The development and performance of a perforated plate burner to produce vitiated flow with negligible swirl under engine-relevant gas turbine conditions.

The development and performance of a perforated plate burner (PPB) operating using premixed natural gas and air at engine-relevant inlet temperatures and combustor pressures with thermal powers up to 1 MW is discussed. A significant benefit of using burners with simplified flow fields, such as the PPB, for experimental studies in the laboratory is the potential for decoupling the complex fluid dynamics in typical combustors from the chemical kinetics. The primary motivation for developing this burner was to use it as a source of vitiated flow with negligible swirl for reacting jet in vitiated crossflow experiments. The design methodology for the PPB is described, including plate geometry selection and flashback mitigation features. The stable operation of the PPB within a high-pressure test rig was validated: successful ignition, effective use of red-lines for flashback mitigation, and long duration steady-state operation in both piloted and nonpiloted modes were all observed. Exhaust gas emissions measured using a Fourier-transform infrared (FTIR) spectrometer showed very good performance of the PPB in terms of the combustion efficiency (based on measured CO and UHC), and a stability diagram of the PPB was developed as a function of the equivalence ratio and the PPB hole velocity. FTIR measurements also showed very low levels of NOX in nonpiloted operation that were generally within 3 ppm (reported dry and referenced to 15% O2). The capability for steady-state operation, high combustion efficiency, and low levels of NOX makes this PPB an excellent burner candidate for combustion experiments in the laboratory.

Accuracy of measurements of mandibular anatomy and prediction of asymmetry in panoramic radiographic images.

OBJECTIVES: Measurements of ideally positioned and systematically mis-positioned skulls were used to evaluate errors in linear measurements and symmetry ratios made with panoramic X-ray images. METHODS: Digital panoramic images of 30 skulls placed in ideal, shifted and rotated positions, were assessed by measuring distances between anatomic points and fiducial references. Differences between photographic measurements (control) and radiographic measurements were compared. Horizontal measurements included a 20 mm wire and the distance from gonion to mental foramen (G-MF). Vertical distances measured included a 40 mm wire, condyle to sigmoid notch length, and condyle to gonion (posterior mandibular height or PMH). A relative symmetry ratio comparing the difference between right and left PMH was also calculated. Distances measured in panoramic images were corrected using the left vertical wire distance or the panoramic unit's stated magnification factor (1.25x). RESULTS: Greatest differences were noted for horizontal measurements and shifted skull positions. Use of an arbitrary magnification correction was consistently less accurate than use of an internal calibration and resulted in general underestimation of actual dimensions. Measures of PMH varied significantly from expected values for each of the three skull positions (P<0.005). Panoramic accuracy for detecting asymmetry was 67% for ideal, 70% for rotated, and 47% for shifted skull positions when an internal reference was used. CONCLUSIONS: Panoramic radiographs should be used with caution in making absolute measurements or relative comparisons. Even when internal fiducial calibration for image distortion of anatomy is used, measurements such as those assessing posterior mandibular facial symmetry may be unreliable.

Signal transduction and HIV transcriptional activation after exposure to ultraviolet light and other DNA-damaging agents.

Short wavelength (254 nm) ultraviolet light (UVC) radiation was much more potent in activating transcription of human immunodeficiency virus 1 (HIV) reporter genes stably integrated into the genomes of human and monkey cells than ionizing radiation (IR) from a 137Cs source at similarly cytotoxic doses. A similar differential was also observed when c-jun transcription levels were examined. However, these transcription levels do not correlate with activation of nuclear factor (NF)-kappa B and AP-1 measured by band-shift assays, i.e. both types of radiation produce similar increases in NF-kappa B and AP-1 activity, suggesting existence of additional levels of regulation during these responses. Because of the well-established involvement of cytoplasmic signaling pathways in the cellular response to tumor necrosis factor-alpha (TNF-alpha), UVC, and IR using other types of assays, the role of TNF-alpha in the UVC response of HIV and c-jun was investigated in our cell system. We demonstrate that UVC and TNF-alpha activate HIV gene expression in a synergistic fashion, suggesting that it is unlikely that TNF-alpha is involved in UVC activation of HIV transcription in stably transfected HeLa cells. Moreover, maximum TNF-alpha stimulation resulted in one order of magnitude lower levels of HIV expression than that observed after UVC exposure. We also observed an additive effect of UVC and TNF-alpha on c-jun steady-state mRNA levels, suggestive of a partial overlap in activation mechanism of c-jun by UVC and TNF-alpha; yet these responses are distinct to some extent. Our results indicate that the HIV, and to some extent also the c-jun, transcriptional responses to UVC are not the result of TNF-alpha stimulation and subsequent downstream cytoplasmic signaling events in HeLa cells. Additional levels of regulation that do not directly involve the NF-kappa B and AP-1 transcription factors, such as changes in chromatin structure associated with the UV repair process, may also be important for a full transcriptional response of HIV and c-jun to UVC. In addition to the new data, this report also summarizes our current views regarding UVC-induced activations of HIV gene expression in stably transfected cells.

