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L J Deftos

Publications and source records attributed to L J Deftos.

At least 37 records · Page 2Linked to original sources
PubMed2000

Parathyroid hormone-related protein reduces alveolar epithelial cell proliferation during lung injury in rats.

Parathyroid hormone-related protein (PTHrP) is a growth inhibitor for alveolar type II cells and could be a regulatory factor for alveolar epithelial cell proliferation after lung injury. We investigated lung PTHrP expression in rats exposed to 85% oxygen. Lung levels of PTHrP were significantly decreased between 4 and 8 days of hyperoxia, concurrent with increased expression of proliferating cell nuclear antigen and increased incorporation of 5-bromo-2'-deoxyuridine (BrdU) into DNA in lung corner cells. PTHrP receptor was present in both normal and hyperoxic lung. To test whether the fall in PTHrP was related to cell proliferation, we instilled PTHrP into lungs on the fourth day of hyperoxia. Eight hours later, BrdU labeling in alveolar corner cells was 3.2 +/- 0.4 cells/high-power field in hyperoxic PBS-instilled rats compared with 0.5 +/- 0.3 cells/high-power field in PTHrP-instilled rats (P < 0. 01). Thus PTHrP expression changes in response to lung injury due to 85% oxygen and may regulate cell proliferation.

Animals↗
PubMed1999

Medical and scientific organizations and scientific evidence in U.S. trials: lessons from European legal theory.

Medical and scientific societies and organizations could help to solve the problem that the U.S. judicial system has with trials involving scientific evidence. This problem is exemplified by infamous trials in which opposing high-paid experts present contradictory legal theories based on the same scientific facts. The conflicting conclusions of such experts often confuse rather than clarify the issues for the jury and even the judge. Dissatisfaction with these "battles of the experts" in both civil (e.g., breast-implant litigation) and criminal (e.g., forensic use of DNA evidence) trials ranges from concern to harsh criticism. Many critics identify as models for reform the European legal systems, where scientific evidence is presented in a relatively objective manner by experts appointed by the trial court. Since they are often selected from lists of the faculties of universities, European experts are more likely to represent prevailing views of the relevant scientific community. Most American judges are reluctant to appoint experts, but there are some examples of their increasing use, and legal mechanisms and procedures exist that would allow this approach. Professional organizations of scientists and physicians could serve an important role in fostering the forensic use of neutral expertise by developing lists of experts for the courts; this would at least provide the potential for unbiased experts in complex cases that involve scientific and medical evidence. Such expertise could help American courts in their quests for scientific and legal truths.

Cross-Cultural Comparison↗
PubMed1998

Parathyroid hormone-related protein in patients with primary breast cancer and eucalcemia.

Parathyroid hormone-related protein (PTHrP) is a causative factor of humoral hypercalcemia in breast cancer and other malignancies. We studied circulating PTHrP levels with three different immunoassays directed against different parts of the PTHrP molecule in 48 patients with breast cancer and eucalcemia. The methods used were: (a) a RIA with antibodies directed toward the midregion (63-78); (b) an immunofluorometric assay with two antibodies against 1-34 and 38-67; and (c) an immunoradiometric assay with antibodies against 1-40 and 1-72. Although most patients had PTHrP levels indistinguishable from normal when measured by all three methods, four patients had increased serum levels in the IFMA. PTHrP was detected by immunohistochemistry in tumors from nearly all patients. One patient with elevated PTHrP in plasma measured by IFMA showed intense staining of tumor by immunohistochemistry; the tumor was histologically graded as III (severe) and was the largest of all tumors in this patient group. The IFMA can identify increased serum PTHrP in some patients with breast cancer who are not hypercalcemic. This assay may be especially useful in screening patients for this tumor during a relative early phase of the disease.

Adult↗
PubMed1998

Granin-A, parathyroid hormone-related protein, and calcitonin gene products in neuroendocrine prostate cancer.

