Series Of Tp Research Articles

Transport Oligonucleotides-A Novel System for Intracellular Delivery of Antisense Therapeutics.

Biological activity of antisense oligonucleotides (asON), especially those with a neutral backbone, is often attenuated by poor cellular accumulation. In the present proof-of-concept study, we propose a novel delivery system for asONs which implies the delivery of modified antisense oligonucleotides by so-called transport oligonucleotides (tON), which are oligodeoxyribonucleotides complementary to asON conjugated with hydrophobic dodecyl moieties. Two types of tONs, bearing at the 5′-end up to three dodecyl residues attached through non-nucleotide inserts (TD series) or anchored directly to internucleotidic phosphate (TP series), were synthesized. tONs with three dodecyl residues efficiently delivered asON to cells without any signs of cytotoxicity and provided a transfection efficacy comparable to that achieved using Lipofectamine 2000. We found that, in the case of tON with three dodecyl residues, some tON/asON duplexes were excreted from the cells within extracellular vesicles at late stages of transfection. We confirmed the high efficacy of the novel and demonstrated that MDR1 mRNA targeted asON delivered by tON with three dodecyl residues significantly reduced the level of P-glycoprotein and increased the sensitivity of KB-8-5 human carcinoma cells to vinblastine. The obtained results demonstrate the efficacy of lipophilic oligonucleotide carriers and shows they are potentially capable of intracellular delivery of any kind of antisense oligonucleotides.

Evaluation of the SeaWiFS and MODIS Chlorophyll a Algorithms Used for the Northern South China Sea during the Summer Season

The present study made evaluations of SeaWiFS-derived and MODIS-derived Chlorophyll a (Chl a) concentrations in the Northern South China Sea (NSCS), using in situ data collected during two research cruises which were conducted during the summer of 2004 (September 18 to October 8) and 2007 (August 10 to 29). The data of ±48 h and 3 × 3 pixels were used for the comparison between satellite and in situ Chl a data, and the results reveal a systematic overestimation of Chl a concentration by National Aeronautics and Space Administration (NASA) global algorithms (OC2v4, OC4v4, and OC3M). The RMSEs of the selected algorithms are larger than 0.35 except OC2_D’Ortenzio (one regional algorithm for the Mediterranean Sea). The overestimation seems to correlate with numerous (≈77%) low Chl a concentration (< 0.1 mg m -3 ) due to the oligotrophic characteristics of the South China Sea (SCS) in summer, and to correlate with the error in atmosphere correction introduced by aerosols. Therefore, the OC2 and OC4 algorithms for SeaWiFS and OC3M algorithm for MODIS are adapted to NSCS by fitting the satellite data set to in situ Chl a data in NSCS. With the new coefficients based on our field data, the regional version of the three algorithms (TP series) showed good performance with RMSE values of 0.245, 0.245, and 0.288 respectively, which were slightly higher than the algorithm “noise” (0.222 in RMSE). Those TP series algorithms may be considered preliminary due to the relatively small number of available in situ data, and they are suitable in summer season in NSCS.

Terpyridine–platinum(II) complexes are effective inhibitors of mammalian topoisomerases and human thioredoxin reductase 1

Terpyridine-platinum(II) (TP-Pt(II)) complexes are known to possess DNA-intercalating activity and have been regarded as potential antitumor agents. However, their cytotoxic mechanism remains unclear. To investigate the possible mechanism, a series of TP-Pt(II) compounds were prepared and their biological activities assessed. The DNA binding activities of the aromatic thiolato[TP-Pt(II)] complexes were stronger than the aliphatic 2-hydroxylethanethiolato(2,2':6',2''-terpyridine)platinum(II) [TP(HET)]. TP-Pt(II) complexes inhibited topoisomerase IIalpha or topoisomerase I activity at IC(50) values of about 5 microM and 10-20 microM, respectively, whereas the human thioredoxin reductase 1 (hTrxR1) activity was inhibited with IC(50) values in the range of 58-78 nM. At the cellular level, they possessed cytotoxicity with IC(50) values between 7 and 19 microM against HeLa cells. Additionally, using X-ray crystallography and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry, we elucidated that the TP-Pt(II) complexes inhibited hTrxR1 activity by blocking its C-terminal active-site selenocysteine. Therefore, TP-Pt(II) complexes possess inhibitory activities against multiple biological targets, and they may be further studied as anticancer agents.

