Low Intermediates Research Articles

Standard CHOP therapy for low (L) or low-intermediate (L-I) risk patients (pts) with aggressive non-Hodgkin's lymphoma (NHL): A multicenter phase II study by Japan Clinical Oncology Group (JCOG 9508)

6703 Background: To confirm the efficacy and safety of standard CHOP therapy in Japanese pts with L or L-I risk aggressive NHL, we conducted a multicenter phase II study with overall survival (OS) as primary endpoint. Methods: Eligibility criteria were as follows: newly-diagnosed, intermediate or high grade NHL by Working Formulation; L or L-I risk by International Prognostic Index (IPI); clinical stage of II, III, IV or bulky I; ages less than 70; PS 0–3. Eight courses of standard CHOP therapy were given every 3 weeks. Involved-field radiotherapy (30 to 40 Gy) was added after chemotherapy for bulky disease at baseline, and was optional for residual tumors. Results: Between June 1995 and May 1999, a total of 213 pts were enrolled, and 173 pts were pathologically eligible (diffuse large B; 68%) by the central review according to WHO classification. Out of 173 pts, 87 and 80 pts were of L and L-I risk, respectively. Three pts with high-intermediate IPI risk, 1 high IPI risk, 1 stage I without bulky disease, and 1 prior radiotherapy were ineligible. % complete response of L and L-I risk pts was 83% (95% CI; 74–90%) and 74% (95% CI; 63–83%), respectively. Five-year OS was 73% (95% CI; 64–83%) and 64% (95% CI; 53–74%), and 5-year progression-free survival (PFS) was 63% (95% CI; 52–73%) and 38% (95% CI; 27–59%). Major toxicity by JCOG toxicity criteria in all treated pts (212 pts) was grade 4 neutropenia (64%). Non-hematologic toxicities were acceptable; the most frequent grade 3 toxicity was nausea/vomiting (3%), and grade 4 toxicity was observed in one who developed paralytic ileus. One treatment-related death was observed due to hepatitis B virus reactivation. Conclusions: CHOP was confirmed to be a standard therapy in Japanese pts with L or L-I risk aggressive NHL. However, the relatively low %PFS suggests the necessity of further investigations to find more effective first-line therapy for L-I risk pts. No significant financial relationships to disclose.

Standard CHOP therapy for low (L) or low-intermediate (L-I) risk patients (pts) with aggressive non-Hodgkin's lymphoma (NHL): A multicenter phase II study by Japan Clinical Oncology Group (JCOG 9508)

6703 Background: To confirm the efficacy and safety of standard CHOP therapy in Japanese pts with L or L-I risk aggressive NHL, we conducted a multicenter phase II study with overall survival (OS) ...

Demonstration of a low-energy on-pathway intermediate in a fast-folding protein by kinetics, protein engineering, and simulation.

It is controversial whether fast-folding proteins can form productive on-pathway intermediates that are more stable than the denatured state because noncovalent intermediates are usually evanescent. Here, we apply the classical criteria for the existence of intermediates: namely, the intermediates form and react rapidly enough to be on pathway and they can be isolated and characterized. The folding of the 71-residue, mainly alpha-helical FF domain from human HYPA/FBP11 fulfills these classical criteria, as was found for Im7. The FF domain folds in two phases, one on the micros and the other on the ms time scale. An engineered mutant folds only to a partly folded state, with some 20-40% of the native helical content. The kinetic properties of the mutant are identical to those found for the fast phase of the wild-type protein, and it is likely that the mutant folds just to the intermediate state. A full kinetic analysis of the folding of wild-type protein, using the amplitudes of its native and denatured states and the observed values for the mutant, rules out an off-pathway scheme but fits an on-pathway scheme, with a low energy intermediate that is modeled by the mutant. The experimental proof benchmarks a molecular dynamics method that identifies an obligatory intermediate observed in multiple simulations. The conformational space defining this intermediate is visited several times in the simulations, leading to high populations consistent with the presence of a low energy intermediate.