BACKGROUND: The importance of the expression of granin A (GRN-A, chromogranin-A), calcitonin (CT) gene products (CGPs), and parathyroid hormone-related protein (PTHrP) has become appreciated in the neuroendocrine (NE) differentiation of prostate cancer. We have studied the prostate expression of these three NE cell products with in vivo and in vitro methods. METHODS: GRN-A secretion was measured by immunoassay in serum samples from patients with prostate cancer. Immunohistology procedures were used to assess GRN-A, CGPs, and PTHrP expression in paraffin-embedded prostate tissue samples. Serum and tumor findings were evaluated according to the patient's clinical status. All three substances were also studied in prostate cancer cell cultures. RESULTS: GRN-A, PTHrP, and CGPs were all secreted products of prostate cancer. Our studies demonstrated that GRN-A can serve as a prostate cancer serum and tumor marker with clinical value for both diagnosis and prognosis. Elevated serum GRN-A levels identified patients with prostate cancer, including some who did not have elevated serum prostate-specific antigen (PSA) levels. Serum GRN-A concentrations also had prognostic value for prostate cancer. PTHrP and CGPs were expressed in prostate cancer in addition to GRN-A, and all three were secreted by prostate cells in culture. Each had effects on prostate cell growth. CONCLUSIONS: GRN-A, PTHrP, and CGPs are produced and secreted by prostate cells. These three NE cell products can serve as tumor and markers for prostate cancer that have diagnostic and prognostic value. In addition, their derived peptides regulate prostate cell growth. However, studies more conclusive than the preliminary observations of our group and of other investigators are needed to define the roles of PTHrP, GRN-A, and CGPs in prostate cancer.

Biomarkers, Tumor↗
PubMed1998

Parathyroid hormone-related proteins is abundant in osteoarthritic cartilage, and the parathyroid hormone-related protein 1-173 isoform is selectively induced by transforming growth factor beta in articular chondrocytes and suppresses generation of extracellular inorganic pyrophosphate.

OBJECTIVE: Parathyroid hormone-related protein (PTHrP) is a major, locally expressed regulator of growth cartilage chondrocyte proliferation, differentiation, synthetic function, and mineralization. Because mechanisms that limit cartilage chondrocytes from maturing and mineralizing are diminished in osteoarthritis (OA), we studied PTHrP expression by articular chondrocytes. METHODS: PTHrP was studied in normal knee cartilage samples and cultured articular chondrocytes, and in cartilage specimens from knees with advanced OA, obtained at the time of joint replacement. RESULTS: PTHrP was more abundant in OA than in normal human knee articular cartilage. Both demonstrated PTH/PTHrP receptor expression. PTHrP 1-173, one of three alternatively spliced PTHrP isoforms, was exclusively expressed and induced by transforming growth factor beta in cultured chondrocytes. Chondrocytes mainly used the GC-rich P2 alternative promoter to express PTHrP messenger RNA. Inhibition by PTHrP 1-173, but not by PTHrP 1-146 or PTHrP 1-87, of inorganic pyrophosphate (PPi) elaboration suggested selective functional properties of the 1-173 isoform. Exposure to a neutralizing antibody to PTHrP increased PPi elaboration by articular chondrocytes. CONCLUSION: Increased expression of PTHrP, including the 1-173 isoform, has the potential to contribute to the pathologic differentiated functions of chondrocytes, including mineralization, in OA.

Adult↗
PubMed1998

Granins and prostate cancer.

OBJECTIVES: The importance of the expression of granin A (GRN-A, chromogranin-A) has become appreciated in the neuroendocrine differentiation of prostate cancer. We studied the expression of GRN-A in prostate cancer using serum immunoassay and tissue immunohistology procedures for this protein in order to define the clinical value of its measurements. METHODS: GRN-A production was measured by immunoassay in serum samples from patients with prostate cancer. Immunohistology procedures were used to assess GRN-A expression in paraffin-embedded prostate tissue samples. Serum and tumor findings were evaluated according to the patient's clinical status in studies by us and others. RESULTS: These studies demonstrated that GRN-A can serve as a prostate cancer serum and tumor marker with clinical value for both diagnosis and prognosis. Serum GRN-A was increased in early- and late-stage disease. Elevated serum GRN-A levels identified some patients with prostate cancer who did not have elevated serum prostate-specific antigen levels. In addition to their diagnostic value, increased serum GRN-A concentrations had prognostic value. CONCLUSIONS: Our own studies as well as those of others support the clinical potential of GRN-A as a marker for early, progressive, and recurrent prostate cancer. This demonstration of clinical utility notwithstanding, further studies are needed to clearly define the clinical value of GRN-A as a serum and tumor marker for this common cancer.

