally enrolled between December 2010 and May 2016, 58 (median age 60 years) started the study treatment. Five patients discontinued treatment in the initial exemestane monotherapy period, and 39 completed the study treatment. Clinical response rates at 8‐12 and 24 weeks were 71% (10/14, 95% confidence interval [CI] 41.9%‐91.6%) and 57% (8/14, 95% CI 28.9%‐82.3%), respectively, in group A, and 16% (4/25, 95% CI 4.5%‐36.1%) and 56% (14/25, 95% CI 34.9%‐75.6%), respectively, in group B. Grade ≥3 adverse events were reported in 8% (1/15) and 53% (20/38) in group A and group B, respectively. The tailored treatment maintained the favorable clinical response to exemestane alone in responders and improved clinical response in nonresponders. Trial number UMIN000004752 (UMIN Clinical Trials Registry)., Change in Ki67 labeling index over the course of the study in patients receiving continued exemestane monotherapy (A) and those receiving exemestane plus docetaxel–cyclophosphamide) (B).

Neoadjuvant endocrine therapy has been reported to decrease tumor size, which leads to increased breast conservation rates. To improve the clinical response, metronomic chemotherapy with endocrine therapy is a promising strategy. A multicenter phase II single‐arm neoadjuvant trial with letrozole and cyclophosphamide was conducted. Eligibility criteria included postmenopausal status, T2–4 N0–1, and estrogen receptor‐positive breast carcinoma. Letrozole (2.5 mg) plus cyclophosphamide (50 mg) was given orally once a day for 24 weeks. The primary endpoint was the clinical response rate (CRR). To investigate anti‐angiogenic effects, circulating endothelial cells (CECs) were quantified using the CellSearch system. From October 2007 to March 2010, 41 patients were enrolled. The CRR was 67.5% (52.0–80.0%), which was above the prespecified threshold (65%). The conversion rate from total mastectomy to breast‐conserving surgery was 64% (18/28). Grade 3 or greater nonhematological toxicity was not reported. Clinical response was associated with improved disease‐free survival (DFS) (P = 0.020). The increase in CEC counts at 8 weeks was observed in nonresponders (P = 0.004) but not in responders. Patients with higher CEC counts at baseline or post‐treatment showed worse DFS than those with lower counts (P

Background and Aims The serrated colorectal carcinoma (CRC) as proposed to arise from serrated adenoma (SA) is characterized by upregulation of HIF1α, suppression of PTCH or EphB2, loss of DNA repair proteins, and BRAF mutation. The aim of this study was to evaluate alterations of these candidates involved in the serrated pathway in colorectal polyps. Methods We analyzed immunoreactivity of these proteins, methylation of PTCH and EphB2, and mutation of BRAF and Kras in sessile SAs (SSAs; n = 32), traditional SAs (n = 28), hyperplastic polyps (HPs; n = 24), and conventional adenomas (ADs; n = 21). Results Increase of nuclear HIF1α expression was more frequent in SA than HP, but less frequent in SA than AD (P

We have shown previously that cytoplasmic p53 is covalently linked to 5.8S rRNA. The covalent complex is associated with a small subset of polyribosomes, which includes polyribosomes translating p53 mRNA. Because 5.8S rRNA resides in or near the ribosomal P site, our findings suggested involvement of p53 in translational regulation. Ninety-seven kiloDaltons eEF2 was found to coimmunoprecipitate in a salt-stable complex with p53. The 97 kDa species was identified as eEF2, because it was (1) recognized by a polyclonal antiserum specific for eEF2, (2) ADP-ribosylated by diphtheria toxin (DT), and (3) radiolabeled by gamma-32P-azido-GTP and UV-irradiation. p53 and eEF2 sedimented in sucrose gradients in both polyribosomal and subribosomal fractions. Subribosomal p53 can bind eEF2 without the mediation of ribosomes, because (1) it binds subribososomal eEF2, (2) it binds phosphorylated eEF2, and (3) subribosomal p53-bound eEF2 can be ADP-ribosylated by DT. No effect of p53 activation was found on eEF2 expression or phosphorylation. However, the binding of eEF2 to p53 decreased when cytoplasmic p53 migrated to the nucleus. Renaturation of temperature sensitive A135V mutant p53 (ts-p53) was found to alter the sensitivity of p53 mRNA translation, but not bulk mRNA translation, to the translocation-specific elongation inhibitor, cycloheximide (Cx). The association of p53 with two translational components involved in ribosomal translocation, eEF2 and 5.8S rRNA, and the effect of p53 on sensitivity to the translocation inhibitor, Cx, as well as the known molecular interactions of these components in the ribosome suggest involvement of p53 in elongation.

