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Biomedical subjects

A Huang

Publications and source records attributed to A Huang.

At least 163 records · Page 9Linked to original sources
PubMed1996

Growth factors in mechanisms of malignancy: roles for TGF-beta and FGF.

Malignant progression is a complex process involving the accumulation of multiple genetic alterations leading to changes in many specialized cell functions. Important in this process is the loss of growth control which is frequently associated with modifications in growth factor production, and growth factor response pathways. Indeed, oncogenes have been characterized that code for polypeptide growth factors or their receptors, and many tumor cell populations release potently mitogenic growth factors which contribute to the malignant properties of tumor cells. In this review, the importance of growth factors in mechanisms of malignant progression is emphasized, using as examples the transforming growth factor-beta (TGF-beta) and fibroblast growth factor (FGF) families. We describe many of the properties and biological activities of these two families of growth factors, focusing on mechanisms of autocrine and intracrine mitogenic stimulation of tumor cell proliferation and malignant progression. The discussion includes evidence for altered growth factor expression in tumor cells, and the relationship between these changes in growth factors and alterations in the regulation of DNA synthesis, cell proliferation, protease production and cell motility required for invasion and metastasis. Recent studies are described that show that aberrant expression of TGF-beta1, bFGF or K-FGF results in dramatic changes in the genetic stability of cells, leading to increased rates of spontaneous gene amplification and the generation of drug resistant variants. These findings describe new malignancy relevant functions for altered growth factor expression.

Animals↗
PubMed1995

Altered regulation of message stability and tumor promoter-responsive cis-trans interactions of ribonucleotide reductase R1 and R2 messenger RNAs in hydroxyurea-resistant cells.

Mammalian ribonucleotide reductase is a highly regulated activity essential for DNA synthesis and repair. The activity and message levels of the enzyme are elevated in cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, and this appears to be mediated through specific cis elements in the 3'-untranslated region of the R1 and R2 mRNAs that interact with R1 and R2 binding proteins called R1BP and R2BP, respectively. Hydroxyurea-resistant cells with increased R1 and R2 message levels were observed to have increased R1 and R2 message half-lives. This was accompanied by alterations in R1 and R2 3'-untranslated region cis-trans interactions, as judged by band shift and UV cross-linking assays, in which R1BP and R2BP binding was markedly reduced. This first description of mutant mammalian cells altered in message stability regulatory determinants indicates another mechanism for acquiring resistance to an antitumor agent. Furthermore, the present study strongly supports the concept that R1BP and R2BP are important general regulators of ribonucleotide reductase message stability and act as message destabilizing factors.

Animals↗
PubMed1995

Early switch from intravenous to oral cephalosporins in the treatment of hospitalized patients with community-acquired pneumonia.

BACKGROUND: Switch therapy is defined as the early transition from intravenous to oral antibiotics during treatment of infection. This study was designed to evaluate the clinical outcome and length of stay of hospitalized patients with community-acquired pneumonia treated with an early switch from intravenous to oral third-generation cephalosporins. METHODS: Patients with a new roentgenographic pulmonary infiltrate and at least two symptoms (cough, fever, or leukocytosis) were enrolled in this study and treated with intravenous ceftizoxime sodium (1 g every 12 hours) or ceftriaxone sodium (1 g every 24 hours). Patients were switched to oral cefixime (400 mg every 24 hours) as soon as they met the following criteria: (1) resolution of fever; (2) improvement of cough and respiratory distress; (3) improvement of leukocytosis; and (4) presence of normal gastrointestinal tract absorption. RESULTS: Of the 120 patients enrolled, 75 (62%) had clinical data evaluated. Long-term follow-up showed that 74 patients (99%) were cured; one patient required readmission for further intravenous therapy. Mean duration of hospital stay was 4 days. CONCLUSIONS: This investigation demonstrated that an early switch to oral cefixime may be reasonable in hospitalized patients with community-acquired pneumonia who have already shown a good clinical and laboratory response to therapy with intravenous third-generation cephalosporins. This approach is clinically effective and minimizes hospital stay.

