Tight binding of the antitumor drug ditercalinium to quadruplex DNA

The structural selectivity of the DNA-binding antitumor drug ditercalinium was investigated by competition dialysis with a series of nineteen different DNA substrates. The 7H-pyridocarbazole dimer was found to bind to double-stranded DNA with a preference for GC-rich species but can in addition form stable complexes with triplex and quadruplex structures. The preferential interaction of the drug with four-stranded DNA structures was independently confirmed by electrospray mass spectrometry and a detailed analysis of the binding reaction was performed by surface plasmon resonance (SPR) spectroscopy. The BIAcore SPR study showed that the kinetic parameters for the interaction of ditercalinium with the human telomeric quadruplex sequence are comparable to those measured with a duplex sequence. Slow association and dissociation were observed with both the quadruplex and duplex structures. The newly discovered preferential binding of ditercalinium to the antiparallel quadruplex sequence d(AG(3)[T(2)AG(3)](3)) provides new perspectives for the design of drugs that can bind to human telomeres.     

Simulation, modeling, and crystal growth of Cd0.9Zn0.1Te for nuclear spectrometers

High-quality, large (10 cm long and 2.5 cm diameter), nuclear spectrometer grade Cd_0.9Zn_0.1Te (CZT) single crystals have been grown by a controlled vertical Bridgman technique using in-house zone refined precursor materials (Cd, Zn, and Te). A state-of-the-art computer model, multizone adaptive scheme for transport and phase-change processes (MASTRAP), is used to model heat and mass transfer in the Bridgman growth system and to predict the stress distribution in the as-grown CZT crystal and optimize the thermal profile. The model accounts for heat transfer in the multiphase system, convection in the melt, and interface dynamics. The grown semi-insulating (SI) CZT crystals have demonstrated promising results for high-resolution room-temperature radiation detectors due to their high dark resistivity (ρ≈2.8 × 10¹¹ Θ cm), good charge-transport properties [electron and hole mobility-life-time product, μτ_e≈(2–5)×10⁻³ and μτ_h≈(3–5)×10⁻⁵ respectively, and low cost of production. Spectroscopic ellipsometry and optical transmission measurements were carried out on the grown CZT crystals using two-modulator generalized ellipsometry (2-MGE). The refractive index n and extinction coefficient k were determined by mathematically eliminating the ∼3-nm surface roughness layer. Nuclear detection measurements on the single-element CZT detectors with ²⁴¹Am and ¹³⁷Cs clearly detected 59.6 and 662 keV energies with energy resolution (FWHM) of 2.4 keV (4.0%) and 9.2 keV (1.4%), respectively.     

Activity of (-)-2'-deoxy-3'-oxacytidine (BCH-4556) against human tumor colony-forming units

BACKGROUND: BCH-4556 ((-)-2'-deoxy-3'-oxacytidine) is an L-nucleoside analogue shown to have broad preclinical anti-cancer activity, particularly against solid neoplasms such as prostate, renal, and hepatoma in vitro and in vivo, in contrast to cytosine arabinoside (ara-C) which is preferentially active against leukemia. MATERIALS AND METHODS: The antitumor activity of BCH-4556 was evaluated using human tumor colony-forming unit (HTCFU) assay, in which fresh tumor specimens were taken directly from patients with and without prior chemotherapy. RESULTS: Overall, in vitro responses (50% or less survival compared to untreated controls) were observed in 11% (two of 18), 29% (five of 17) and 50% (nine of 18) of specimens treated for one hour with BCH-4556 at 1, 10 and 100 micrograms/ml, respectively; and 16% (nine of 55), 32% (24 of 74), 48% (35 of 73) and 65% (11 of 17) of specimens treated continuously with BCH-4556 at 0.1, 1, 10 and 100 micrograms/ml, respectively. With the one-hour schedule, a significant difference in response rates was noted between 100 micrograms/ml and 1 microgram/ml (P = 0.02). With the continuous schedule, significant differences in response rates were observed between 1 microgram/ml and 0.1 microgram/ml (P = 0.02), between 10 micrograms/ml and 0.1 microgram/ml (P = 0.0001), as well as between 10 micrograms/ml and 1 microgram/ml (P = 0.01). A trend suggesting the superiority of continuous exposure was observed in paired specimens (n = 18) at comparable drug concentrations. Activity was noted against ovarian (nine of 16 = 56%), renal (three of four = 75%), and melanoma (two of two = 100%) HTCFU at 10 micrograms/ml using the continuous schedule. Comparisons between BCH-4556 and paclitaxel were made in 32 specimens at 10 micrograms/ml using the continuous exposure. Twenty-three specimens showed similar responses with both drugs; seven showed better responses with BCH-4556; and two showed better responses with paclitaxel (P = 0.18). CONCLUSIONS: Promising activity was observed with BCH-4556 against ovarian, renal, and melanoma HTCFU. There appeared to be a positive relationship between BCH-4556 concentration and response using both one-hour and continuous exposures. Continuous exposure to BCH-4556 provided high response rates especially at concentrations above 10 micrograms/ml. For both one-hour and continuous exposures, BCH-4556 had similar, and at times, greater potency than paclitaxel against the same tumor specimens in the present study.     