Background We have previously reported that the addition of nucleosides and a nucleotide mixture (OG-VI) to total parenteral nutrition (TPN) prevents TPN-induced intestinal mucosal atrophy and results in increased intestinal cathepsin activities under TPN. The aims of the present study are to examine the effects of OG-VI on mucosal barrier functions and to clarify whether the intestinal cathepsins can be used as a new marker of mucosal barrier function. Methods Male Wistar rats were divided into three groups: FED (food ad libitum), TPN (a standard TPN solution), and OG (OG-VI in addition to the TPN solution). Mucosal barrier functions were analyzed by the lactulose/mannitol (L/M) test, mucosal ZO-1 messenger RNA level, and electron micrographs in the gut. Intestinal cathepsin B, H, and L activities were also measured. Results The L/M ratio for TPN was much higher than that for FED. Only lactulose excretion was significantly reduced by OG-VI. The intercellular spaces of the mucosal cells for TPN were significantly wider than those for FED, but were reduced in size by the addition of OG-VI. All cathepsin activities of the ileum were higher for TPN than for FED, whereas OG showed no increase. Conclusion OG-VI contributes to the improvement of gut mucosal barrier function. Intestinal cathepsin activities can be used as a new marker of mucosal barrier function.

The reduction is assumed to occur on the alumina surface, since its absence results in a negligible conversion of the starting sulfoxide.

The oxidation of aliphatic and alicyclic secondary alcohols with chromium(VI) trioxide in the presence of “wet”-aluminum oxide in hexane gave the corresponding ketones in excellent yields under mild conditions.

The oxidation of 2,6-di- and 2,4,6-tri-substituted phenols with cobalt(III) acetate has been investigated in acetic acid under an inert atmosphere; the former gave the corresponding diphenoquinones in excellent yields, and the latter yielded side-chain or nuclear acetoxylated products in moderate to good yields.

The title oxidation has been performed in dichloromethane in the presence of “wet”-montmorillonite and -kaolin. The substrates studied include dialkyl, alkyl aryl, diaryl, and cyclic sulfides, which give the corresponding sulfoxides in good yields under neutral and mild conditions.

Aliphatic primary alcohols and 1,ω-diols were oxidized to the dimeric esters and lactones, respectively, by peracetic acid in ethyl acetate in the presence of sodium bromide under mild conditions. Aliphatic secondary and benzylic alcohols were converted smoothly to the corresponding carbonyl compounds by the same system.

Lipase from Rhizopus arrhizus catalyzed deacylation of two classes of glyceroglycolipids, monogalactosyl diacylglycerol(MGDG). and digalactosyl diacylglycerol(DGDG), proceeded regiospecifically to furnish sn-1 lysoglyceroglycolipids quantitatively. The lipase also catalyzed complete acyl migration of sn-1 lysoglycerogalactolipids leading to sn-2 lysoglycerogalactolipids.

The title oxidation of diols with two primary hydroxy groups (symmetrical diols) and those with both a primary and a secondary hydroxy group (unsymmetrical diols) gives the corresponding lactones or the hydroxy ketones, being dependent upon the types of diols.

The title oxidation of a variety of sulfides was effectively performed in dichloromethane in the presence of H+-exchanged zeolite F-9, affording the corresponding sulfoxides in good yields under mild and neutral conditions.

Dispersion of CrO3 and a “wet” -alumina in hexane, followed by a simple work-up, affords the title reagent, which is valid for the chemoselective oxidation of a wide range of alcohols for an extended period.

Convenient synthesis of 1-O-acyl-3-O-(6'-O-acyl-β-D-galactopyranosyl-sn-glycerol was studied. The lipase from Achromobacter sp. catalyzed acylation of 3-O-β-D-galactopyranosyl-sn-glycerol, which contains two primary hydroxyl functions, proceeded regioselectively to furnish 1-O-acyl-3-O-β-D-galactopyranosyl-sn-glycerol.

(1995). OXIDATION OF VARIOUS ALCOHOLS WITH IN SITU GENERATED MONTMORILLONITE K10-SUPPORTED FERRIC NITRATE REAGENT IN AN APROTIC SOLVENT. Organic Preparations and Procedures International: Vol. 27, No. 6, pp. 703-706.