Administration, Oral↗
PubMed1995

Drug resistance and gene amplification potential regulated by transforming growth factor beta 1 gene expression.

Transforming growth factor beta 1 (TGF-beta 1) regulates a multitude of diverse biological functions in mammalian cells, and there is good evidence that aberrant expression of this growth factor can play an important role in mechanisms of malignant progression. We show that a TGF-beta 1-overexpressing mouse 10T1/2 cell line transfected with a TGF-beta 1 sequence that allows the synthesis of bioactive growth factor exhibits reduced sensitivity to the cytotoxic effects of the drug N-(phosphonacetyl)-L-aspartate (PALA) in colony-forming experiments. Furthermore, six independent 10T1/2 TGF-beta 1-transfected cell lines containing TGF-beta 1 gene expression under the control of a zinc sulfate-responsive metallothionein promoter were selected. In all cases, sensitivity to PALA cytotoxic effects was significantly reduced when cells were cultured under conditions that led to elevated levels of TGF-beta 1 gene expression when compared to cells containing basal levels of this growth factor. Fluctuation analysis to determine the rate of PALA resistance was performed with several TGF-beta 1-transfected cell lines in which growth factor expression was regulated by the metallothionein promoter. We observed significantly higher rates of PALA resistance/cell/generation in cell populations expressing high levels of TGF-beta 1 than in the same cells expressing relatively low levels of this growth factor. The only mechanism known for PALA resistance in mouse cells involves the amplification of the gene coding for the protein target of PALA, CAD, a multifunctional polypeptide containing carbamyl phosphate synthetase, aspartate transcarbamylase, and dihydroorotase. Southern blot analysis of colonies that survived normally cytotoxic concentrations of PALA exhibited CAD gene amplification. In total, these observations indicate that aberrant expression of TGF-beta 1 gene expression decreases the genetic stability of 10T1/2 cells, leading to increased rates of drug resistance and elevated gene amplification potential. The results of this study indicate a new malignancy related function for TGF-beta 1 alterations and suggest a novel role for aberrant expression of this growth factor in mechanisms of drug resistance and tumor progression.

Animals↗
PubMed1995

Cytochemical characteristics of cat spinal neurons activated during fictive locomotion.

Using standard immunohistochemical and histochemical techniques, we have examined the neurochemical characteristics of a subpopulation of locomotor-related neurons as labeled by the activity-dependent marker c-fos. Results were compared to those obtained from a small sample of intracellularly labeled locomotor-related neurons. In the paralyzed, decerebrate cat, fictive locomotion was evoked by electrical stimulation of the mesencephalic locomotor region. Most c-fos-immunoreactive neurons were distributed in medial lamina VI and VII and in lamina VIII and X. Double labeling of c-fos with various cytochemical markers revealed that about one-third of the c-fos-immunoreactive neurons were choline acetyltransferase immunoreactive, about one-third were glutamate immunoreactive, and about one-third were aspartate immunoreactive. In addition, approximately 15% of the c-fos-labeled neurons contained NADPH-diaphrorase reaction product, while almost 40% appeared to receive close contacts from calcitonin gene-related peptide-immunoreactive fibers and boutons. Choline acetyltransferase- or aspartate immunoreactivity was observed in some intracellularly labeled neurons. These findings have implications regarding the putative neurotransmitters utilized by subpopulations of locomotor-related neurons in the cat spinal cord.

Animals↗
PubMed1995

Therapy of nonnecrotizing anterior scleritis with subconjunctival corticosteroid injection.