Time to relapse has prognostic value in patients with aggressive lymphoma enrolled onto the Parma trial

PURPOSE: The purpose of this study was to investigate the prognostic value of time to relapse in 188 adult patients with intermediate- or high-grade non-Hodgkin's lymphoma (NHL) included on the Parma trial at the time of their first relapse. PATIENTS AND METHODS: The median follow-up of these patients is 102 months after registration onto the Parma study. Time to relapse was calculated from initial diagnosis, and a cutoff of 12 months was used to separate 77 patients defined as early relapse from 111 patients defined as late relapse. RESULTS: Patients with early and late relapses had significantly different overall response rates to salvage therapy with two courses of dexamethasone, high-dose cytarabine, and cisplatin (DHAP; 40% v 69%; P=.00007) and different 8-year survival rates (13% v 29%; P=.00001). Features at relapse with a negative prognostic value in univariate analysis were higher than normal lactic dehydrogenase (LDH) levels, tumor size greater than 5 cm, Ann Arbor stages III to IV, and Karnofsky score less than 80%. Therefore, multivariate analyses were performed. Time to relapse (P=.001) and LDH levels at relapse (P=.003) had independent prognostic value, whereas tumor size did not reach statistical significance in the logistic model that predicted overall response after two courses of DHAP. The study of prognostic factors for overall survival (OS) and progression-free survival (PFS) confirmed the prognostic value of time to relapse (P < .0001 for OS and P=.005 for PFS) independent of response or treatment after two courses of DHAP. CONCLUSION: Time to relapse may be used to stratify patients at time of first relapse of intermediate to high-grade non-Hodgkin's lymphoma.     

Endothelin-1-induced in vitro cerebral venoconstriction is mediated by endothelin ETA receptors