Advanced/Retarded Criterion on Ignition of Fuel/Air Mixtures with Formaldehyde Doping(HCCI, Effect of Fuel and Additives)

Formaldehyde artificially added into the mixtures is efficacious as an ignition control medium for hydrocarbon fuels in engine cylinders. The vapor added into the mixtures has given the premixed compression-ignition (HCCI) engine a stable ignition timing, which is controllable to get the MET by the amount of formaldehyde to be added. The effect of formaldehyde addition is either suppressing or promoting. A universal criterion of the formaldehyde effect resulting whether in the advanced or in the retarded hot-flame appearance from the original ignition events has been elucidated through experiments over a wide range of parameters on the fuel octane or butane rating, the equivalence ratio of the mixture, and the mixture temperature to be raised. The formaldehyde would be a suppressing additive under the cool-flame generating constituents, temperature and pressure conditions, and a promoting additive under the poor cool-flame generating conditions in the cylinder charge during the preflame reactions leading to the ignition. The added formaldehyde is superfluous to the ignition event originally belonging to the cool-flame dominant regime, which would give a suppressing effect. On the other hand, the artificially added formaldehyde could be a starting point of preflame reactions leading to the final hot ignition belonging to the blue-flame-dominant regime, where a few fuel transition and low intermediates appear, and where the high temperature chemistry dominates. It allows a short cut of the preflame induction period, in consequence, a promoting effect for the ignition. The low-temperature-ignition classification; three typical regime, "cool-flame dominant regime", "negative-temperature-coefficient regime" and "blue-flame dominant regime" would be a universal advanced/retarded criterion on ignition of fuel/air mixtures with formaldehyde doping for the ignition timing control in the piston compression engines.

Too Many to Fail? Inter-Enterprise Arrears in Transition Economies

In advanced market economies, the use of trade credits is an important way of short-term financing and generally considered as being part of normal business practice. Some transition economies, however, have experienced a rapid accumulation of trade credits which have led to interlocking webs of arrears and collective bailouts by the government. In this paper, firm-level data is used to test whether trade credits are just part of normal business practice comparable to more advanced market-economies or whether trade credits represent a systematic phenomena supporting soft budget constraints of firms in transition. The results suggest that trade credits are not just normal business practice but that they can have negative spill-over effects on other firms by worsening their financial situation. We conclude that the problem of interlocking effects is more pronounced in countries with less developed institutions, low financial intermediation and, overall, no credible commitment to market economic reforms.

Differences in growth with international capital markets and financial innovation

This paper presents a model in which technological progress affects the productivity of the financial sector. When technological progress moves quicky, the financial intermediation costs are low, which increases the incentives to invest in new technology. This feedback process involves two types of long-run equilibria: one with low financial intermediation costs and high growth, and the other with high financial intermediation costs and low growth. These divergences in growth rates among countries hold even in the presence of international capital markets with free capital mobility, a very unusual result in the endogenous growth literature.

Significance of Cross-cultural Trust in Streamlining Supply-chains for Global Enterprises

In high-velocity global markets, streamlining enterprise supply-chains and increasing trust can reduce high transaction costs. In this article, we integrate previous research studies on the evolution of supply-chains for global enterprises and the role of trust in inter-organizational transactions. We propose that the streamlining of supply-chains with low intermediation is most likely to be associated with the selection of tristworthy agents, deployment of trust-building interactions, and the institutionalization of trust in the participating enterprise. Future implications for researchers and practitioners include the study of resistance to change for implementing streamlined supply-chains.

Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin's lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: A GELA study on 974 patients

Incidence of central nervous system (CNS) recurrence in patients with aggressive non-Hodgkin's lymphoma who did not receive meningeal prophylaxis is about 5%. Controversy remains regarding risk factors associated with such an event preventing a rational approach of prophylactic strategies. We analyzed a cohort of 974 patients with aggressive lymphoma in complete remission (CR). All the patients received a CNS prophylaxis consisting of intrathecal injections and intravenous high-dose methotrexate. The risk repartition on the basis of the international prognostic index (IPI) of these 974 CR-patients was low (L): 41%, low-intermediate (LI): 27%, high-intermediate (HI): 19%, high (H): 13%. The incidence of isolated CNS relapse was 1.6%. In a first multivariate logistic regression analysis an increased LDH (P = 0.05, RR = 5) and the presence of more than one extranodal site (P = 0.05, RR = 3) were identified as independent risk factors for isolated CNS relapse. Another multivariate analysis incorporating IPI as a unique parameter showed that only IPI remained significantly associated with a higher risk of CNS relapse (L-LI: 0.6% vs. HI H: 4.1%, P = 0.002; RR = 7). Prophylaxis notably reduces the risk of CNS recurrence in the higher risk patients. By contrast, we propose the deletion of prophylactic intrathecal injections in the lower risk patients.

The specificity of enteropeptidase relative to the chimeric proteins and trypsinogen processing

Abstract: The limited proteolysis by enteropeptidase of the recombinant chimeric proteins incorporating the linker (Asp)4- Lys was studied. The resistant to the hydrolysis chimeric proteins was shown to be the competitive inhibitors in re­ lation to the effectively splitting chimeric proteins and to the low molecular intermediates of the linker, but not of the trypsinogen processing. The linker was shown to be defined the binding of the protein substrates by enzyme only, rather than the efficiency, determined by the C-terminal component of enzyme specificity.