OBJECTIVE: To determine the safety and efficacy of subconjunctival triamcinolone (Kenalog) in treating nonnecrotizing anterior scleritis. DESIGN: The authors conducted a retrospective review of all patients treated with depot subconjunctival corticosteroid injection for scleritis from January 1988 to May 1993. Response to therapy was determined by subjective improvement in pain and a decrease in clinical signs of ocular inflammation. All patients received subconjunctival injections of triamcinolone by the same technique, and the minimum observation period for complications was 6 weeks. RESULTS: Eighteen patients (90%) had relief of their symptoms with clinically observable improvement in inflammation, whereas two patients (10%) responded poorly. Nine patients (45%) required no further therapy. Average symptom-free interval was 18 weeks in patients with recurrent scleritis. No complications of scleral thinning, perforation, or glaucoma occurred in any patients. CONCLUSION: Subconjunctival triamcinolone injection is highly efficacious in treating nonnecrotizing anterior scleritis without unreasonable risk of thinning and/or perforation and should be considered as adjunctive therapy in localized disease.

Adult↗
PubMed1995

Shear stress-induced dilation is attenuated in skeletal muscle arterioles of hypertensive rats.

Hypertension is thought to alter many of the functions of the vascular endothelium. The present study examines whether shear stress-induced endothelium-dependent skeletal muscle arteriolar dilation is compromised in genetically hypertensive rats. Changes in the diameter of isolated, perfused arterioles (approximately 60 microns) from gracilis muscles of 12-week-old normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR) were investigated. At a constant perfusion pressure (80 mm Hg), the active diameter of NWR and SHR arterioles was 57.1 +/- 2.0 and 50.9 +/- 3.5 microns, respectively (mean +/- SEM), while the passive diameter (in Ca(2+)-free solution) was 113.2 +/- 3.1 and 100.6 +/- 2.9 microns, respectively. Increases in wall shear stress (from 0 to 100 dyne/cm2) elicited by increases in perfusate flow (from 0 to 25 microL/min) resulted in marked increases in the diameter of NWR arterioles, but such increases produced substantially smaller dilations in SHR arterioles (43.0 versus 18.9 microns). The prostaglandin synthesis inhibitor indomethacin (10(-5) mol/L) significantly attenuated the shear stress-induced dilations in both strains of rats. In contrast, the nitric oxide synthase inhibitor N omega-nitro-L-arginine (10(-4) mol/L) significantly shifted the shear stress-diameter curve to the right in vessels from NWR (by 50 dyne/cm2) but not in those from SHR. Thus, in gracilis muscle arterioles of SHR, the reduced dilation to increases in shear stress seems to be due to the lack of nitric oxide synthesis and/or release in response to shear stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Exercise training augments flow-dependent dilation in rat skeletal muscle arterioles. Role of endothelial nitric oxide and prostaglandins.

We aimed to test the hypothesis that as a consequence of short-term daily exercise, flow (shear stress)-dependent dilation and its mediation by the endothelium are altered in skeletal muscle arterioles. After initial familiarization with the protocol, rats ran on a treadmill once a day (with gradually increasing intensity up to 40 minutes and 28 m/min) for approximately 3 weeks (EX group); a control group remained sedentary (SED group). The active (internal) diameters of isolated gracilis muscle arterioles of SED and EX rats at 80 mm Hg were significantly different (55.2 +/- 2.1 and 49.3 +/- 2.0 microns, P < .05), and their passive diameters (in Ca(2+)-free solution) were 105.3 +/- 3.1 and 111.2 +/- 2.4 microns (not significantly different), respectively. Increases in flow of the perfusion solution from 0 to 12 microL/min elicited a significantly greater increase in diameter of EX arterioles (by 83.5% at maximum flow). This enhanced sensitivity maintained a lower shear stress in EX arterioles (15 to 20 dyne/cm2) compared with SED arterioles (25 to 35 dyne/cm2). In both SED and EX arterioles, flow-dependent dilation was eliminated after removal of the endothelium. Either N omega-nitro-L-arginine, a nitric oxide synthase inhibitor, or indomethacin, an inhibitor of prostaglandin synthesis, shifted the flow-diameter and calculated wall shear stress-diameter curves significantly to the right. Each of the inhibitors reduced flow-dependent dilation to a similar degree (approximately 40% to 45%); their combined administration nearly completely eliminated the dilation of arterioles of both SED and EX rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗
PubMed1995

Flow-dependent dilation and myogenic constriction interact to establish the resistance of skeletal muscle arterioles.