Rediscovering copper-based catalysts for intramolecular carbon–hydrogen bond functionalization by carbene insertion

A series of Tp(x)Cu complexes (Tp(x) = hydrotrispyrazolylborate ligand) have been tested as catalysts for the decomposition of several diazoacetates and N,N-disubstituted diazoacetamides and the subsequent formation of lactones and lactams, respectively. The complexes containing the ligands Tp(Br3) or Tp(Ms) have provided activities and selectivities for these transformations comparable with or, in some cases, better than the well-known rhodium catalyst Rh(2)(OAc)(4).

New asymmetric monostyrylamine dopants for blue light-emitting organic electroluminescence device

Four new dopant materials containing a monostyrylamine moiety, 4-(1,2-diphenylvinyl)-4′-( N, N-diphenylamino)biphenyl (TP-BP), 4-(1,2-diphenylvinyl)-4′-( N, N-ditolylamino)biphenyl (TP-MP), 4-(1,2-diphenylvinyl)-4′-( N-naphthyl- N-phenylamino)biphenyl (TP-NP) and 4-[1-phenyl-2-(4-biphenyl)vinyl]-4′-( N, N-diphenylamino)biphenyl (TP-BiP) were synthesized by the Wittig–Horner reaction, followed by an amination reaction with various aromatic diamines. Blue OLEDs were obtained from the distyrylarylene host materials TPM-BP, TPM-MP and TPM-BiP. The structure of the device is an ITO/DNTPD/NPB/TPM host, TP dopant/Alq 3/Al–LiF. Here, NPB is used as the hole transport layer, DNTPD as the hole injection layer, the TPM series host as the blue emitting host, TP series as dopant, Alq 3 as the electron transport layer, and Al as the cathode. Their photophysical and electroluminescent properties, including efficiency, current density, and CIE coordinates were examined.

Solid state and solution structures of rhodium and iridium poly(pyrazolyl)borate diene complexes

The structures adopted by a range of poly(pyrazolyl)borate complexes [ML2Tp(x)] [M = Rh, Ir; L2 = diene; Tp(x) = Bp' {dihydrobis(3,5-dimethylpyrazolyl)borate}, Tp' {hydrotris(3,5-dimethylpyrazolyl)borate}, Tp {hydrotris(pyrazolyl)borate}, B(pz)4 {tetrakis(pyrazolyl)borate}] have been investigated. Low steric hindrance between ligands in [Rh(eta-nbd)Tp] (nbd = norbornadiene), [Rh(eta-cod)Tp] (cod = cycloocta-1,5-diene) and [Rh(eta-nbd)Tp'] results in K3 coordination of the pyrazolylborate but [M(eta-cod)Tp'] (M = Rh, Ir) are kappa2 coordinated with the free pyrazolyl ring positioned above and approximately parallel to the square plane about the metal. All but the most sterically hindered Tp(x) complexes undergo fast exchange of the coordinated and uncoordinated pyrazolyl rings on the NMR spectroscopic timescale. For [Rh(eta-cod){B(pz)4}], [Rh(eta-dmbd)Tp'] (dmbd = 2,3-dimethylbuta-1,3-diene) and [Rh(eta-cod)Tp(Ph)] {Tp(Ph) = hydrotris(3-phenylpyrazolyl)borate} the fluxional process is slowed at low temperatures so that inequivalent pyrazolyl rings are observed. The bonding modes of the Tp' ligand (but not of other pyrazolylborate ligands) can be determined by 11B NMR and IR spectroscopy. The 11B chemical shifts (for a series of Tp' complexes) show the general pattern, kappa3 < -7.5 ppm < kappa2 and the nu(BH) stretch kappa3 > 2500 cm(-1) > kappa2. The electrochemical behaviour of the pyrazolylborate complexes is related to the degree of structural change which occurs on electron transfer. One-electron oxidation of complexes with Tp', Tp and B(pz)4 ligands is generally reversible although that of [Ir(etacod)Tp] is only reversible at higher scan rates and that of [Ir(eta-cod){B(pz)4}] is irreversible. Of the complexes with the more sterically hindered Tp(Ph) ligand, only [Rh(eta-nbd)Tp(Ph)] shows any degree of reversible oxidation. The ESR spectra of a range of Rh(II) complexes show coupling to both 14N and 103Rh nuclei in most cases but what appears to be coupling to rhodium and one hydrogen atom, possibly a hydride ligand, for the oxidation product of [Rh(eta-nbd)Tp(Ph)].

