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Biomedical subjects

Richard Chang

Publications and source records attributed to Richard Chang.

At least 19 recordsLinked to original sources
PubMed2007

TGF-beta1 calcium signaling in osteoblasts.

Transforming growth factor-beta1 (TGF-beta1) action is known to be initiated by its binding to multiple cell surface receptors containing serine/threonine kinase domains that act to stimulate a cascade of signaling events in a variety of cell types. We have previously shown that TGF-beta1 and BMP-2 treatment of primary human osteoblasts (HOBs) enhances cell-substrate adhesion. In this report, we demonstrate that TGF-beta1 elicits a rapid, transient, and oscillatory rise in the intracellular Ca(2+) concentration, [Ca(2+)](i), that is necessary for enhancement of cell adhesion in HOBs but does not alter the phosphorylation state of Smad proteins. This rise in [Ca(2+)](i) in HOB is not observed in the absence of extracellular calcium or when the cells are treated with the L-type Ca(2+) channel blocker, nifedipine, but is stimulated upon treatment with the L-type Ca(2+) channel agonist, Bay K 8644, or under high K(+) conditions. The rise in [Ca(2+)](i) is severely attenuated after treatment of the cells with thapsigargin, a selective endoplasmic reticulum Ca(2+) pump inhibitor. TGF-beta1 enhancement of HOB adhesion to tissue culture polystyrene is also inhibited in cells treated with nifedipine. These data suggest that intracellular Ca(2+) signaling is an important second messenger of the TGF-beta1 signal transduction pathway in osteoblast function.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2005

A phase I clinical trial of 12- O-tetradecanoylphorbol-13-acetate for patients with relapsed/refractory malignancies.

Phorbol esters activate protein kinase C and modulate a variety of downstream cell signaling pathways. 12-O-tetradecanoylphorbol-13-acetate (TPA) is a phorbol ester that induces differentiation or apoptosis in a variety of cell lines at low concentrations. A phase I dose escalation trial of TPA was undertaken for patients with relapsed or refractory malignancies. The starting dose was 0.063 mg/m2 and most patients were treated with an intravenous infusion of TPA on days 1-5 and 8-12 followed by a 2-week rest period prior to retreatment. Thirty-five patients were treated. A biological assay was used to monitor levels of TPA-like activity in the blood after treatment. Serious adverse events included individual episodes of gross hematuria, a grand mal seizure, syncope, and hypotension. Many patients had transient fatigue, mild dyspnea, fever, rigors, and muscular aches shortly after the infusion. Dose-limiting toxicities included syncope and hypotension at a dose of 0.188 mg/m2. Only a single patient had evidence of tumor response. These studies establish 0.125 mg/m2 as the maximally tolerated dose when TPA is administered on this schedule.

Adult↗
PubMed2005

An assessment of petrosal sinus sampling for localization of pituitary microadenomas in children with Cushing disease.

CONTEXT: Pituitary adenomas in Cushing disease (CD) are usually small and difficult to visualize. Bilateral inferior petrosal venous sampling (BIPSS) before and after ovine CRH stimulation is reserved for patients who have ACTH-dependent Cushing syndrome and negative magnetic resonance imaging (MRI) or positive MRI but inconsistent biochemical data. OBJECTIVE: The objective of the study was to evaluate the usefulness of BIPSS as a tool for localization of a pituitary adenoma in children with CD. DESIGN: The study was a retrospective review of the records of 141 children who were admitted for evaluation of CD from 1982 to 2004. SETTING: The study was conducted at a tertiary care center. INTERVENTIONS AND OUTCOME MEASURES: Lateralization of ACTH secretion during BIPSS was compared with MRI and surgical findings for the localization of a microadenoma. RESULTS: A total of 94 patients, 49 males and 45 females with an age range of 5.3 to 18.7 yr (13 +/- 3.2 yr), underwent BIPSS. Localization of a microadenoma by BIPSS agreed with surgical location in only 58% of the cases (95% confidence interval, 43-66). The combined use of information from the MRI and inferior petrosal venous sampling did not predict the location of the tumor more frequently than MRI alone (P > 0.1), which in this study localized a lesion in 39% of the patients (95% confidence interval, 28-50). The procedure was completed successfully in all patients, and no serious complications were recorded. CONCLUSIONS: Although BIPSS was safe and well tolerated in an experienced center, lateralization of the ACTH gradient during BIPSS was a poor predictor of the site of the adenoma in children with CD.