OBJECTIVE: To test the hypothesis that the diameter of skeletal muscle arterioles is determined by the interaction of responses elicited by intravascular pressure and flow. METHODS: Experiments were conducted on isolated, cannulated, first-order arterioles of cremaster muscle of male Wistar rats. The diameter of arterioles was followed by videomicroscopy. Perfusion pressures and flows were controlled. RESULTS: In the absence of perfusate flow, increases in perfusion pressure (from 0 to 120 mm Hg), after initial dilation, elicited endothelium independent constrictions of arterioles. At 60 mm Hg of perfusion pressure, the active diameter of vessels was 84.9 +/- 1.9 microns. The passive diameter of arterioles (Ca2(+)-free solution)was 150.6 +/- 2.4 microns. Increases in perfusate flow resulted in a significant upward shift in the pressure-diameter curves; in the presence of perfusate flows of 20, 40, and 60 microL/min, the constriction of the vessels at a pressure of 60 mm Hg was attenuated by 25.1 +/- 3.9%, 35.2 +/- 3.0%, and 46.8 +/- 4.4%, respectively. In contrast, the corresponding diameter of arterioles at perfusate flows of 10 to 60 microL/min was significantly reduced when perfusion pressure was increased from 60 to 80 and 100 mm Hg (at a flow of 60 microL/min) by 12.0 +/- 4.3% and 37.1 +/- 2.8%, respectively. Hence, both flow- and shear stress-diameter curves were significantly shifted downward when perfusion pressure increased from 60 to 100 mm Hg. CONCLUSION: These results demonstrate that an interplay between pressure and flow-sensitive mechanisms is an important determinant of the arteriolar resistance in skeletal muscle.

Animals↗
PubMed1995

Calcium mobilization in density subpopulations of rabbit washed platelets.

To estimate the responsiveness of an individual platelet, rather than a group of platelets, we determined the intracellular calcium concentration ([Ca2+]i) of single platelets using digital imaging microscopy after density fractionation. The mean [Ca2+]i of non-fractionated resting single platelets was 74.0 +/- 4.2 nM (n = 71). Immediately after thrombin stimulation (100 mu/ml), [Ca2+]i increased markedly in the entire cytoplasm, reaching maximum levels of 400-1000 nM, and decreased slightly thereafter. These maximum levels varied markedly from cell to cell in non-fractionated platelets. Although there was no significant difference in the resting levels of [Ca2+]i of single platelets even after density fractionation, the peak [Ca2+]i levels after thrombin stimulation (10 and 100 mu/ml) in platelets with higher density ( > 1.062) were significantly higher than those in platelets with intermediate density (1.052-1.061) or lower density ( < 1.051). This higher responsiveness of higher-density platelets in calcium mobilization was accompanied by higher aggregability and higher reactivity in the release reaction. These results suggest that higher responsiveness in higher-density platelets may be explained by the higher reactivity in [Ca2+]i mobilization.

Animals↗
PubMed1994

Characterization of mutated transforming growth factor-beta s which possess unique biological properties.

Transforming growth factor-beta (TGF-beta) is a potent regulator of cell growth and differentiation. On the basis of the crystal structure of TGF-beta 2, we have designed and synthesized two mutant TGF-beta s, TGF-beta 1 (71 Trp) and TGF-beta 1 (delta 69-73). Although both of these molecules inhibited the growth of Mv1Lu mink lung epithelial cells and LS1034 colorectal cancer cells, which are affected equally by TGF-beta 1 and TGF-beta 2, TGF-beta 1 (delta 69-73) was much less potent than TGF-beta 1 or TGF-beta 1 (71 Trp) at inhibiting the growth of LS513 colorectal cancer cells which are growth-inhibited by TGF-beta 1 but not TGF-beta 2. Both TGF-beta 1 (71 Trp) and TGF-beta 1 (delta 69-73) increased levels of mRNAs for fibronectin and plasminogen activator inhibitor with Mv1Lu cells, whereas only TGF-beta 1 (71 Trp) and not TGF-beta 1 (delta 69-73) up-regulated the mRNA level of carcinoembryonic antigen in LS513 cells. The expression level of carcinoembryonic antigen mRNA in LS1034 cells was not altered by either wild-type or mutant TGF-beta s. Receptor labeling experiments demonstrated that TGF-beta 1 (71 Trp) bound with high affinity to the cell-surface receptors of Mv1Lu, LS1034, and LS513 cells while TGF-beta 1 (delta 69-73) bound effectively to the receptors of Mv1Lu and LS1034 cells but much less to the receptors on LS513 cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1994