Biomarkers, Tumor↗
PubMed1998

Characterization of the cell-specific expression of parathyroid hormone-related protein in normal and neoplastic prostate tissue.

OBJECTIVES: Parathyroid hormone-related protein (PTHrP) is a primary factor in the pathogenesis of malignancy-associated hypercalcemia. By alternative splicing, the human PTHrP gene can generate three different species of mRNA that encode three initial translational isoforms of 139, 173, and 141 amino acids. We recently reported that PTHrP was present in normal prostatic neuroendocrine cells and was overexpressed in prostate cancer tissue as demonstrated by immunostaining. This study was undertaken to further clarify the complex expression of PTHrP gene in normal prostate tissue and prostate cancer. METHODS: PTHrP mRNA in samples prepared from normal prostate tissue, prostate cancer, and three prostate cancer cell lines, PC3, LNCaP, and DU145 was assessed using Northern hybridization. Expressed PTHrP isoforms were deduced from differential reverse transcription-polymerase chain reaction (RT-PCR) assays with exon-specific primers. Further localization of different species of PTHrP mRNA was performed using nonradioactive in situ hybridization with exon-specific probes on consecutive sections of normal and neoplastic prostate tissue. RESULTS: Northern hybridization showed that the PTHrP expression level was higher in prostate cancer than in normal prostate tissue. All three PTHrP isoforms could be detected in normal prostate tissues and prostate cancer with differential RT-PCR. Further analysis using in situ hybridization with exon-specific probes revealed that all three PTHrP isoforms were present in prostatic neuroendocrine cells and only PTHrP-1-139 isoform could be clearly detected in prostate cancer tissue. Two androgen-insensitive cell lines, PC3 and DU145, derived from a bone metastasis and a brain metastasis, respectively, expressed all three mRNA species encoding for the three isoforms, but DU145 cells expressed less than PC3 cells. Androgen-sensitive LNCaP cells exhibited a low level of expression of mRNA species encoding for PTHrP-1-139 and PTHrP-1-173, and no expression of PTHrP1-141 isoform. CONCLUSIONS: All three initial translational isoforms of PTHrP are produced by prostatic neuroendocrine cells. The mature products of PTHrP might exert their effects on other prostatic epithelial cells in a paracrine fashion and also participate in the homeostatic regulation of the ejaculate. In prostate cancer, differential expression of these three isoforms is evident and PTHrP-1-139 isoform is more abundant than the other two forms. These findings are valuable for designing future research studies to further elucidate the biological functions of PTHrP in normal prostatic glands and prostate cancer.

Blotting, Northern↗
PubMed1998

Influence of heterotopic ossification of the hip on bone densitometry: a study in spinal cord injured patients.

OBJECTIVE: To evaluate (1) the magnitude of falsely elevated bone density results caused by heterotopic ossification (HO) around the hip and (2) effect of age of patients when the measurement was taken, age of patients at injury, and age of injury (time since event) to the prevalence of HO. SUBJECTS AND METHODS: We blindly analyzed plain radiographs of the hip [(obtained within 1 month of dual energy X-ray absorptiometry (DEXA)] in 107 spinal cord injured (SCI) patients for HO and matched the result to the three regions of interest (ROI): the femoral neck, Ward's triangle, and the trochanter. The influence of HO on bone densitometric values was determined by the analysis of variance (ANOVA) and post-hoc analysis. RESULTS: Nineteen (18%) patients had HO; overlying the femoral neck (79%), trochanter (74%) and Ward's triangle (37%), respectively. Significant elevation of densitometric values (P < 0.05 or less) was observed in a various magnitude at each ROI, with the greatest elevation at Ward's triangle. The prevalence of HO was high when the patients were injured at age range of 20-39 years. CONCLUSIONS: HO around the hip can cause significantly elevated bone densitometry results at all ROIs, which can obscure underlying osteoporosis, leading to underestimation of fracture risk. Determination of bone density in this region with corresponding plain radiographs would be of help. In SCI patients, prevalence of HO was high when the age of patients at injury was 20-39 years.