Adenoma↗
PubMed2005

Genome-wide analysis of mouse transcripts using exon microarrays and factor graphs.

Recent mammalian microarray experiments detected widespread transcription and indicated that there may be many undiscovered multiple-exon protein-coding genes. To explore this possibility, we labeled cDNA from unamplified, polyadenylation-selected RNA samples from 37 mouse tissues to microarrays encompassing 1.14 million exon probes. We analyzed these data using GenRate, a Bayesian algorithm that uses a genome-wide scoring function in a factor graph to infer genes. At a stringent exon false detection rate of 2.7%, GenRate detected 12,145 gene-length transcripts and confirmed 81% of the 10,000 most highly expressed known genes. Notably, our analysis showed that most of the 155,839 exons detected by GenRate were associated with known genes, providing microarray-based evidence that most multiple-exon genes have already been identified. GenRate also detected tens of thousands of potential new exons and reconciled discrepancies in current cDNA databases by 'stitching' new transcribed regions into previously annotated genes.

Algorithms↗
PubMed2005

Malignant insulinoma: spectrum of unusual clinical features.

BACKGROUND: Malignant insulinoma occurs in a few patients with insulinoma. Due to the small sample of patients, there are little data regarding their clinical manifestation as well as the preferred treatment modalities. The aims of the current study were to summarize the National Institutes of Health experience during the last two decades and to conduct a critical review of the current literature. METHODS: The authors identified 10 patients with metastatic insulinoma. RESULTS: The patients presented with four patterns of clinical behavior. First, four patients presented with lymph node metastasis and, after surgical excision, maintained a prolonged tumor-free survival. Second, four patients presented with metastatic disease to the liver, which appeared years after the initial diagnosis and presumed curative surgery. Third, one patient presented with a large alpha-fetoprotein-secreting liver mass. Finally, 9 of the 10 patients had a prolonged survival. Various treatment modalities were used to control hypoglycemia. Short-term benefits were most often achieved with embolization and diazoxide. Less successful modalities included radiofrequency ablation, radical debulking surgery, verapamil therapy, octreotide therapy, and chemotherapy. CONCLUSIONS: The current study, as well as others, suggested that metastatic insulinoma may have a variable natural history. After the initial surgical resection, the biology of the tumor, rather than any treatment modality, was most likely the major determinant of long-term survival.

Adult↗
PubMed2005

Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies.

PURPOSE: We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan. PATIENTS AND METHODS: The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response. RESULTS: A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses. CONCLUSION: Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

Adult↗
PubMed2005

A prospective evaluation of laparoscopic exploration with intraoperative ultrasound as a technique for localizing sporadic insulinomas.

BACKGROUND: Preoperative imaging studies localize insulinomas in less than 50% of patients. Arteriography with calcium stimulation and venous sampling (ASVS) regionalizes greater than 90% of insulinomas but requires specialized expertise and an invasive procedure. This prospective study evaluated laparoscopic exploration with IOUS compared with the other localization procedures in patients with a sporadic insulinoma. METHODS: Between March 2001 and October 2004, 14 patients (7 women and 7 men; mean age, 53) with an insulinoma were enrolled in an IRB-approved protocol. Computed tomography, magnetic resonance imaging, ultrasound scan, and arteriography with calcium stimulation and venous sampling were performed preoperatively. A surgeon, blinded to the results of the localizing studies, performed a laparoscopic exploration with intraoperative ultrasound (IOUS). At the completion of the exploration, the success of laparoscopy for localization was scored, and the tumor was resected. RESULTS: Twelve of 14 tumors were localized successfully before laparoscopy (noninvasive, 7 of 14; invasive, 11 of 14). Laparoscopic IOUS localized successfully 12 of 14 tumors. All lesions were resected, and all patients were cured (median follow-up, 36 months). CONCLUSION: Laparoscopic IOUS identified 86% of tumors. The authors consider laparoscopic IOUS to be equivalent to ASVS in localizing insulinomas. Further study is therefore warranted to determine the role of laparoscopy with IOUS in the localization and treatment algorithm for patients with sporadic insulinoma.