A variety of unsubstituted and mono- or di-substituted cycloalkanones can be oxidised with modest excess of magnesium monoperoxyphthalate hexahydrate in acetonitrile to produce the corresponding lactones in a facile, selective, and high yielding manner.

1-O-Acyl-3-O-(6'-O-acyl-β-D-galactopyranosyl-sn-glycerol, which was isolated from a nitrogen-fixing freshwater cyanobacterium, Anabaena flos-aquae f. flos-aquae, was synthesized by utilizing lipase-catalyzed acylation.The antitumor-promoting activities of these galactolipids were evaluated using a short-term in vitro assay of Epstein-Barr virus activation in Raji cells induced by 12-O-tetradecanoyl-phorbol 13-acetate (TPA). The glyceroglycolipids which have a palmitoleoyl residue at the 1-O-position exhibited more potent activities than the others in this assay.

— Aromatic, aliphatic, and alicyclic thiols can be readily oxidized to the disulfides quantitatively by calcium hypochlorite and moist Montmorillonite K10 under mild and neutral conditions.

1,3-Dithianes derived from aromatic, aliphatic, and alicyclic ketones or aldehydes can be conveniently converted to the parent carbonyl compounds with a combination of ferric nitrate and silica gel in hexane in excellent to quantitative yields.

A combination of sodium chlorite, (salen)manganese(III) catalyst, and chromatographic neutral alumina in dichloromethane can be successfully utilized for the aromatic monochlorination of a variety of alkyl phenyl ethers in excellent to quantitative yields under mild and anhydrous conditions.

Regioselective and high-yielding nuclear monobromination of aromatic ethers can be accomplished with a combination of NaClO2, NaBr, and Mn(acac)3 catalyst in dichloromethane under mild and neutral conditions with the aid of Montmorillonite K10.

Oxidation of α,ω-diols with sodium bromite can be readily performed in dichloromethane to afford lactones in fair good yield under mild and neutral conditions with the aid of chromatographic acidic alumina.

Chlorination of a variety of aliphatic, alicyclic, and aromatic ketones with a reagent combination of NaClO2 and Mn(acac)3 catalyst can be readily performed in dichloromethane to afford α-chloroket...

Nuclear monobromination of aromatic ethers can be achieved with a NaClO2/NaBr/Mn(acac)3 catalyst/silica gel system in dichloromethane in regioselective and high-yielding manner under mild conditions.

(1998). A SIMPLE REGIOSELECTIVE NUCLEAR BROMINATION OF ALKYL PHENYL ETHERS. Organic Preparations and Procedures International: Vol. 30, No. 2, pp. 218-222.

Aliphatic, alicyclic, and aromatic alkenes underwent smooth vic-dichlorination upon treatment with a reagent combination of NaClO2, Mn(acac)3 catalyst, and chromatographic neutral alumina preloaded with a small amount of water in dichloromethane under mild conditions.

(1998). SYNTHESIS OF DISULFIDES BY THE OXIDATIVE COUPLING OF THIOLS WITH CALCIUM HYPOCHLORITE AND SILICA GEL IN HEXANE. Organic Preparations and Procedures International: Vol. 30, No. 3, pp. 360-363.

An inexpensive combination of common laboratory reagents, dimethyl sulfoxide (DMSO) and chromatographic neutral alumina, gives an efficient, selective, and high-yielding oxidation of aromatic, aliphatic and alicyclic thiols to the corresponding disulfides in excellent yields under relatively mild conditions.

Moist kaolin catalyses the regioselective and high-yielding chlorination and bromination of C6H5OR (R=C1–C8 alkyl, But, allyl, cyclohexyl, benzyl) to 4-XC6H4OR (X=Cl and Br, respectively) with NaClO2 and Mn(acac)3 in CH2Cl2 in the absence and presence of NaBr, respectively, under mild and neutral conditions.

A combination of NaBH4 and alumina preloaded with a small amount of water is a highly efficient reducing agent for cycloalkanones, substituted cyclohexanones and unsaturated and aromatic ketones in hexane, affording the corresponding alcohols in excellent yields under mild conditions (20–60°C).

An inexpensive, stable, commercially available reagent, chemical manganese dioxide, can be used for the oxidation of a wide variety of benzylic alcohols and the C–C bond cleavage of aromatic diols in hexane under relatively mild conditions.

A variety of aromatic, aliphatic, and alicyclic thiols were readily oxidised with a combination of sodium iodate and chromatographic neutral alumina in hexane to afford the corresponding disulfides in excellent yields under mild and neutral conditions.