Absorptiometry, Photon↗
PubMed1998

The evolving duty to disclose the presence of genetic disease to relatives.

Under the aegis of the Human Genome Project, research laboratories are identifying the genetic bases of human diseases almost daily. This explosion in molecular biology has raised many medical-legal issues about genetic information, such as privacy, discrimination, and insurability. Less appreciated is another issue that faces physicians who deal with genetic information in their practices--their duty to disclose a genetic disease to relatives of their patients who have the disease. Few cases have addressed the issue directly, and there has been little statutory and policy development in this area. However, because a physician's diagnosis of a genetic disease could have such a profound impact on the patient's relatives, there is a developing duty to consider disclosing genetic information to relatives. The case law and policy that support such disclosure reflect the evolution of medicine and the law away from paternalism toward an expanded concept of legal and moral duty. Since genetic information is presumed to be confidential by the law, as is essentially all medical information, guidelines need be developed regarding a physician's duty to disclose a genetic disease to a patient's relatives. These guidelines should consider the patient, the genetic test, the disease, and the third-party relative. Disclosure should be considered for a disease that is serious or fatal, treatable or curable, and transmitted dominantly with high penetrance. Specifics notwithstanding, these policies should be developed by physicians who care for patients and their families, not by lawyers and ethicists with no clinical training.

Ethics, Medical↗
PubMed1998

Hypercalcemia due to parathyroid hormone-related protein secretion by melanoma.

About 1-2% of melanoma patients develop hypercalcemia. We report hypercalcemia without bone metastasis in a 46-year-old woman with advanced melanoma. The hypercalcemia was associated with elevated serum parathyroid hormone-related protein (PTHrP) levels. An even higher concentration (10 times the serum level) in pleural effusion caused by pleural metastases implied that the source of the increased circulating PTHrP was the melanoma. Immunohistochemical staining of paraffin sections, performed using a monoclonal antibody (9H7) against the peptide sequence 109-141 of human PTHrP, detected PTHrP in the cytoplasm and nucleoli of melanoma cells in an autopsy specimen but not in specimens from this patient prior to onset of hypercalcemia. Considering the evidence, it is very likely that PTHrP production by melanoma caused hypercalcemia in this patient.

Female↗
PubMed1998

Parathyroid hormone-related protein in tracheal aspirates of newborn infants.

PTH-related protein (PTHrP) is found with its receptor in a variety of normal mammalian embryonic tissues where it apparently regulates cellular growth and differentiation. PTHrP stimulates phosphatidylcholine synthesis in rat fetal lung explants, suggesting a role in fetal type II alveolar maturation and surfactant production. We investigated PTHrP levels in tracheal aspirates of newborn infants. We collected tracheal aspirates from 40 intubated newborn infants within the first 24 h of life. PTHrP levels were measured by a RIA using rabbit antisera to PTHrP peptide 38-64. We found significantly lower PTHrP levels in tracheal aspirates from infants born at less than 35 wk of gestation (p = 0.02) and with a birth weight less than 2 kg (p = 0.04). We also found significantly lower PTHrP levels in male preterm (<35 wk of gestation) infants compared with female infants (p = 0.01), and in preterm infants who required multiple doses of surfactant (p = 0.005). Preterm infants exposed to antenatal steroids had significantly higher levels of PTHrP in tracheal aspirates (p = 0.02). PTHrP is associated with various indices of lung maturation and may prove to be a mediator of differentiation and growth.

Animals↗
PubMed1998

Bone morphogenetic proteins and bFGF exert opposing regulatory effects on PTHrP expression and inorganic pyrophosphate elaboration in immortalized murine endochondral hypertrophic chondrocytes (MCT cells).

