PubMed Health⌕ Search

Biomedical subjects

R B Howard

Publications and source records attributed to R B Howard.

At least 19 recordsLinked to original sources
PubMed1992

Mucin gel formed by tumorigenic squamous lung carcinoma cells has Le(a)-X oligosaccharides and excludes antibodies from underlying cells.

Cells of cloned lines of human squamous lung carcinomas elaborate large glycoproteins that are associated with their tumorigenic potential. Two groups of clones (called Le(a)-X-positive and Le(a)-X-negative) were studied that either do or do not express the Le(a)-X oligosaccharide associated with large glycoproteins and mucins secreted by these clones. Le(a)-X-positive cells elaborate a mucin gel complex associated with their apical surfaces, which appears as a mosaic of extracellular plates. Clones of this type are tumorigenic in nude rodents when injected s.c. or when introduced into the lungs via intrabronchial aerosol. By contrast, the Le(a)-X-negative clones do not form extracellular plates and are not tumorigenic in the lungs or subcutaneously. We demonstrate that the extracellular plates of Le(a)-X-positive cells exclude antibodies from interacting with the underlying squamous lung carcinoma cells and may therefore exert an immunoprotective effect. In support of this possibility it was found that: (a) There is a substantial inflammatory cell infiltrate associated with regressing nodules of Le(a)-X-negative cells in nude rodent lung and subcutaneous nodules, while there is no observable infiltration associated with progressing Le(a)-X-positive tumors. (b) In the brain (an immunoprivileged site) tumors develop and progress when either Le(a)-X-negative or -positive cells are introduced.

Animals↗
PubMed1992

Secondary screening system for preclinical testing of human lung cancer therapies.

The National Cancer Institute has instituted a primary screening system for testing new agents against cultured cancer cell lines. The purpose of this study was to determine the feasibility of using a nude rat orthotopic (organ-specific) human lung cancer model system as an in vivo secondary screen for general evaluation of new anticancer agents and therapies active against lung cancer. To make this determination, we tested whether this system allows measurement of uptake and tumoricidal activity of anticancer therapies. Tumor-bearing lungs from 53 Rowett nude rats with orthotopically implanted human large-cell undifferentiated lung carcinoma (NCI-H460) were perfused ex vivo for 1 hour with or without each of two anticancer modalities. Lungs were perfused with blood-free perfusate alone (untreated control), perfusate with 100 micrograms/mL doxorubicin (treated positive control), or perfusate with lymphokine-activated killer cells plus human recombinant interleukin-2 (LAK/rIL-2). Weight gain during perfusion was the criterion used to quantitate lung injury. Treatment efficacy was measured by clonogenic assay after enzymatic disaggregation of the perfused tumors. Doxorubicin levels in the tumor and in the uninvolved lung were measured by high-performance liquid chromatography. Both treatment groups showed only slight increases in lung weight compared with that in the untreated control group, suggesting good lung tolerance of the procedure. Lung and tumor levels of doxorubicin were 320 +/- 21 ng/mg of tissue and 32 +/- 5 ng/mg of tissue (means +/- SE), respectively. Clonogenic assay demonstrated a fivefold to 10-fold reduction in the surviving fraction of tumor cells with doxorubicin but no change with LAK/rIL-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Lung tolerance to hyperthermia by in vivo perfusion.

In vivo isolated lung perfusion is a novel technique for targeting anticancer therapy to the lung while avoiding systemic toxicity as normal lung toxicity from the antitumour therapy becomes the limiting factor. This study was performed to investigate the effects of hyperthermia on lung function in an intact animal model in which both acute and subacute toxicity could be monitored. Dogs underwent in vivo isolated lung perfusion. A control group was perfused to a lung temperature of 37 degrees C (group 1) and two other groups were treated in an identical manner except that the perfusion temperature was 43 degrees-44.8 degrees C in group 2 and greater than 45 degrees C in group 3. An assessment of lung injury was performed pre-perfusion, immediately post-perfusion and 2 weeks post-perfusion by measurement of extravascular lung water (Qev), serotonin uptake and wet weight to dry weight ratio. Our findings showed that the lung was tolerant to hyperthermia up to about 44 degrees C for 1 h. Analysis of 4 animals who survived perfusion above 3/44.0 degrees C showed a highly significant decrease in serotonin uptake between pre- and post-perfusion values (82.4 +/- 1.2 vs 40.4 +/- 3.9, P less than 0.02); at 2 weeks serotonin uptake had returned to normal in all 3 dogs. Fulminating pulmonary oedema developed at temperatures over 45 degrees C. Serotonin uptake may be a sensitive predictor of thermal lung injury.