Adult↗
PubMed2005

Epidermal growth factor receptor inhibitors for the treatment of epithelial ovarian cancer.

The majority of patients with ovarian cancer, especially those who present with stages IIIC and IV, will relapse soon after completion of platinum-based induction treatment. It is imperative to find ways to improve and/or enhance the efficacy of induction and to prolong the duration of the first remission. The epidermal growth factor receptor (EGFR) family has been exploited, and currently, three agents that directly target this group of receptors are in use in the treatment of colorectal, non-small-cell lung and breast cancers. EGFR and HER2/neu are overexpressed in a significant percentage of epithelial ovarian cancers. Thus, it would be reasonable to explore directly targeted therapy in ovarian cancer. Numerous investigational trials involving a variety of EGFR inhibitors in ovarian cancer are ongoing. Our institution has an active phase II clinical study that seeks to define the role of erlotinib (Tarceva) in potentiating first-line chemotherapy, and to determine whether the drug offers a significant contribution as maintenance therapy. It is hoped that data from these and other studies will help investigators to understand more clearly the biology of ovarian cancer and to delineate the role of EGFR inhibitors in the management of ovarian cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

The functional landscape of mouse gene expression.

BACKGROUND: Large-scale quantitative analysis of transcriptional co-expression has been used to dissect regulatory networks and to predict the functions of new genes discovered by genome sequencing in model organisms such as yeast. Although the idea that tissue-specific expression is indicative of gene function in mammals is widely accepted, it has not been objectively tested nor compared with the related but distinct strategy of correlating gene co-expression as a means to predict gene function. RESULTS: We generated microarray expression data for nearly 40,000 known and predicted mRNAs in 55 mouse tissues, using custom-built oligonucleotide arrays. We show that quantitative transcriptional co-expression is a powerful predictor of gene function. Hundreds of functional categories, as defined by Gene Ontology 'Biological Processes', are associated with characteristic expression patterns across all tissues, including categories that bear no overt relationship to the tissue of origin. In contrast, simple tissue-specific restriction of expression is a poor predictor of which genes are in which functional categories. As an example, the highly conserved mouse gene PWP1 is widely expressed across different tissues but is co-expressed with many RNA-processing genes; we show that the uncharacterized yeast homolog of PWP1 is required for rRNA biogenesis. CONCLUSIONS: We conclude that 'functional genomics' strategies based on quantitative transcriptional co-expression will be as fruitful in mammals as they have been in simpler organisms, and that transcriptional control of mammalian physiology is more modular than is generally appreciated. Our data and analyses provide a public resource for mammalian functional genomics.

Animals↗
PubMed2004

Induction of diabetes in nonhuman primates by means of temporary arterial embolization and selective arterial injection of streptozotocin.

PURPOSE: To develop and assess a technique for induction of C peptide-negative diabetes in adult nonhuman primates in preparation for preclinical investigation of type 1 diabetes treatments. MATERIALS AND METHODS: First, temporary embolization of the hepatic and gastric arteries was performed in 14 adult nonhuman primates (six cynomolgus, five rhesus, and three pigtail macaques). After embolization was confirmed with angiography, streptozotocin was injected at a dose of 50-70 mg/kg into the celiac artery and branches supplying the pancreas. The macaques then were given intravenous injections of arginine and glucose, and blood levels of insulin and C peptide were measured with an enzyme-linked immunosorbent assay to determine whether diabetes had been induced. RESULTS: All but one of the macaques developed persistent long-term C peptide-negative diabetes after the streptozotocin injection. One macaque did not develop diabetes after the initial injection and was given a second dose of streoptozotocin, which did induce diabetes. None of the macaques showed any symptoms of hepatic or renal injury, and only one died (of gastric dilatation 5 days after the procedure). CONCLUSION: Streptozotocin injection after temporary embolization of the hepatic and gastric arteries is a safe and reproducible method for inducing C peptide-negative diabetes in adult nonhuman primates in preparation for preclinical investigation of type 1 diabetes treatments.