A fundamental question in endochondral development is why the expression of parathyroid hormone-related protein (PTHrP), which inhibits chondrocyte maturation and mineralization, becomes attenuated at the stage of chondrocyte hypertrophy. To address this question, we used clonal, phenotypically stable SV40-immortalized murine endochondral chondrocytes that express a growth-arrested hypertrophic phenotype in culture (MCT cells). Addition of individual cytokines to the medium of MCT cells revealed that bone morphogenetic protein (BMP)-6, which commits chondrocytes to hypertrophy, markedly inhibited PTHrP production. This activity was shared by three other osteogenic bone morphogenetic proteins (BMP-2, BMP-4, and BMP-7) and by transforming growth factor beta (TGF-beta), which all inhibited the level of PTHrP mRNA. In contrast, basic fibroblast growth factor (bFGF), an inhibitor of chondrocyte maturation to hypertrophy, induced PTHrP in MCT cells and antagonized the effects of BMP-2, BMP-4, BMP-6, and BMP-7 and TGF-beta on PTHrP expression. Opposing effects of bFGF and BMPs also were exerted on the elaboration of inorganic pyrophosphatase (PPi), which regulates the ability of hypertrophic chondrocytes to mineralize the matrix. Specifically, BMP-2 and BMP-4, but not BMP-6 and BMP-7, shared the ability of TGF-beta to induce PPi release, and this activity was inhibited by bFGF in MCT cells. Our results suggest that effects on PTHrP expression could contribute to the ability of BMP-6 to promote chondrocyte maturation. BMPs and bFGF exert opposing effects on more than one function in immortalized hypertrophic chondrocytes. Thus, the normal decrease in bFGF responsiveness that accompanies chondrocyte hypertrophy may function in part by removing the potential for bFGF to induce PTHrP expression and to oppose the effects of BMPs. MCT cells may be useful in further understanding the mechanisms regulating the differentiation and function of hypertrophic chondrocytes.

Animals↗
PubMed1998

Coexpression of parathyroid hormone-related protein and its receptor in breast carcinoma: a potential autocrine effector system.

Parathyroid hormone-related protein (PTHrP), the pathogenic factor in most cases of humoral hypercalcemia of malignancy, is also expressed by many normal tissues. Its diverse biologic activities in these tissues are mediated by the PTH/PTHrP receptor through autocrine and paracrine mechanisms. Recent data suggest that PTHrP and its receptor might also influence the growth and metastatic spread of some cancers through similar local actions. Accordingly, immunohistochemical studies using murine monoclonal antibodies to detect coexpression of PTHrP and the PTH/PTHrP receptor were performed on 52 invasive breast carcinomas to assess the existence of this potential autocrine effector system. All of the 52 invasive breast carcinomas expressed reactivity for PTHrP, and 50 (96%) of these tumors also expressed reactivity for the receptor. Although additional investigations are necessary for evaluation of the role of PTHrP and PTH/PTHrP receptor in tumor pathogenesis, our current study demonstrates the presence of this potential autocrine effector system in the great majority of invasive breast carcinomas.

Adult↗
PubMed1997

Parathyroid hormone-related protein is not an autocrine growth factor for normal prostatic epithelial cells.

BACKGROUND: Parathyroid hormone-related protein (PTHrP) is the primary factor responsible for humoral hypercalcemia of malignancy. The hypercalcemic actions of PTHrP occur via stimulation of renal distal tubular calcium reabsorption and increased osteoclastic bone resorption. These effects of PTHrP are thought to be mediated through a common parathyroid hormone (PTH)/PTHrP receptor. In addition to the well-established role of PTHrP in bone remodeling, PTHrP is believed to be an important mediator of cellular growth and differentiation in a number of nonbony tissues. We recently demonstrated abundant expression of PTHrP in normal and malignant human prostatic tissues, and in cultured prostatic epithelial cells. METHODS: In vitro assays were used to test growth-regulatory activity of synthetic and endogenous PTHrP peptides on normal prostatic epithelial cells. RESULTS: No growth-regulatory activity could be demonstrated. CONCLUSIONS: PTHrP is not an autocrine growth factor for normal prostatic epithelial cells.

Cell Count↗
PubMed1997

Prostate cancer progression, metastasis, and gene expression in transgenic mice.