The in vitro effects of endothelin-1 on cerebral veins were studied using cylindrical segments, 5 mm long, from dog pial veins. Isometric responses to endothelin-1 (10(-12)-10(-7) M) and to the endothelin ET(B) receptor agonist, IRL 1620 (Suc-[Glu9,Ala11,15]endothelin-1-(8-21), 10(-12) -10(-7) M), were recorded in veins under control conditions and pretreated with the endothelin ET(A) receptor antagonist, BQ-123 (cyclo-(D-Asp-Pro-D-Val-Leu-D-Trp), 10(-8) -10(-5) M), and the endothelin ETB receptor antagonist, BQ-788 (N-[N-[N-[(2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl]-1-(me thoxycarbonyl)-D-tryptophyl]-D-norleucine monosodium, 10(-6) and 10(-5) M). The response to endothelin-1 was also recorded in veins pretreated with the nitric oxide synthesis inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 10(-4) M), or the cyclooxygenase inhibitor, meclofenamate (10(-5) M), and in veins without endothelium or placed in medium without Ca2+ but with EDTA (0.1 mM). In control veins, endothelin-1 produced a concentration-dependent contraction (EC50 = 2.0 x 10(-10) M; maximal contraction = 113 +/- 6 mg) and IRL 1620 induced no effects or a small contraction only with high concentrations (10(-8) - 10(-6) M) (EC50 = 1.5 x 10 (-8) M; maximal contraction = 9 +/- 3 mg). BQ-123 shifted the response to endothelin-1 to the right in a parallel, concentration-dependent way, whereas BQ-788, L-NAME or meclofenamate did not modify the response to endothelin-1. Compared with the control, veins in a medium without Ca2+ had similar EC50 values, but a lower maximal contraction induced by endothelin-1 (57 +/- 10 mg, P < 0.05), and veins without endothelium exhibited similar EC50 values. Thus, endothelin-1 produces marked cerebral venoconstriction that could be mainly mediated by activation of endothelin ETA receptors, may be dependent on extracellular Ca2+, and may be independent of endothelium, nitric oxide and prostanoids.     

Effect of ambulatory utilization review on referrals from generalists to specialists

We studied whether ambulatory utilization review (UR) alters how many patients internal medicine residents refer to sub-specialists, and whether the effect persists without reinforcement. We compared referral rates of residents from a firm that held UR meetings (intervention firm residents, n = 20) with those of residents from a firm that did not (control firm residents, n = 21). We then compared referral rates of 17 intervention firm residents while they were participating in UR with their rates after not participating for at least 4 weeks. Intervention firm residents submitted 30% fewer referrals than control firm residents (9% vs 13%, p = .05). However, the effect was short-lived; after 4 weeks without UR, intervention firm resident referral rates were similar to control firm referral rates.     

Analysis of normal parameters of gastric chemism after pentagastrin stimulation, its diagnostic value in duodenal ulcer

The development of puberty, the sexual debut and the sexual function were investigated in a longitudinal study of an unselected material of 220 primary cases of hypospadiacs, treated during the period 1965 to 1969 and followed-up during the period 1965 to 1974. The development of puberty in hypospadiacs strongly resembled that in a normal male population. Out of 121 hypospadiacs between 13 and 30 years of age 66 had had sexual intercourse. The median age for the sexual debut was 16.9 years compared to 16.6 years in a normal male population. Thirty out of 55 hypospadiacs without experience of sexual intercourse were in the age-group 13-16. Hypospadiacs with experience of sexual intercourse continued their sexual function was normal. Forty-one out of 66 were married and 24 out of 41 had children. In order to study the influence of the surgical treatment on the sexual debut and sexual function the 121 hypospadiacs were divided into two groups: those in whom treatment was completed before or at the age of 12 years, and those in whom treatment was completed at 13 years of age or later. The median age for the sexual debut was 15.5 years in the former group and 17.6 in the later group. An interesting finding was that almost half of the hypospadiacs in whom treatment was complted at 13 years of age or later had had a preoperative sexual debut despite the presence of curvature in all cases, and despite the fact that all types of hypospadias were represented. The median age for the sexual debut in this group was 17.1 years.     

Human spinal arachnoid villi and granulations

A commercially available recording of Northwestern University Auditory Test No. 6 (N.U. No. 6) produced by Auditec of St. Louis was evaluated in a series of four studies. Interlist equivalence of this version was initially investigated, and then normative intelligibility functions were developed using listerners with normal hearing. Intelligibility functions for the original version of N.U. No. 6. prepared by Northwestern University, were then derived, concurrently with functions of the Auditec version, using (1) a group of listeners with normal hearing; and (2) a group with sensorineural hearing loss. The results demonstrated good interlist equivalence for the Auditec version of N.U. No. 6. The comparative intelligibility functions for the Auditec and Northwestern versions of N.U. No 6 furthermore indicated a difference between the two recordings, but it was concluded that for clinical purposes the two versions may be considered equivalent.