Chemoprevention and therapy of mouse mammary carcinomas with doxorubicin encapsulated in sterically stabilized liposomes.

BACKGROUND: The objective of this study was to determine the ability of doxorubicin, encapsulated in sterically stabilized liposomes (Doxil [Liposome Technology, Inc., Menlo Park, CA]), to inhibit the spontaneous development of mammary carcinomas in mice. METHODS: Monthly prophylactic intravenous injections of 6 mg/kg doses of Doxil were started when retired breeding C3H/He mice were 26 weeks old. Mice that developed a mammary carcinoma were then given weekly intravenous injections of 6 mg/kg doses to determine whether the tumors were susceptible or resistant to Doxil therapy. RESULTS: The monthly injections reduced the incidence of first mammary carcinomas in up to 88-week-old retired breeding C3H/He mice from 65 of 66 (98%) in untreated mice to 22 of 47 (47%) in treated mice. The first 15 mice that developed a mammary tumor while on the prophylactic protocol were then placed on a weekly therapeutic protocol. The therapeutic use of Doxil cured 3 of 15 mice and inhibited the growth of 12 tumors. Drug resistance as a result of treatments was not observed. The mean survival of tumor-bearing mice was extended from 24 days in untreated mice to 87 days in treated mice. Toxic side effects were limited to transient weight loss during the weekly Doxil treatments and to epidermal necrosis and dermal fibrosis due to drug extravasation at the sites of intravenous injections. CONCLUSIONS: The authors concluded that doxorubicin in sterically stabilized liposomes deserves to be explored further in comparative studies with free doxorubicin for the prophylaxis and therapy of mammary cancer.

Animals↗
PubMed1994

Liposomes and hyperthermia in mice: increased tumor uptake and therapeutic efficacy of doxorubicin in sterically stabilized liposomes.

We have shown that sterically stabilized (Stealth) liposomes (SL), can accumulate in the extracellular space within tumors, and may improve pharmacokinetics and therapeutic efficacy of encapsulated doxorubicin (SL-DOX). When SL-DOX were incubated in vitro at different temperatures with 50% bovine serum, approximately 20% of the encapsulated DOX was released at 42 degrees C within 1 min, compared with less than 1% DOX released at 37 degrees C. In vivo, mice were implanted s.c. with C-26 colon carcinoma in both flanks to produce matched tumors 6-10 mm in diameter. Topical hyperthermia treatment consisting of 42 degrees C minimum tumor temperature for 30 min was applied with a microwave device to the tumor on one side only at 1 h after i.v. injection of SL-DOX or free DOX. Tumor DOX concentration in the group which was given injections of SL-DOX and sacrificed 2 h after drug injection was 1.5-fold higher compared with the nonheated tumor in mice given injections of SL-DOX. At 24 h after injection the thermal enhancement ratio for DOX accumulation in tumor remained at 1.5. In addition, there was a 15-fold higher concentration of DOX in tumor from the group given injections of SL-DOX compared to mice given injections of free doxorubicin. To assess therapeutic efficacy, we treated mice with hyperthermia for 15 min either at 1, or at 24 h or at both time points after injection of SL-DOX. We have found that the life span of the group of mice treated with SL-DOX and two 15-min hyperthermia treatments increased 51% compared with control groups receiving the same dosage of SL-DOX but without hyperthermia, and 59% compared to those receiving two hyperthermia treatments but with free DOX. A single hyperthermia treatment either at 1 or 24 h was less effective in increasing life span compared with two treatments, but all groups treated with SL-DOX and single hyperthermia were still superior to the control groups, showing a 27-38% increase in life span.