Animals↗
PubMed1992

Rat ovarian angiotensin II receptors, renin, and angiotensin I-converting enzyme during pregnancy and the postpartum period.

The ovarian renin-angiotensin system (RAS) has been studied extensively in the virgin cycling rat, but little information is available about this system in pregnant and postpartum rats. We show that renin and angiotensin I-converting enzyme (ACE)--the key enzymes involved in angiotensin II (Ang II) formation--and Ang II receptors, are present in pregnant and postpartum rat ovaries. From gestation Days 2-4 to 10-12, active ovarian renin ranged from 1.12 +/- 0.13 to 1.27 +/- 0.19 ng Ang I/h/mg and comprised between 68 and 86% of total (active+inactive) ovarian renin activity. Between Days 10-12 and Days 14-16 of pregnancy, ovarian active renin activity increased slightly, but inactive renin disappeared, suggesting its activation; the remaining active renin then decreased 62% by Days 18-20 (p < 0.05). On postpartum Day 2, both active and total ovarian renin activity exceeded that of Days 2-20 of pregnancy (p < 0.05); levels of both then declined sharply by postpartum Day 3 (p < 0.05). In pregnant rats, levels of ovarian Ang II receptors, identified by the specific binding of [125I]-[Sar1,Ile8]Ang II to ovarian membranes, were high between Days 2-4 and 10-12 of pregnancy, ranging from 12.8 +/- 1.7 to 15.7 +/- 3.4 fmol/mg, but steadily declined by 82% between gestation Days 10-12 and 18-20 (p < 0.05). Postpartum Ang II receptor levels on Days 2, 3, and 4 showed a gradual increase from low levels comparable to Days 18-20 of pregnancy. Ovarian ACE activity did not change throughout pregnancy or during the postpartum period.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Chest roentgenographic techniques for demonstrating human lung tumour xenografts in nude rats.

Roentgenographic techniques were investigated for imaging orthotopic lung tumours in anaesthetized nude rats endobronchially implanted with human lung cancer cells. A conventional radiographic unit with a dual-screen, double-emulsion film mammographic receptor produced images preferable to those from a mammographic unit because of superior resolution. Typical exposure factors were 300 mA, 29 kVp, and 17 ms at a focus-film distance of 76 cm with a 2.11 by 2.41 mm effective focal spot and inherent filtration of 1.2 mm aluminium. Sensitivity for tumour detection was 0.93 for 59 animals with pathologically proved tumours and 0.96 for 54 animals with tumours larger than 4 mm or 50 mg. For 24 pathologically tumour-free animals, specificity was 1.00. For 55 animals radiographically judged to have tumours, positive predictive value was 1.00. For all 83 animals, accuracy was 0.95. This technique effectively demonstrates orthotopic human lung tumours in nude rats and should be useful for noninvasive monitoring of tumour presence, location, size, and changes in size.

Adenocarcinoma↗
PubMed1991

Irradiated nude rat model for orthotopic human lung cancers.

The development of improved animal models for biological and preclinical studies of human lung cancer is important because lung cancer is the leading cause of cancer death in the United States. To determine whether the Rowett nude rat could serve as an orthotopic (organ-specific) model of this disease, nude rats (CR: NIH-RNU), with and without 500 rads of prior gamma-irradiation, were implanted intrabronchially with 10(7) cultured cells from 3 human lung cancer lines. Without irradiation, the NCI-H460 large-cell undifferentiated carcinoma had a 54% take-rate, whereas the NCI-H125 adenosquamous carcinoma and A549 adenocarcinoma had take-rates of 7 and 33%, respectively; irradiation increased the respective take-rates to 100, 83, and 90%. In irradiated rats, tumor age versus weight measurements showed progressive growth for all three tumors, with growth rates in the order: NCI-H460 greater than A549 greater than NCI-H125, requiring approximately 3, 5, and 9 weeks, respectively, for average tumor sizes to exceed 500 mg. The small-cell carcinoma cell line NCI-H345 was implanted only into irradiated rats and resulted in more slowly growing tumors. Histopathological study showed all model tumor types to have histological characteristics consistent with the clinical tumors from which the cell lines were derived. Each tumor type had a different growth pattern, with some of the the A549- and NCI-H125-derived tumors metastasizing to contralateral lung and/or regional lymph nodes. There was no evidence for immunological rejection in irradiated, tumor-bearing rats. Nonirradiated, implanted rats without gross tumor exhibited peribronchiolar mononuclear cell infiltration with or without fibrosis, suggesting prior immunological rejection. The successful orthotopic growth of these 4 human lung cancer cell lines in irradiated nude rats suggests that this model could be useful for biological and preclinical studies of human lung cancer, both in intact rats and via ex vivo perfusion of their tumor-bearing lungs.