Activation of human immunodeficiency virus gene expression by ultraviolet light in stably transfected human cells does not require the enhancer element.

Ultraviolet light (UV) exposure of cells infected with human immunodeficiency virus type I (HIV) or transfected with HIV reporter genes increases virus-directed gene expression. Here we report the mapping of the UV response on the long terminal repeat (LTR) by using human cells stably transfected with HIV promoter plasmids harboring different mutations and controlling the expression of the chloramphenicol acetyltransferase (cat) reporter gene. Promoter mutation analysis revealed that no specific upstream region of the LTR was associated with UV activation, although a significant decrease was observed with mutations in the basal promoter elements Spl and TATA. Most importantly, UV activation was not diminished by removal of the - 119 to -69 region encompassing the LTR enhancer region or, more specifically, by point mutations in the NF -kappa B binding elements. Consistent with this result, we found that the phorbol ester (PMA) response, which is known to act through the enhancer, occurred independently and was synergistic with the UV response. Removal of the -119 to -69 region did not affect UV activation; however, it resulted in total abrogation of the PMA response. These results suggest that UV activation is distinct from NF -kappa B activation and does not act through the enhancer in stably transfected cells. This is in dramatic contrast to what is found with transient expression analysis of these responses. Lastly, RNA protection experiments revealed that UV may act on preassembled basal transcription complexes by allowing elongation of nascent short mRNAs generated from the LTR.(ABSTRACT TRUNCATED AT 250 WORDS)

Ionizing radiation activates nuclear factor kappa B but fails to produce an increase in human immunodeficiency virus gene expression in stably transfected human cells.

We have investigated the differential effects of ultraviolet light(UV) and ionizing radiation (IR) on human immunodeficiency virus type 1 (HIV) and c-jun expression in HIVcat/HeLa cells. This cell line harbors integrated copies of the chloramphenicol acetyltransferase (cat) gene under control of the HIV promoter. Both UV and IR increased the binding of nuclear proteins to an oligonucleotide spanning the HIV enhancer region nuclear factor kappa B sites, but only UV increased HIVcat steady-state mRNA and CAT activity. By comparison, transcription of the cellular c-jun gene increased after both types of radiation, but UV was at least 5-fold more effective than IR despite the fact that protein binding to an activator protein 1 oligonucleotide increased similarly after both UV and IR. The lack of HIVcat transcriptional response after IR does not appear to be the result of the repressor binding to upstream promoter elements since cells stably transfected with different HIV promoter deletions showed a lack of response to IR distinguishable from that of the intact promoter. While our findings indicate no correlation between increased binding of transcription factors to upstream promoter elements and increased expression of these genes after radiation, we did observe major differences in how UV and IR affected chromatin structure. UV produced extensive global chromatin decondensation, whereas IR did not, as seen in the microscope and determined by the increased susceptibility of chromatin to micrococcal nuclease digestion.(ABSTRACT TRUNCATED AT 250 WORDS)

Antitumor drug cross-resistance in vivo in a cisplatin-resistant murine P388 leukemia.