Animals↗
PubMed2004

Effect of nesiritide on length of hospital stay in patients with decompensated heart failure.

We examined the effect of nesiritide, administered as initial therapy, on length of hospital stay (LOS) and renal function through a retrospective analysis of 129 consecutive admissions to the coronary care unit in 98 patients diagnosed with congestive heart failure. Nesiritide was infused during 58 admissions (nesiritide group) while other therapies, not including nesiritide, were used during 71 admissions (non-nesiritide group). Although the nesiritide group showed lower baseline left ventricular ejection fraction and systolic blood pressure, higher serum creatinine, and a longer QRS interval, the LOS of this group was significantly shorter compared to the non-nesiritide group (3.91 +/- 1.3 vs 4.77 +/- 1.7 days, P = .0023). Both groups were similar with respect to body weight change (negative fluid balance), a slight decrease in blood urea nitrogen, and unchanged serum creatinine. Nesiritide as an initial therapy for treatment of congestive heart failure results in a more rapid hospital discharge without compromising renal function.

Aged↗
PubMed2004

Jugular venous sampling: an alternative to petrosal sinus sampling for the diagnostic evaluation of adrenocorticotropic hormone-dependent Cushing's syndrome.

Bilateral sampling of the inferior petrosal sinuses (IPSS) to distinguish Cushing's disease from the ectopic ACTH syndrome is accurate but risky and technically difficult. Bilateral sampling of the internal jugular vein (JVS) is simpler and presumably safer. To compare jugular and petrosal sinus venous sampling for distinguishing Cushing's disease from ectopic ACTH syndrome, we studied 74 patients with surgically proven Cushing's disease, 11 with surgically confirmed, and three with occult ectopic ACTH secretion. Patients underwent JVS and IPSS with administration of CRH on separate days. Ratios of central-to-peripheral ACTH in venous samples were calculated. At 100% specificity, IPSS correctly identified 61 of 65 patients with Cushing's disease [sensitivity, 94%; confidence interval (CI), 84-98%]. When patients with abnormal venous drainage were excluded, sensitivity was 98% (CI, 90-100%). JVS had a sensitivity of 83% (CI, 71-91%) at 100% specificity. Receiver operated characteristics plot areas under the curve were similar (0.968 +/- 0.020 and 0.974 +/- 0.016, area under the curve +/- se, JVS vs. IPSS). Although petrosal sampling had better diagnostic accuracy, CIs overlapped (95% CI, 90-100% vs. 86% CI, 78-94%). Centers with limited sampling experience may choose to use the simpler JVS and refer patients for IPSS when the results are negative.

ACTH Syndrome, Ectopic↗
PubMed2003

Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience.

OBJECTIVE: The aim of this study was to describe the National Institutes of Health's experience initiating an islet isolation and transplantation center, including descriptions of our first six recipients, and lessons learned. RESEARCH DESIGN AND METHODS: Six females with chronic type 1 diabetes, hypoglycemia unawareness, and no endogenous insulin secretion (undetectable serum C-peptide) were transplanted with allogenic islets procured from brain dead donors. To prevent islet rejection, patients received daclizumab, sirolimus, and tacrolimus. RESULTS: All patients noted less frequent and less severe hypoglycemia, and one-half were insulin independent at 1 year. Serum C-peptide persists in all but one patient (follow-up 17-22 months), indicating continued islet function. Two major procedure-related complications occurred: partial portal vein thrombosis and intra-abdominal hemorrhage. While we observed no cytomegalovirus infection or malignancy, recipients frequently developed transient mouth ulcers, diarrhea, edema, hypercholesterolemia, weight loss, myelosuppression, and other symptoms. Three patients discontinued immunosuppressive therapy: two because of intolerable toxicity (deteriorating kidney function and sirolimus-induced pneumonitis) while having evidence for continued islet function (one was insulin independent) and one because of gradually disappearing islet function. CONCLUSIONS: We established an islet isolation and transplantation program and achieved a 50% insulin-independence rate after at most two islet infusions. Our experience demonstrates that centers not previously engaged in islet transplantation can initiate a program, and our data and literature analysis support not only the promise of islet transplantation but also its remaining hurdles, which include the limited islet supply, procedure-associated complications, imperfect immunosuppressive regimens, suboptimal glycemia control, and loss of function over time.