A stable monomeric nickel borohydride.

A stable discrete nickel borohydride complex (Tp*NiBH(4) or Tp*NiBD(4)) was prepared using the nitrogen-donor ligand hydrotris(3,5-dimethylpyrazolyl)borate (Tp*-). This complex represents one of the best characterized nickel(II) borohydrides to date. Tp*NiBH(4) and Tp*NiBD(4) are stable toward air, boiling water, and high temperatures (mp > 230 degrees C dec). X-ray crystallographic measurements for Tp*NiBH(4) showed a six-coordinate geometry for the complex, with the nickel(II) center facially coordinated by three bridging hydrogen atoms from borohydride and a tridentate Tp(-) ligand. For Tp*NiBH(4), the empirical formula is C(15)H(26)B(2)N(6)Ni, a = 13.469(9) A, b = 7.740(1) A, c = 18.851(2) A, beta = 107.605(9) degrees, the space group is monoclinic P2(1)/c, and Z = 4. Infrared measurements confirmed the presence of bridging hydrogen atoms; both nu(B[bond]H)(terminal) and nu(B[bond]H)(bridging) are assignable and shifted relative to nu(B-D) of Tp*NiBD(4) by amounts in agreement with theory. Despite their hydrolytic stability, Tp*NiBH(4) and Tp*NiBD(4) readily reduce halocarbon substrates, leading to the complete series of Tp*NiX complexes (X = Cl, Br, I). These reactions showed a pronounced hydrogen/deuterium rate dependence (k(H)/k(D) approximately 3) and sharp isosbestic points in progressive electronic spectra. Nickel K-edge X-ray absorption spectroscopy (XAS) measurements of a hydride-rich nickel center were obtained for Tp*NiBH(4), Tp*NiBD(4), and Tp*NiCl. X-ray absorption near-edge spectroscopy results confirmed the similar six-coordinate geometries for Tp*NiBH(4) and Tp*NiBD(4). These contrasted with XAS results for the crystallographically characterized pseudotetrahedral Tp*NiCl complex. The stability of Tp*Ni-coordinated borohydride is significant given this ion's accelerated decomposition and hydrolysis in the presence of transition metals and simple metal salts.

Kinetic isotope effects in cycloreversion of rhenium (V) diolates.

Cycloreversion of 4-methoxystyrene from the corresponding Tp'Re(O)(diolato) complex (Tp' = hydrido-tris-(3,5-dimethylpyrazolyl)borate) was measured competitively for various isotopomers at 103 degrees C. Primary ((12)C/(13)C) and secondary ((1)H/(2)H) kinetic isotope effects were determined. The primary KIEs were k(12C)/k(13C) = 1.041 +/- 0.005 at the alpha position and 1.013 +/- 0.006 at the beta position. Secondary KIEs were k(H)/k(D) = 1.076 +/- 0.005 at the alpha position and 1.017 +/- 0.005 at the beta position. Computational modeling (B3LYP/LACVP+) located a transition state for concerted cycloreversion of styrene from TpRe(O)(OCH(2)CHPh) exhibiting dramatically different C-O bond lengths. A Hammett study on cycloreversions of substituted styrenes from a series of Tp'Re(O)(diolato) showed dichotomous behavior for electron donors and electron-withdrawing groups as substituents: rho = -0.65 for electron donors, but rho = +1.13 for electron-withdrawing groups. The data are considered in light of various mechanistic proposals. While the extrusion of 4-methoxystyrene is concluded to be a highly asynchronous concerted reaction, the Hammett study reflects a likelihood that multiple reaction mechanisms are involved.