Since 1978, over 50 clinically useful antitumor drugs or new candidate antitumor agents have been evaluated in vivo against cisplatin-resistant P388 leukemia (P388/DDPt) in our laboratories. Analysis of this data base has yielded insights into the cross-resistance, collateral sensitivity, and mechanisms of resistance of P388/DDPt. P388/DDPt was cross-resistant or marginally cross-resistant to eight agents [carmethizole.HCl, rhizoxin, dibromodulcitol, spirohydantoin mustard, hepsulfam, arabinosyl-5-azacytosine (ara-AC), tiazofurin, and deoxyspergualin]. Of these eight agents, the latter six have entered various phases of clinical trials. For these trials, it may be important to exclude or to monitor with extra care patients who have previously been treated with cisplatin. P388/DDPt was collaterally sensitive to six agents [fludarabine phosphate (2-F-ara-AMP), amsacrine (AMSA), mitoxantrone, etoposide (VP-16), batracylin, and flavone acetic acid] and, possibly, to two others (merbarone and echinomycin). These observations of collateral sensitivity suggest that a combination of cisplatin plus any one of these drugs might exhibit therapeutic synergism. Therapeutic synergism has been observed in animal models for combinations of cisplatin plus VP-16, AMSA, or mitoxantrone. The observation of collateral sensitivity for P388/DDPt to four agents (AMSA, mitoxantrone, merbarone, and VP-16) that have been reported to interact with DNA topoisomerase II suggests the possible involvement of the latter in cisplatin resistance. Both the increased sensitivity of P388/DDPt to these agents and a portion of its resistance to cisplatin could be the result of an increase in DNA topoisomerase II activity.

Antitumor activity of ethyl 5-amino-1,2-dihydro-2-methyl-3-phenyl-pyrido [3,4-b]pyrazin-7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) against selected tumor systems in culture and in mice.

Ethyl 5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin- 7-ylcarbamate, 2-hydroxyethanesulfonate, hydrate (NSC 370147) was evaluated for antitumor activity against a spectrum of tumor systems in culture and in mice. NSC 370147 was cytotoxic to a variety of mouse and human cell lines at nanomolar concentrations. The compound exhibited good in vivo antitumor activity against several murine tumors (P388 and L1210 leukemia, colon 11/A and 36, mammary 16/C, and M5076 sarcoma). Activity was largely independent of route of administration but favored a prolonged treatment schedule. NSC 370147 was as active against murine leukemia sublines resistant to Adriamycin, amsacrine, vincristine, melphalan, cisplatin, methotrexate, and CI-920 (a topoisomerase II inhibitor) as against the corresponding parental lines. Only the 1-beta-D-arabinofuranosylcytosine-resistant P388 subline exhibited any cross-resistance to NSC 370147. NSC 370147 has a spectrum of activity similar to that of vincristine and, unlike vincristine, is active against multidrug-resistant cell lines. Therefore, NSC 370147 is a candidate for clinical trial because of its favorable activity compared to vincristine, its effectiveness against multidrug-resistant cells, and its retention of activity for p.o. administration.

Magnetic resonance imaging of the paranasal sinuses: frequency and type of abnormalities.

This retrospective study reports on sinus abnormalities detected in patients having magnetic resonance imaging (MRI) scans. Over a 12-month period, 1120 patients (aged 2-87 years) had MRI scans done for suspected intracranial pathology. Scans were reviewed independently for abnormal sinuses using four criteria: increased signal of the epithelial lining, cloudy or opacified sinus cavity, air-fluid levels, and intrasinus polyps. Thirteen percent of the 1120 patients had abnormal sinus images with the maxillary being the most involved cavity. A cloudy or opacified sinus was found in 43% of these cases. An increased signal to the epithelial lining was present in 44%. Intrasinus polyps were found in 27 paranasal sinus cavities (27 subjects). Furthermore, a seasonal pattern was evident for abnormal sinus scans. The months of July, August, September, and December had the highest frequency of abnormalities noted (greater than 16% of total scans done) whereas there was a low percentage (less than 8%) found during February and November. In summary, abnormalities of the paranasal sinuses occur frequently and vary with the time of year.

Antitumor activity of 2-chloroethyl (methylsulfonyl)methanesulfonate (clomesone, NSC 33847) against selected tumor systems in mice.

Clomesone was evaluated for antitumor activity against a spectrum of animal tumor models. Clomesone exhibited significant antitumor activity against the murine L1210 leukemia implanted i.p., s.c., and intracerebrally (i.c.). Activity against s.c.-implanted tumor was largely independent of schedule and route of administration. Therapeutically optimal single-dose treatment (for tumored mice) was less toxic to nontumored mice than therapeutically optimal prolonged treatment. Clomesone also exhibited activity against other murine tumors (P388 leukemia, B16 melanoma, Lewis lung carcinoma, and M5076 sarcoma). It was active against P388 leukemia sublines resistant to cyclophosphamide, L-phenylalanine mustard, and cis-diamminedichloroplatinum(II). No activity was observed against a P388 subline resistant to N,N'-bis(2-chloroethyl)-N-nitrosourea or against Ridgway osteogenic sarcoma, a nitrosourea-resistant murine solid tumor. Clomesone is generally as effective as the chloroethylnitrosoureas against experimental tumor models. Since clomesone does not have the hydroxyethylating and carbamoylating activities of the chloroethylnitrosoureas (which do not appear to contribute to antitumor activity), it would likely be a more toxicologically selective compound. It may prove to be less carcinogenic than the chloroethylnitrosoureas, and it may contribute less target organ toxicity and less interference with the actions of other drugs when used in combinations.