Low hapticity intermediates in the carbonylation of ( η5-2,6-dimethyl-5-hydro- s-indacenide)-Ir( η4-COD)

The isomeric ( η 1-5-hydro-2,6-dimethyl- s-indacenide)-Ir( η 4-COD)(CO) 2 and ( η 1-7-hydro-2,6-dimethyl- s-indacenide)-Ir( η 4-COD)(CO) 2) complexes are produced in a 1/1 ratio in the first step of the carbonylation reaction of ( η 5-2,6-dimethyl-5-hydro- s-indacenide)-Ir( η 4-COD) at 233 K. At 243 K, in the presence of excess CO, they slowly convert into the isomeric ( η 1-5-hydro-2,6-dimethyl- s-indacenide)-Ir[ η 2-COD)(CO) 3) and ( η 1-7-hydro-2,6-dimethyl- s-indacenide]-Ir( η 2-COD)(CO) 3. The unprecedented η 2-coordination of COD towards iridium has been detected both by conventional variable temperature 1D 1H NMR spectroscopy and by a single-temperature 2D EXSY experiment.

Wet oxidation of acetic acid by H2O2 catalyzed by transition metal-exchanged NaY zeolites

During the wet oxidation of contaminated wastewaters, the destruction of low molecular weight carboxylic acid intermediates such as acetic, glyoxalic, and oxalic acids is often the rate-controlling step. Oxidation of acetic acid, a very recalcitrant intermediate, requires compelling treatment severity. Heterogeneous catalytic wet oxidation of model acetic acid aqueous solutions was conducted under mild conditions (below the normal boiling point of water) using hydrogen peroxide over various transition metal-exchanged NaY zeolites. Treatment of Cu2+–NaY with oxalic acid [OA] led to a catalyst, Cu2+–NaY [OA], with significantly improved properties in terms of total organic carbon (TOC) removal efficiency and catalyst stability against leaching. This catalyst outperformed homogeneous Cu2+ by a factor of 2–2·5 times. Continuous feeding of H2O2 reduced its undesirable decomposition. Improvement of the TOC-degradation performance by Cu2+–NaY [OA] was tentatively attributed to the removal of sodium and possibly aluminium in the zeolite. © 1998 Society of Chemical Industry

Iron transport in K562 cells: a kinetic study using native gel electrophoresis and 59Fe autoradiography

The exact mechanisms of iron transport from endosomes to the target iron containing cellular proteins are currently unknown. To investigate this problem, we used the gradient gel electrophoresis and the sensitive detection of 59Fe by autoradiography to detect separate cellular iron compounds and their iron kinetics. Cells of human leukemic line K562 were labeled with [ 59Fe]transferrin for 30–600 s and cellular iron compounds in cell lysates were analyzed by native electrophoretic separation followed by 59Fe autoradiography. Starting with the first 30 s of iron uptake, iron was detectable in a large membrane bound protein complex (Band I) and in ferritin. Significant amounts of iron were also found in labile iron compound(s) with the molecular weight larger than 5000 as judged by ultrafiltration. Iron kinetics in these compartments was studied. Band I was the only compound with the kinetic properties of an intermediate. Transferrin, transferrin receptor and additional proteins of the approximate molecular weights of 130 000, 66 000 and 49 000 were found to be present in Band I. The labile iron compounds and ferritin behaved kinetically as end products. No evidence for low molecular weight transport intermediates was found. These results suggest that intracellular iron transport is highly compartmentalized, that iron released from endosomal transferrin passes to its cellular targets in a direct contact with the endosomal membrane complex assigned as Band I. The nature of the labile iron pool and its susceptibility to iron chelation is discussed.

Synthesis of New Thermoelectric Materials Using Modulated Elementary Reactants

AbstractModulated elemental reactants have been used to synthesize metastable ternary compounds with the skutterudite crystal structure. The initial reactants are made up of multiple repeats of a unit containing elemental layers of a ternary metal, iron or cobalt (or a combination of these two) and antimony. The elemental layers interdiffuse upon low temperature annealing and form amorphous reaction intermediates. In this paper we target the compounds PbxFe4−yCoySb12. On annealing at temperatures between 12° and 150° C (depending on the composition) crystallization of the skutterudite structure occurs. The compounds are only kinetically stable, decomposing into a mixture of binary compounds upon annealing past a temperature of about 600°C. Preliminary data for the Seebeck coefficient and the electrical conductivity was collected The thermoelectric properties of the lead cobalt antimony skutterudite - films were measured as a function of lead occupancy.