Animals↗
PubMed1994

Tissue distribution and therapeutic effect of intravenous free or encapsulated liposomal doxorubicin on human prostate carcinoma xenografts.

BACKGROUND: The authors compared the therapeutic effects of doxorubicin in two formulations: free in saline suspension and encapsulated in sterically stabilized liposomes composed of hydrogenated soy phosphatidylcholine/2cholesterol/polyethylene glycol-distearoyl-phosphatidyl-ethanolamine (Doxil, Liposome Technology, Inc., Menlo Park, CA). METHOD: The drug formulations were injected intravenously to treat human prostate carcinoma PC-3, implanted subcutaneously into nude Swiss mice. Confocal laser scan microscopy and microfluorometry were used to determine tissue distribution and to quantitate drug uptake. RESULTS: Laser scan microscope and microfluorometer studies showed that the liposome-encapsulated drug entered the liver, the kidneys, and the tumor in greater quantity and remained in the liver and in the tumor longer than the free drug. The liposome formulation produced a 25-fold increase in doxorubicin at the disease site. Doxil was significantly more effective than the free drug in inhibiting growth and in effecting cures and had only minor and temporary systemic toxic effects. CONCLUSIONS: The current study demonstrated the therapeutic efficacy of doxorubicin, encapsulated in sterically stabilized liposomes, against prostate carcinoma. Decreased systemic elimination, increased penetration into the tumor, and long liposome presence with slow drug release into the tumor probably accounted for the enhanced therapeutic effect of doxorubicin in sterically stabilized liposomes.

Animals↗
PubMed1994

Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes.

In preclinical studies, a doxorubicin liposome formulation containing polyethylene-glycol (Doxil) shows a long circulation time in plasma, enhanced accumulation in murine tumors, and a superior therapeutic activity over free (unencapsulated) doxorubicin (DOX). The purpose of this study was to characterize the pharmacokinetics of Doxil in cancer patients in comparison with free DOX and examine its accumulation in malignant effusions. The pharmacokinetics of doxorubicin and/or liposome-associated doxorubicin were analyzed in seven patients after injections of equivalent doses of free DOX and Doxil and in an additional group of nine patients after injection of Doxil only. Two dose levels were examined, 25 and 50 mg/m2. When possible, drug levels were also measured in malignant effusions. The plasma elimination of Doxil followed a biexponential curve with half-lives of 2 and 45 h (median values), most of the dose being cleared from plasma under the longer half-life. Nearly 100% of the drug detected in plasma after Doxil injection was in liposome-encapsulated form. A slow plasma clearance (0.1 liter/h for Doxil versus 45 liters/h for free DOX) and a small volume of distribution (4 liters for Doxil versus 254 liters for free DOX) are characteristic of Doxil. Doxorubicin metabolites were detected in the urine of Doxil-treated patients with a pattern similar to that reported for free DOX, although the overall urinary excretion of drug and metabolites was significantly reduced. Doxil treatment resulted in a 4- to 16-fold enhancement of drug levels in malignant effusions, peaking between 3 to 7 days after injection. Stomatitis related to Doxil occurred in 5 of 15 evaluable patients and appears to be the most significant side effect in heavily pretreated patients. The results of this study are consistent with preclinical findings indicating that the pharmacokinetics of doxorubicin are drastically altered using Doxil and follow a pattern dictated by the liposome carrier. The enhanced drug accumulation in malignant effusions is apparently related to liposome longevity in circulation. Further clinical investigation is needed to establish the relevance of these findings with regard to the ability of liposomes to modify the delivery of doxorubicin to solid tumors and its pattern of antitumor activity.

Adult↗