Effect of homoharringtonine on the viability of murine leukemia P388 cells resistant to either adriamycin, vincristine, or 1-beta-D-arabinofuranosylcytosine.

Cultured murine leukemia P388 cell populations were derived from P388 cells resistant to vincristine (P388/VCR), adriamycin (P388/ADR), and 1-beta-D-arabinofuranosylcytosine (P388/ARA-C) that were developed in vivo and to the parental drug-sensitive cells (P388/O) that were passaged in vivo. The doubling times of the cultured cell populations (mean +/- SD) between cell densities of 5 x 10(4) and 1 x 10(6) cells/ml were 14.2 +/- 2 h (P388/O), 16.5 +/- 1.9 h (P388/VCR), 16.9 +/- 1.2 h (P388/ADR), and 15.0 +/- 1.4 h (P388/ARA-C). Exponentially proliferating cultured cell populations were exposed to selected homoharringtonine (HHT) concentrations for 24 h and the surviving cell fractions were determined by colony formation in semisolid medium. The results, based on differential sensitivity of the cell populations to HHT, indicated that cultured P388/VCR cells were cross-resistant to 0.018-1.8 micrograms/ml HHT, P388/ADR cells were cross-resistant to 0.058-1.8 micrograms/ml HHT, and P388/ARA-C cells were collaterally sensitive to 0.09-0.36 micrograms/ml HHT. The results with the cultured P388/VCR, P388/ADR, P388/ARA-C, and P388/O cell populations were confirmed in animal experiments. CD2F1 mice bearing intraperitoneal (i.p.) implants of 1 x 10(6) P388/VCR, P388/ADR, P388/ARA-C, or P388/O leukemia cells were given HHT i.p. qd on days 1-9 postimplantation. Optimal treatment (less than or equal to LD10) produced in vivo cell kills of 2 to 3 log10 units in P388/O and about 7 log10 units in P388/ARA-C, whereas P388/VCR and P388/ADR cells actually increased by 1-2 log10 units during treatment. The results of this study indicate that cross-resistance (P388/VCR and P388/ADR) or collateral sensitivity to HHT (P388/ARA-C) is a function of the cellular properties of the target tumor cell populations that is independent of host factors.

Cross-resistance of drug-resistant murine leukemias to deoxyspergualin (NSC 356894) in vivo.

Deoxyspergualin, the 15-deoxy derivative of the antibiotic spergualin, is a novel guanidino analog structurally related to spermine. Deoxyspergualin has significant activity in selected experimental tumor models, and clinical trials have been initiated. Described here are in vivo evaluations of the therapeutic activity of deoxyspergualin against murine leukemia lines specifically resistant to eight clinically useful antitumor drugs. These were P388 lines resistant to doxorubicin, vincristine, L-phenylalanine mustard, cisplatin, ara-C, and methotrexate and L1210 lines resistant to 5-FU, L-phenylalanine mustard, and cyclophosphamide. Sensitivity to deoxyspergualin was evaluated in parallel comparisons of each resistant leukemia to the sensitive line from which it had been derived. All experiments were repeated at least once for confirmation of results. Responses were quantitated in terms of the change in tumor cell numbers from the beginning of treatment to the end of treatment as estimated from the median survival times of dying mice. The results indicated that P388 leukemia resistant to cisplatin (P388/DDPt) was cross-resistant to deoxyspergualin. No cross-resistance was observed in leukemias resistant to doxorubicin, vincristine, ara-C, methotrexate, or cyclophosphamide. L1210 resistant to 5-FU (L1210/5-FU) was collaterally sensitive to deoxyspergualin. Although cross-resistance was also observed in P388/L-PAM, L1210/L-PAM retained sensitivity to deoxyspergualin. Total glutathione concentrations in P388/L-PAM and L1210/L-PAM provided no apparent explanation for this unexpected result. It may be tentatively concluded that resistance to cisplatin, L-PAM, or other DNA alkylators or cross-linkers may increase the potential for cross-resistance to deoxyspergualin. This conclusion requires verification with additional alkylating agents, with drug-resistant human tumor cell lines, and with prospective clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Response of drug-sensitive and -resistant L1210 leukemias to high-dose chemotherapy.