We previously reported that a transgenic mouse line containing the fetal globin promoter linked to the SV40 T antigen (T Ag) viral oncogene (Ggamma/T-15) resulted in prostate tumors. In this study, we further explored tumor origin, frequency, invasiveness, androgen sensitivity, and gene expression pattern. T Ag was detected in adult but not fetal and neonatal prostates, suggesting a role for androgens in tumor progression. However, castration shortly after prostate morphogenesis did not prevent tumor development, suggesting an androgen-independent phenotype. Tumors originated within ventral or dorsal prostate lobes and involved intraepithelial neoplasia, rapid growth in the pelvic region, and metastasis to lymph nodes and distant sites. In addition, the primary cancers could be propagated in nude mice or nontransgenic mice. Seventy-five percent of hemizygous and 100% of homozygous transgenic males developed prostate tumors, suggesting a T Ag dosage effect. Biochemical characterization of advanced tumors revealed markers of both neuroendocrine and epithelial phenotypes; markers of terminal differentiation are lost early in tumorigenesis. Tumor suppressor genes (p53 and Rb), normally bound to T Ag, were up-regulated; bcl-2 proto-oncogene, which prevents apoptosis, was slightly up-regulated. Myc, a stimulus to cell cycle progression, was unchanged. We propose the Ggamma/T-15 transgenic line as a model of highly aggressive androgen-independent metastatic prostate carcinoma with features similar to end-stage prostate cancer in humans.

Adenocarcinoma↗
PubMed1997

Influence of spondylopathy on bone densitometry using dual energy X-ray absorptiometry.

Spinal cord injury (SCI), as well as other neuromuscular disorders, not only results in osteopenia but also induces various patterns of osseous, articular, and soft tissue alterations. In the spinal column, a variety of abnormalities occur. To evaluate the magnitude of discrepancy of bone densitometry results caused by spondylopathy in SCI patients, we analyzed anteroposterior (AP) radiographs of the lumbar spine [obtained within 1 month of dual energy X-ray absorptiometry (DXA)] in 116 SCI patients for various manifestations of spondylopathy, and matched the result to each vertebral level (L1, 2, 3, 4). The dataset was stratified by individual vertebra (totally 463 vertebrae) as valid (no demonstrable other abnormal density on plain radiograph except osteopenia), abnormal without, and abnormal with hardware. The influence of spondylopathy on bone densitometry results was determined by the analysis of variance (ANOVA) and post hoc analysis. Our results showed that 227 (49%) vertebrae were abnormal. Significant elevation (15%, 15%, 18%, 20%; P < 0.001-P < 0.05) of bone mineral density (BMD; g/cm2) was observed at all levels (L1, 2, 3, 4, respectively), particularly at those abnormal vertebrae without hardware compared with valid (no other abnormal density on radiograph except osteopenia (Table 1). The L4 level was most severely affected. We concluded that in SCI patients, owing to various secondary progressive skeletal abnormalities, particularly neuropathic spondylopathy, can have strongly and significantly elevated vertebral bone densitometry results, which can obscure underlying osteoporosis, leading to misinterpretation and underestimation of fracture risk. DXA, although characterized by improving spatial resolution, cannot replace radiography in establishing the magnitude of this skeletal pathology. Therefore, determination of bone density in this region with corresponding plain radiographs is highly recommended.

Absorptiometry, Photon↗
PubMed1997

Intrapulmonary drug delivery of salmon calcitonin.

Calcitonin (CT) and other bone-active peptides have been restrained in clinical use by the need for parenteral administration. Although nasal and other transmucosal routes can be used for CT treatment, bioavailability and bioactivity of the peptide thus delivered are limited. We have evaluated the intrapulmonary route (IP) for the delivery of salmon calcitonin (SCT) in normal subjects. SCT was administered with a dry powder delivery inhaler. For comparison, each subject also received intramuscular (IM) SCT. Inhaled SCT produced significant hypocalcemia in all subjects as did injected SCT, and the peptide could be readily measured in serum by immunoassay. Compared by dose, IP SCT had 66% of the bioactivity and 28% of the bioavailability of IM SCT. This intrapulmonary route of administration should enhance the clinical acceptability of SCT and could also be applicable to other bone-active peptides.

Administration, Inhalation↗