Expression and glucocorticoid regulation of surfactant protein C in human fetal lung.

The hydrophobic surfactant protein C (SP-C) is known to modulate the biophysical properties of surfactant phospholipid. Although SP-C mRNA has been demonstrated in human fetal lung, there is limited information regarding developmental expression and processing of proSP-C protein. Two epitope-specific human proSP-C antisera, anti-hCPROSP-C (His59-Ser72) and anti-hCTERMSP-C (Gly162-Gly175), were generated to complement previously produced anti-NPROSP-C (Met10-Gln23) for the study of proSP-C expression in human fetal lung. Western blotting and immunocytochemistry detected expression of proSP-C protein by 12-16 wk of gestation. ProSP-C immunoreactivity of preculture lung, limited to expression of proSP-C21 in airway epithelial cells, was markedly enhanced by culture of lung explants in dexamethasone. To examine synthesis of proSP-C, homogenates from explants were labeled with 35S-Met/Cys for 0.5-4 h. Immunoprecipitation with anti-NPROSP-C detected 35S-proSP-C21 by 30 min and, after 2 h of labeling, there was a 15-fold increase in 35S-proSP-C21 in dexamethasone-treated lungs versus controls. Synthesis of proSP-C21 was followed by the appearance of a 24-kD form and smaller processing intermediates including 6-10-kD forms. Posttranslational processing of proSP-C21 was not observed in control explants. SP-C(6-10) were not recognized by either anti-CPROSP-C or anti-hCTERMSP-C. These results indicate that low level expression of proSP-C protein first occurs in epithelial cells early in the second trimester and that expression can be enhanced by dexamethasone. Initial posttranslational processing of human proSP-C involves modification of proSP-C21 to SP-C24 and subsequent proteolysis of C-terminal propeptide domains. We speculate that absence of low Mr intermediates in unstimulated second trimester fetal lung tissue reflects developmental and glucocorticoid dependent regulation of proSP-C21 synthesis and posttranslational processing.

Results of Treatment with Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (CHOP) for Non-Hodgkin’s Aggressive Lymphoma Analyzed According to the International Prognostic Index

Forty patients with aggressive (intermediate-grade and high-grade) non-Hodgkin’s lymphoma (NHL) were treated primarily with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen, and then evaluated for prognostic features. Age, tumor stage, performance status, number of extranodal disease sites and serum concentrations of lactate dehydrogenase (LDH) were considered prognostic features. All the patients treated with the CHOP regimen were grouped into four risk categories, including low (L), low-intermediate (LI), high-intermediate (HI) and high (H) according to the International Prognostic Index. Twenty-one of 23 patients (91.3%) in the L plus LI risk groups and 5 of 17 patients (29.4%) in the H plus HI risk groups had complete response and the difference between these percentages was statistically significant (P<0.001). The overall survival rate (2 yr) of 23 patients in the L+LI risk group was 52.1% and of 17 patients in H+HI risk group was 11.7% and this difference was statistically significant (P<0.05). Our results indicated that the CHOP regimen is not effective in the HI+H risk groups of patients with aggressive NHL. New experimental approaches are needed for these patients.

Low force actomyosin intermediate of skeletal muscle and its role in contraction.

The low force actomyosin complex, formed prior to force generation in skeletal muscle, has characteristics distinct from those of conventional weak- or strong-binding complexes and therefore constitutes a third class of intermediate in the ATPase reaction. Its dual strain sensitivity enables the muscle to resist an externally applied stretch by isomerizing to a forcesupporting form, while reducing excessive energy consumption during shortening by limiting the number of myosin molecules which enter the force-generating event.

Computational investigations of protein denaturation: apomyoglobin and chaotrope-arene interactions

Molecular dynamics (MD) and Monte Carlo (MC) simulations are being used to investigate protein denaturation. The calculations use the AMBER/OPLS force field with explicit representation of the solvent via the TIP3P and TIP4P models of water. The thermal denaturation of apomyoglobin has been followed in two 500 ps MD simulations at 85 °C. The resultant structures provide a detailed model of a molten globule, and close agreement is obtained with experimental data on the helical content of both native apomyoglobin and the low pH folding intermediate. The mechanism of protein denaturation by chaotropic agents is also being pursued. The possibility of direct contact between the chaotropes and aromatic sidechains is supported by MC computations of free energy profiles for the approach of urea and guanidinium ion to aromatic hydrocarbons in water.