Alkylating agent-sensitive and -resistant L1210 leukemia cell lines were used to determine the tumor response to dose levels of drugs that exceeded conventional doses up to a factor of 10. Since those dose levels were lethal to the host mice, tumor response was based on the results of in vivo bioassays of spleen and/or tumor from drug-treated and control mice. When mice bearing about 10(8) drug-sensitive leukemic cells were treated with a single, conventional (approximately 10% lethal) dose of cis-diamminedichloroplatinum, L-phenylalanine mustard (melphalan), or 1,3-bis(2-chloroethyl)-1-nitrosourea, 10(1) to 10(4) tumor cells were recovered by bioassay. Treatment at doses that were 2 to 8 times the 10% lethal dose of either of those drugs resulted in no recoverable cells and survival of all bioassay recipient mice. Mice bearing advanced L1210 leukemia resistant to cis-diamminedichloroplatinum (L1210/DDPt), 1,3-bis-(2-chloroethyl)-1-nitrosourea (L1210/BCNU), cyclophosphamide (L1210/CPA), or melphalan(L1210/L-PAM) also were treated with a 10% lethal dose and greater doses of the drug to which the tumor line was resistant. Bioassay results indicated a direct correlation between dose intensity and tumor cell kill, the response being linear. Similarly, when mice with L1210/BCNU were treated with high doses of N-(2-chloroethyl)-N''-(2,6-dioxo-3-piperidinyl)-N-nitrosourea or 1,1',1''-phosphinothioylidynetrisaziridine (thioTEPA) and when mice with L1210/DDPt were treated with cyclophosphamide, an increasing, linear cell kill resulted throughout the high-dose range. Overall, these results indicate that resistance to these alkylating agents can be overcome by dose intensification and that the tumor response is linear in relation to increasing dose level.

2-Chloroethyl (methylsulfonyl)methanesulfonate and related (methylsulfonyl)methanesulfonates. Antineoplastic activity in vivo.

2-Haloethyl and ethyl (methylsulfonyl)methanesulfonates were prepared via sulfene intermediates. 2-Chloroethyl (methylsulfonyl)methanesulfonate is highly active against P388 leukemia in vivo; the majority of leukemic mice treated with this compound at 50 mg/kg per day, qd 1-5, survived more than 30 days and about 37% survived for more than 60 days. 2- Fluoroethyl (methylsulfonyl)methanesulfonate is also highly effective against P388 cells in vivo, but it is more toxic. Other (methylsulfonyl)methanesulfonate esters are more active than the analogous methanesulfonates and chloromethanesulfonates .

Establishment of cross-resistance profiles for new agents.

Sublines of murine leukemias (L1210 and P388) and solid tumors selected for resistance to representatives of all of the chemical and functional classes of clinically useful anticancer drugs have been isolated and established in serial in vivo passage and, in some cases, in vitro culture. Extensive resistance, cross-resistance, and collateral-sensitivity patterns have been established with most of the sublines of the drug-resistant murine leukemias under treatment with greater than 100 different established and clinically useful anticancer drugs or new candidate anticancer drugs currently under study. Patients selected for inclusion in phase I-II trials usually have tumors that have failed to respond to treatment with established clinically useful drugs, either from the start of treatment or during continuing treatment after initial useful response. These treatment failures are no doubt due, in many cases, to drug-resistant tumors if initially unresponsive or to the overgrowth of drug-resistant mutant tumor stem cells in initially responding patients who ultimately failed under continuing treatment. Therefore, the cross-resistance profiles of drug-resistant murine tumors to treatment with new drugs going into phase I-II trials should provide useful guides for patient selection for those trials. Also, these cross-resistance profiles will provide useful information indicating likely biochemical mechanism of action of new drugs with promising anticancer activity, thus guiding drug selection for combination chemotherapy trials in animals or man. Numerous examples of all of the above indications for useful application of such information derived from chemotherapy trials with drug-resistant murine tumors are reported.

Bilateral internuclear ophthalmoplegia in carcinomatous meningitis.

A 53-year-old man with oat cell carcinoma of the lung developed a bilateral internuclear ophthalmoplegia in association with carcinomatous meningitis. While bilateral internuclear ophthalmoplegia has been described in one case of cryptococcal meningitis, this is the first reported case occurring in association with carcinomatous meningitis.