Animals↗
PubMed1988

Rat ovarian renin: characterization and changes during the estrous cycle.

To demonstrate the existence and help clarify the function of renin in the rat ovary, we have characterized rat ovarian renin and examined ovarian renin levels during different stages of the rat estrous cycle. We show that high concentrations of active renin are present in the rat ovary (2.9 ng angiotensin I/h/mg). Ovarian renin activity has a pH optimum of about 7.0 and is due to a glycosylated aspartyl protease with an apparent mol wt of 39,000. These properties of rat ovarian renin are identical to previously characterized rat kidney renin. In PMSG-treated immature and adult 5-day cycling rats, ovarian renin was increased about 2-fold at estrus. At all stages of the estrous cycle in the 5-day cycling rat, the ratio of active to inactive ovarian renin was about 3:1, whereas about 90% of the renin in plasma was inactive. In the hypophysectomized diethylstilbestrol-treated rat ovary, over 90% of active renin remained in the residual ovary after the granulosa cells had been expressed, suggesting a theca-interstitial localization for renin. These studies indicate that active renin exists in the rat ovary, that its levels are cyclically increased at estrus, and that this increase may be due to enhanced local production and activation of the renin precursor. These findings greatly strengthen the concept of a functional renin-angiotensin system in the rat ovary.

Ammonium Sulfate↗
PubMed1987

Control of human placental blood flow.

An overall scheme is proposed for the control of blood flows in both fetal and maternal circulations of the human placenta. The first part of the hypothesis is that fetoplacental vascular resistance is controlled locally by a reversible hypoxic fetoplacental vasoconstriction (HFPV) in response to reduced local maternoplacental oxygen delivery. Also suggested is humoral limitation of the extent of HFPV by substances circulating in hypoxic fetal blood. Secondly, it is hypothesized that maternoplacental vascular resistance is controlled humorally by release of hormones into maternal blood from the fetoplacental unit. Finally, it is proposed that chronic local maternoplacental ischemia associated with placental "aging" can induce an irreversible fetoplacental vasoconstriction by a mechanism different from HFPV in order to permanently shut down fetal blood flow to the area(s) affected.

Female↗
PubMed1987

Hypoxia-induced fetoplacental vasoconstriction in perfused human placental cotyledons.

Effects of maternal hypoxia on fetoplacental vascular resistance in the human placenta were investigated in an in vitro model in which single anatomic subunits (cotyledons) from term placentas were perfused at constant flow through both fetal and maternal circuits by means of a physiologic salt solution containing dextran. Acute reduction of oxygen tension in the maternal perfusate induced prompt fetoplacental vasoconstriction that recovered rapidly on restoration of oxygen to the perfusate. The response, hypoxic fetoplacental vasoconstriction, could be repeatedly demonstrated in the same cotyledon. The time course of hypoxic fetoplacental vasoconstriction was inversely related to oxygen tension of maternal arterial and maternal and fetal venous perfusates. Maternal and fetal venous perfusate pH and PCO2 did not change during the response. It is concluded that hypoxic fetoplacental vasoconstriction is triggered by decreased oxygen availability. It is suggested that hypoxic fetoplacental vasoconstriction may play a role in local regulation of human fetoplacental blood flow in vivo and may contribute to poor fetal prognosis in preeclampsia.

Female↗
PubMed1986

Pressor and depressor actions of prostanoids in the intact human fetoplacental vascular bed.

Effects of the prostanoids PGE2, PGF2 alpha, PGI2, PGE1, 6-keto-PGE1 and the PGH2 analogue U46619, on fetoplacental perfusion pressure were measured in human term placental cotyledons in which both fetal and maternal circuits were perfused at constant flow. Fetal arterial injections of bolus doses of PGE2, PGF2 alpha and U46619 caused reversible increases in fetal perfusion pressure. Pressor responses to PGF2 alpha and U46619 were dose-related, with threshold doses of less than or equal to 2 nmoles and 14 pmoles, respectively. Reversible dose-related decreases in fetoplacental perfusion pressure were elicited by fetal arterial injection of PGI2, 6-keto-PGE1 and PGE1; threshold concentrations were: PGI2 less than or equal to 10 pmoles, PGE1 less than or equal to 141 pmoles and 6-keto-PGE1 less than or equal to 270 pmoles. The potent depressor effect of PGI2 and the potent pressor effect of U46619, a TxA2 mimetic, in the intact human fetoplacental vascular bed suggest that endogenous PGI2 and TxA2 could play a role in modulating fetoplacental blood flow in the term placenta.

Alprostadil↗