Efficacy of a liquid-based thin layer method for cervical cancer screening in a population with a low incidence of cervical cancer

The performance of the ThinPrep(R) Pap Testtrade mark (TP) (Cytyc Corp., Boxborough, MA) for detection of cervical cancer precursors in a population with a low incidence of disease was evaluated. This prospective trial compared results obtained with TP to those obtained with the standard cytologic smear in women from the general community who were being screened for cervical cancer from January 1, 1995-December 31, 1997 by physicians in private practice (n x 130, 381 conventional examinations and 39,864 TP examinations). In the TP series there was a significant increase in the proportion of "satisfactory" examinations (91.9% TP vs. 72.2% conventional) and positive diagnoses (5.5% TP vs 2.4% conventional, odds ratio x 2.21; 95% confidence interval (CI), 2.08-2.34). The likelihood of detecting a high-grade squamous intraepithelial lesion (HSIL) by TP was significantly greater than in controls (odds ratio x 1.86; 95% CI, 1.68-2.06). Detection of low-grade squamous intraepithelial lesions (LSIL), or atypical squamous cells of undetermined significance (ASCUS), was significantly greater in the TP series than in controls (LSIL odds ratio x 3.41; 95% CI, 3.07-3.79; ASCUS odds ratio x 1.68; 95% CI, 1.56-1.82). A histologic lesion was confirmed in 141 (93%) of the biopsies for HSIL (130 HSIL or greater, 10 LSIL, 1 SIL not otherwise specified). In conclusion, both diagnostic sensitivity and sample adequacy were significantly improved using the ThinPrep(R) Pap test under routine conditions in an outpatient population with a low incidence of cervical cancer.

Efficacy of a liquid‐based thin layer method for cervical cancer screening in a population with a low incidence of cervical cancer

The performance of the ThinPrep® Pap Test™ (TP) (Cytyc Corp., Boxborough, MA) for detection of cervical cancer precursors in a population with a low incidence of disease was evaluated. This prospective trial compared results obtained with TP to those obtained with the standard cytologic smear in women from the general community who were being screened for cervical cancer from January 1, 1995–December 31, 1997 by physicians in private practice (n × 130,381 conventional examinations and 39,864 TP examinations). In the TP series there was a significant increase in the proportion of “satisfactory” examinations (91.9% TP vs. 72.2% conventional) and positive diagnoses (5.5% TP vs 2.4% conventional, odds ratio × 2.21; 95% confidence interval (CI), 2.08–2.34). The likelihood of detecting a high-grade squamous intraepithelial lesion (HSIL) by TP was significantly greater than in controls (odds ratio × 1.86; 95% CI, 1.68–2.06). Detection of low-grade squamous intraepithelial lesions (LSIL), or atypical squamous cells of undetermined significance (ASCUS), was significantly greater in the TP series than in controls (LSIL odds ratio × 3.41; 95% CI, 3.07–3.79; ASCUS odds ratio × 1.68; 95% CI, 1.56–1.82). A histologic lesion was confirmed in 141 (93%) of the biopsies for HSIL (130 HSIL or greater, 10 LSIL, 1 SIL not otherwise specified). In conclusion, both diagnostic sensitivity and sample adequacy were significantly improved using the ThinPrep® Pap test under routine conditions in an outpatient population with a low incidence of cervical cancer. Diagn. Cytopathol. 2000;22:52–59. © 2000 Wiley-Liss, Inc.