Binding modes of cyanide at trinuclear clusters. Crystal structure of [Pt 3(μ 3-CO)(CN)(dppm) 3][PF 6

The trinuclear clusters [M 3(μ 3-CO)(μ-dppm) 3] 2+, dppm=Ph 2PCH 2PPh 2, M=Pt ( 1a), Pd ( 1b), were reacted with cyanide to give the adducts [M 3(CN)(μ 3-CO)(μ-dppm) 3] +, M=Pt ( 2a), Pd ( 2b). Complex 2a [PF 6] has been characterized by X-ray diffraction. Crystal data for 2a [PF 6]·Me 2CO·H 2O: P 1 , a=11.3731(6), b=15.4180(15), c=24.0242(29) Å, α=79.839(9), β=82.117(7), γ=81 422(6)°, V=4073.5(7) Å 3, Z=2, R=0.047, R w=0.066. Low temperature intermediates were characterized spectroscopically and found to be [Pd 3(CN) 2(μ-CO)(μ-dppm) 3] and [Pt 3(CN)(μ-CO)(μ-dppm) 3] +, with a marked difference between the Pd 3 and Pt 3 clusters. Complexes 2 were found to be fluxional in solution, with the cyanide migrating rapidly around the M 3 triangle even at low temperature. Thus, they exhibit a mobility presumably modelling that found for terminal cyanide ligands on metal surfaces. However, the binding mode of cyanide to the metal triangle appears to be different from that of CN on a Pd(111) or Pt(111) surface.

An orientational perturbation theory for pure liquid water

This work develops a statistical mechanical perturbation theory for understanding and quantifying the role of directional hydrogen bonding in pure water at any given temperature or density. A reference fluid has been defined with no orientational preferences, but which reproduces the short-ranged oxygen order as determined by x-ray or neutron diffraction. The orientational anisotropy can be reintroduced by perturbing the reference potential toward a fully coupled water potential; we have developed a new water model, ST4, which provides some noticeable structural improvements over its predecessor, ST2, to provide these anisotropic interactions. Monte Carlo simulations at 25 °C and 1 kg/ℓ mass density have been implemented for various values of the coupling parameter to determine the importance of directed hydrogen bonds at various strengths in dictating energetic and structural features of liquid water. We find that virtually full hydrogen bond strength is required to recover the basic structural features of liquid water. We have also evaluated and contrasted the inherent structures (potential energy minima) for the reference fluid and the ST4 model, where we find that hydrogen bonding provides significant structural rigidity to resist vibrational distortion. Furthermore, we show that the ST4 model exhibits bifurcated hydrogen bonds which only occur in local regions of high density, i.e., they are found as tetrahedral network defects. These high density clusters also include tetrahedral oxygen triplets, sometimes linearly hydrogen-bonded, which may well serve as low energy intermediates for flow processes in liquid water.

DNA replication and repair of Tilapia cells. II. Effects of temperature on DNA replication and ultraviolet repair in Tilapia ovary cells.

TO-2 is a fish cell line derived from the Tilapia ovary. It grows over a wide range of temperature (15-34 degrees C). While most fish cells lack DNA excision repair and are hypersensitive to ultraviolet light (u.v.), Tilapia cells are more u.v.-resistant than mammalian cells. In this paper we report the effects of temperature on DNA replication and u.v. repair in TO-2 cells. When the cells were moved from 31 degrees C to the sublethal high temperature of 37 degrees C, the rate of DNA synthesis first decreased to 60%, then speedy recovery soon set in, and after 8 h at 37 degrees C the rate of DNA synthesis overshot the 31 degrees C control level by 180%. When moved to low temperature (18 degrees C) Tilapia cells also showed an initial suppression of DNA synthesis before settling at 30% of the control level. u.v. reduced but could not block DNA synthesis completely. The inhibition was overcome in 3 h at 37, 31 and 25 degrees C, but not at 18 degrees C. Initiation of nascent DNA synthesis was blocked at 4 J m-2 in TO-2 cells compared with less than or equal to 1 J m-2 in mammalian cells. After 9 J m-2 u.v. irradiation, low molecular weight DNA replication intermediates started to accumulate, and they could be chased into high molecular weight DNA with little delay. TO-2 cells showed low levels of u.v.-induced excision repair; but this was prominent compared with other fish cells. The u.v.-induced incision rate has been measured at various temperatures, and the activation energy of incision estimated to be 13 kcal mol-1 (1 cal approximately equal to 4.184 J).