Selective and high-yielding synthesis of alcohols can be easily achieved by the reduction of a variety of ketones and aldehydes with a combination of inexpensive and readily available laboratory reagents, NaBH4 and silica gel, in hexane under mild and neutral conditions.

A broad range of aliphatic, alicyclic, and aromatic ketones and aldehydes underwent smooth reduction with a combination of common, inexpensive laboratory reagents, sodium borohydride and chromatogr...

Basic fibroblast growth factor (bFGF) modulates functions of a variety of cell types. Whereas bFGF is known to act extracellularly, the protein lacks a transient signal peptide. No defined mechanism for bFGF secretion has been characterized besides release from dead or injured cells. To study this problem we devised an experimental system to examine bFGF-mediated migration of isolated single cells. Under these conditions individual cells are not affected by bFGF derived from other cells. By this method we have previously shown that bFGF released by NIH 3T3 cells transfected with bFGF cDNA modulates migration in an autocrine manner. We have now examined the effects on cell motility of drugs or treatments known to affect various pathways of protein secretion. Drugs that block secretion via the endoplasmic reticulum (ER)-Golgi complex or via multidrug resistance proteins did not inhibit cell motility. Migration was enhanced by the calcium ionophore A23187, which stimulates exocytosis, and was inhibited by methylamine, serum-free, and low temperature (18°C) conditions, which block endoand exocytosis. The reversal of these effects by the concomitant addition of affinity-purified anti-bFGF IgG or recombinant bFGF showed that the alterations in cell migration were mediated by changes in bFGF externalization. Thus bFGF can be released via a mechanism of exocytosis independent of the ER-Golgi pathway. © 1992 Wiley-Liss, Inc.

The subcellular distribution of basic fibroblastic growth factor (bFGF) was analyzed by subcellular fractionation and immunofluorescence to gain insight into potential mechanisms for its release from cells. Subcellular fractionation of either SK-Hep-1 cells or NIH 3T3 cells transfected with a bFGF cDNA revealed that the 18 kd form of bFGF was found primarily in the cytosolic fraction, whereas the 22 and 24 kd forms of bFGF were found preferentially in ribosomal and nuclear fractions. Analysis of bFGF distribution by immunofluorescence using an antibody that recognized all forms of bFGF indicated both cytoplasmic and nuclear localization but failed to reveal any growth factor in structures representing secretory vesicles. Therefore, bFGF has a distribution inconsistent with that of a secretory protein.

Aliphatic and aromatic alkenes were hydrogenated quantitatively to the corresponding alkanes with sodium borohydride, catalyzed by nickel chloride in the presence of moist alumina in hexane under mild conditions.

The title oxidation in acetic acid resulted in a selective formation of the corresponding ketones in excellent yields under mild conditions.

Benzyl alcohol and its o-, m-, and p-substituted derivatives afforded fairly good yields of the corresponding benzaldehydes through a reaction with a Co(III)–NaBr system. With allylic alcohols, this system failed in a selective formation of unsaturated carbonyl compounds. In the latter cases, the products were effectively obtained by using a higher concentration of cobalt(III) acetate in the absence of NaBr.

4,5-Dimethoxy-o-benzoquinone has been prepared by the oxidation of catechol with sodium iodate in methanol. In higher alcohols, the same oxidation occurs in the presence of a crown ether to give the corresponding 4,5-dialkoxy-o-benzoquinones. In the latter cases using 18-crown-6, the potassium salt is more effective than the sodium salt.

The oxidation of aliphatic and aromatic conjugated dienes by cobalt(III) acetate in acetic acid has been investigated. Open chain dienes were smoothly oxidized by cobalt(III) acetate to give vic-diol derivatives. Cyclo-octadiene was slowly converted into allylic acetate by the oxidant. The reaction mechanism is discussed in terms of a Co-co-ordinated radical cation.

The effect of added sodium bromide on the allylic oxidation of olefins by cobalt(III), manganese(III), and cerium(IV) acetates has been studied. Sodium bromide strongly accelerated the oxidation of cyclohexene by these oxidants to give cyclohex-2-enyl acetate in good yield. Only one product was obtained in the oxidation of cycloalkenes, but two allylic acetates were obtained in the oxidations of methyl-substituted cyclohexenes, which have two kinds of allylic hydrogen. A mechanism involving hydrogen abstraction from allylic sites by bromine radicals is suggested.