Adult↗
PubMed2002

Integrin expression by human osteoblasts cultured on degradable polymeric materials applicable for tissue engineered bone.

The use of biodegradable polymers in the field of orthopaedic surgery has gained increased popularity, as surgical pins and screws, and as potential biological scaffolds for repairing cartilage and bone defects. One such group of polymers that has gained considerable attention are the polyesters, poly(lactide-co-glycolide) (PLAGA) and polylactic acid (PLA), because of their minimal tissue inflammatory response, favorable biocompatibility and degradation characteristics. The objective of this study was to evaluate human osteoblastic cell adherence and growth on PLAGA and PLA scaffolds by examining integrin receptor (alpha2, alpha3, alpha4, alpha5, alpha6 and beta1) expression. Primary human osteoblastic cells isolated from trabecular bone adhered efficiently to both PLAGA and PLA, with the rate of adherence on PLAGA comparable to that of control tissue culture polystyrene (TCPS), and significantly higher than on PLA polymers at 3, 6 and 12 h. Human osteoblastic phenotypic expression, alkaline phosphatase (ALP) activity was positive on both degradable matrices, whereas osteocalcin levels were significantly higher on cells grown on PLAGA than on PLA composites. Interestingly, the integrin subunits, alpha2, alpha3, alpha4, alpha5, alpha6 and beta1 were all expressed at higher levels by osteoblasts cultured on PLAGA than those on PLA as analyzed by westerns blots and by flow cytometry. Among the integrins, alpha2, beta5 and beta1 showed the greatest difference in levels between the two surfaces. Thus, both PLA and PLAGA support osteoblastic adhesion and its accompanying engagement of integrin receptor and expression of osteocalcin and ALP. However PLAGA consistently appeared to be a better substrate for osteoblastic cells based on these parameters. This study is one of the first to investigate the ability of primary human osteoblastic cells isolated from trabecular bone to adhere to the biodegradable polymers PLAGA and PLA, and to examine the expression of their key adhesion receptors (integrins) on these substrates.

Absorbable Implants↗
PubMed2002

TGF-beta1 calcium signaling increases alpha5 integrin expression in osteoblasts.

TGF-beta1 is a potent osteoactive factor and exhibits a wide variety of effects on osteoblasts, most of which are mediated through receptor associated Smad proteins. We have recently reported a novel TGF-beta1 intracellular Ca2+ signaling pathway in osteoblasts, and found that this signaling is required for the TGF-beta1 mediated enhancement of osteoblast adhesion to substrate. Given that interaction between the extracellular matrix protein fibronectin and alpha5beta1 integrin on the cell surface is principally responsible for osteoblast substrate adhesion, we examined here whether the TGF-beta1 stimulated Ca2+ signal is involved in this pathway. Our results show that, in primary human osteoblasts, the TGF-beta1 induced intracellular Ca2+ signal is responsible, in part, for the stimulation of expression of alpha5 integrin, but not of beta1 integrin or fibronectin. Increased levels of alpha5 integrin protein and mRNA were seen as early as 12 h after TGF-beta1 treatment, but were inhibited by co-treatment of cells with nifedipine, a selective L-type Ca2+ channel blocker. TGF-beta1 treatment increased both fibronectin and beta1 integrin protein production within 48 h, in a manner unaffected by co-treatment with nifedipine. Immunofluorescence observations revealed that TGF-beta1 treatment resulted in increased alpha5 integrin staining, and more prominent alpha5 integrin clustering, with increased co-localization with the actin cytoskeleton, effects that were blocked by co-treatment with nifedipine. The TGF-beta1 induced intracellular Ca2+ signal in human osteoblasts is thus an important mechanistic step in the regulation of alpha5 integrin expression, later contributing to enhanced cell adhesion.

Calcium Channel Blockers↗