Phospho-akt expression is associated with a favorable outcome in non-small cell lung cancer.

Akt, a Serine/Threonine protein kinase, mediates growth factor-associated cell survival. Constitutive activation of Akt (phosphorylated Akt, P-Akt) has been observed in several human cancers, including lung cancer and may be associated with poor prognosis and chemotherapy and radiotherapy resistance. The clinical relevance of P-Akt in non-small cell lung cancer (NSCLC) is not well described. In the present study, we examined 82 surgically resected snap-frozen and paraffin-embedded stage I to IIIA NSCLC samples for P-Akt and Akt by Western blotting and for P-Akt by immunohistochemistry. P-Akt protein levels above the median, measured using reproducible semiquantitative band densitometry, correlated with a favorable outcome (P = 0.007). Multivariate analysis identified P-Akt as a significant independent favorable prognostic factor (P = 0.004). Although associated with a favorable prognosis, high P-Akt levels correlated with high tumor grade (P = 0.02). Adenocarcinomas were associated with low P-Akt levels (P = 0.039). Akt was not associated with either outcome or clinicopathologic variables.Cytoplasmic (CP-Akt) and nuclear (NP-Akt) P-Akt tumor cell staining was detected in 96% and 42% of cases, respectively. Both CP-Akt and NP-Akt correlated with well-differentiated tumors (P = 0.008 and 0.017, respectively). NP-Akt also correlated with nodal metastases (P = 0.022) and squamous histology (P = 0.037).These results suggest P-Akt expression is a favorable prognostic factor in NSCLC. Immunolocalization of P-Akt, however, may be relevant as NP-Akt was associated with nodal metastases, a known poor prognostic feature in this disease. P-Akt may be a potential novel therapeutic target for the management of NSCLC.     

The effects of changes to action potential duration on the calcium content of the sarcoplasmic reticulum in isolated guinea-pig ventricular myocytes

. We have estimated sarcoplasmic reticulum calcium content using rapid application of caffeine on voltage clamped, isolated guinea-pig ventricular myocytes. Caffeine induces the release of calcium from the sarcoplasmic reticulum and this calcium is extruded from the cells by the sarcolemmal Na/Ca exchange. Integrating the inward Na/Ca exchange current thus allows estimations of sarcoplasmic reticulum calcium content. Ventricular myocytes were stimulated to reach new steady-states by action potential voltage clamps of varying duration. Once contractile steady-state had been reached caffeine was rapidly applied in place of the next action potential and sarcoplasmic reticulum calcium content measured. Prolonging the action potential duration increased sarcoplasmic reticulum calcium content and vice-versa. This calcium loading may underlie the positive inotropic effect of increased action potential duration. Received: 11 July 1996 / Received after revision: 15 October 1996 / Accepted: 26 November 1996     

Relationship of "bleeding on probing" and "gingival index bleeding" as clinical parameters of gingival inflammation

Abstract Bleeding on probing (BOP) and the gingival index have been used to clinically characterize the degree of gingival inflammation. It is, however, unclear to what extent these parameters correlate to each other and to probing pocket depth (PD). The purpose of this clinical study was to evaluate the association between BOP and GI bleeding (scores of 2 and 3), as well as the relationship of these variables to PD, in a group of patients presenting with naturally-occurring gingivitis. Based on screening examinations of 125 subjects with at least 20 teeth, no more than 4 sites with PD over 6 mm, a BOP frequency of 30% or greater, and no systemic condition that would influence the inflammatory response, were selected. 2 weeks after screening they were examined at 6 sites per tooth for plaque index, GI, PD and BOP. A standardized pressure sensitive probe (Florida Probe) with 20 g probing force was used for BOP and PD measurements. In this population, means of 40.9% (S.E.= 1.36) BOP sites and 35.3% (S.E, = 1.81) GI bleeding sites per patient were found. A total of 20,008 sites ranging in PD up to 5.9 mm were evaluated; however, the majority of sites (19,723, 98.6%) presented with <4 mm PD. When sites were evaluated, BOP demonstrated a positive correlation with PD, whereas GI bleeding correlated with PH. For sites characterized by the absence of BOP as well as the absence of GI bleeding (scores 0 and 1), the highest % of agreement between the 2 indices (77.7%) was found in shallow sites (0.1–2 mm). In contrast, when sites presenting with both BOP and GI bleeding were analyzed, the highest % of agreement (85,4%) was found for sites with PD >4.0 mm. In this gingivitis population group, it appears that BOP and GI bleeding evaluate distinct inflammatory1 conditions of the gingival tissues, and the relationship between the 2 clinical parameters may vary according to PD at the individual site examined.     

Ecology of a Southern Ohio stream receiving fly ash pond discharge: Changes from acid mine drainage conditions

Prior to 1975, Stingy Run was a third-order tributary of Kyger Creek, which empties into the Ohio River at Mile 260 (Gallia County, Ohio). Both streams drained strip mine refuse areas and physicochemical measurements indicated acidicmine drainage conditions (e.g., low pH). A depauperate macroinvertebrate community, dominated by a few acid-tolerant taxa, was found in both streams and no fishes were collected. In 1974, Stingy Run was impounded to form a fly ash pond which contains fly ash sluiced from Ohio Power Company's General James M. Gavin coal-fired power plant. Physicochemical and biological sampling during 1975–1986 indicated marked changes in the aquatic ecology of Stingy Run between 1) pre-impoundment and post-impoundment conditions; and 2) effluent pH control treatments after impoundment. Fly ash discharge eliminated acidicmine drainage characteristics in Stingy Run and lower Kyger Creek. After impoundment, net spinning caddisflies and a few dipteran taxa dominated the Stingy Run benthic community, reflecting changes in functional niches likely due to improved habitat and greater food availability. Replacement of acid feed by CO₂ injection for effluent pH control and changes in ash pond chemistry occurred concomitant with elimination of a substrate floc; increased species richness and densities of invertebrates were subsequently observed. In Stingy Run, species richness and diversity of fishes increased from 1983 to 1986, reflecting improved water quality and increased benthic production after impoundment. Many of these fishes are opportunistic feeders on drifting insects.     

The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.     

Phase I and pharmacologie study of liposomal daunorubicin (DaunoXome)

Summary We have completed a phase I and pharmacology study of liposomally-encapsulated daunorubicin (DaunoXome). Of 32 patients entered, 30 were evaluable. No toxicity was encountered at the initial doseescalation steps from 10 to 60 mg/m². At 80 mg/m², two patients manifested grade 2 neutropenia. At least grade 3 neutropenia occurred in all patients receiving 120 mg/m². Alopecia and subjective intolerance were mild. Cardiotoxicity was not observed except for an episode of arrhythmia in a patient with lung cancer and prior radiation. Only one minor objective response was observed in this population of refractory solid tumors. Pharmacokinetics differed from those of the free drug with no detection of daunorubicinol. We recommend future phase II studies with a dose of 100 mg/m² in previously treated and 120 mg/m² of DaunoXome in previously untreated patients with solid tumors.EDW is supported in part by ACS award 92-14-1