A large-scale investigator-sponsored field study of the test performance of the ThinPrep papanicolaou test in a low-risk routine outpatient setting

The performance of the ThinPrep Papanicolaou test (TP)(CYTYC Corp., Boxborough, MA) was evaluated in a low- risk outpatient population in order to assess its efficacy in routine clinical use. A total of 18,246 cervical cytology samples were prepared using TP during a 6-month evaluation period from January through June 1997. Results of TP interpretation, assessed for specimen quality and diagnostic information as reported according to the Bethesda system terminology, were reviewed and compared with corresponding results from 2 historical control series of 35,347 and 35,409 conventional cervical smears (Papanicolaou smears). Archived conventional smears obtained during the first 6 months of 1995 and 1996 from the same general patient population by the same group of gynecologists and general practitioners were selected for analysis. Positive cytologic diagnoses in the TP series were reviewed and cytologic-histologic correlations were analyzed when biopsy material was available. The results demonstrated that the proportion of cytologic examinations classified as “satisfactory” was significantly greater in the TP series as compared to conventional controls (88.8% vs 71.1%, P < .0001). There was a significant increase in the number of TP examinations with an adequate endocervical component as compared to conventional controls (90.2% vs 86.9%, P < .005) and a significant decrease in the number of TP examinations that were classified as “satisfactory but limited by” either poor fixation or obscuring factors, such as blood, neutrophils, and contaminants (1.1% TP vs 14.1% nonTP, P < .0001). The overall sensitivity of detection for abnormal cells as indicated by the number of positive diagnoses was increased in the TP series (5.7% vs 2.4%, P < .01). The cytologic diagnoses of ASCUS, LSIL, and HSIL were respectively 1.6, 3.6, and 3 times more frequent in the TP series than in controls. Cytologic-histologic correlations were available for 110 (27%) of the 403 cytologic diagnoses of LSIL and for 90 (83%) of the 121 cytologic diagnoses of HSIL. The presence of a histologic lesion (LSIL or HSIL) was confirmed in 71 (65%) biopsies for LSIL and in 81 (90%) biopsies for HSIL. In conclusion, both sample quality and diagnostic sensitivity were significantly improved using the ThinPrep Papanicolaou test under routine conditions in a low-risk population.

Smectic Characteristics of Main-Chain Polyesters as Elucidated from a Variation of Layer Thickness with Carbon Number of Aliphatic Spacer in a Wide Range, 5 to 20

We prepared the main-chain type of TP- n polyesters, which are based on the terphenyl dicarboxylic acid and alkane diols with the carbon number of n = 5–20. All the TP- n polyesters form a smectic liquid crystal, exhibiting the well known odd–even oscillation with respect to the thermodynamic parameters of transitions and smectic structure. From the x-ray patterns of the oriented fibres, the SA and SCA structures were identified for the even and odd series of TP- n respectively. The structural characteristics of the polymeric SA and SCA phases are presented by examining the variation of layer spacing with n in a wide range of n = 5 to 20.

1-((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo [2.2.1]-heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperaz ine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor.

Modifications to the previously reported spiroindenylpiperidine camphor-sulfonamide oxytocin (OT) antagonist L-366,509 have produced a new series of o-tolylpiperazine (TP) camphor-sulfonamides. A number of analogues in the TP series that incorporate a modified or unmodified L-methionine sulfone amide at the C2 endo position on the camphor ring exhibit high affinity for OT receptors (IC50 = 1.3-15 nM) and good selectivity for binding to OT versus arginine vasopressin V1a and V2 receptors. Several of these analogues were additionally characterized as potent antagonists of OT-stimulated contractions of the isolated and/or in situ rat uterus. Compound 7 (L-368,899) exhibited the best overall profile of OT receptor affinity (IC50 = 8.9 nM, rat uterus; 26 nM, human uterus), potency for inhibition of OT-stimulated contractions of the isolated rat uterus (pA2 = 8.9) and in situ rat uterus (AD50 = 0.35 mg/kg after intravenous (i.v.) administration and 7.0 mg/kg after intraduodenal administration), aqueous solubility (3.7 mg/mL at pH 5.0), and oral bioavailability in several species (35% (rat), 25% (dog), and 21% (chimpanzee) as estimated from radioreceptor determination of drug levels in plasma after oral and i.v. dosing). On the basis of these favorable properties, 7 has begun clinical testing for use as an oral and i.v. tocolytic agent. Molecular modeling alignment studies have provided support for the hypothesis that the TP camphor-sulfonamide portion of the non-peptide structures may serve as a mimetic of the important D-AA2-Ile3 dipeptide (AA = aromatic amino acid) found in many potent OT antagonists from the cyclic hexapeptide and OT analogue structural classes.