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Biomedical subjects

David Chang

Publications and source records attributed to David Chang.

At least 37 records · Page 2Linked to original sources
PubMed2005

The p160 family coactivators regulate breast cancer cell proliferation and invasion through autocrine/paracrine activity of SDF-1alpha/CXCL12.

Estrogen receptors (ERs) regulate the transcription of genes involved in breast cancer cell proliferation, invasion and metastasis. In addition to ligand concentration, phosphorylation and coactivator/corepressor levels control ER-dependent transcription. In this study, we used MCF-7 breast cancer sublines with variable levels of the steroid receptor coactivator 1 (SRC-1) to investigate the importance of coactivator levels in basal and estrogen-inducible expression of SDF-1alpha/CXCL12, cathepsin D and cMyc. Basal expression of SDF-1alpha and cMyc but not of cathepsin D was substantially lower in a MCF-7 subline lacking SRC-1 ((MCF-7/p2) compared with MCF-7 sublines expressing SRC-1 (MCF-7/p1 and LCC2). Although estrogen efficiently induced SDF-1alpha in MCF-7/p1 cells, very little induction of this gene was observed in MCF-7/p2 cells. The absence of SRC-1 had no effect on estrogen-inducible expression cMyc and cathepsin D suggesting that coactivator levels determine the expression of only a subset of estrogen-regulated genes. Introduction of SRC-1, SRC-2/TIF-2 or SRC-3/AIB1 increased basal expression of SDF-1alpha in MCF-7/p2 cells. Consistent with the role of SDF-1alpha in mediating estrogen-induced proliferation, estrogen failed to increase proliferation of MCF-7/p2 cells. In matrigel invasion assays, conditioned media from MCF-7/p1 but not MCF-7/p2 cells increased invasion of cancer cells expressing metastasis-associated genes and CXCR4, the receptor for SDF-1alpha. These results suggest that coactivators control SDF-1alpha expression, which mediates estrogen-induced proliferation and invasion through autocrine and paracrine mechanisms, respectively. These results also provide a molecular explanation for recent observations linking co-overexpression of coactivators and her2/neu with poor prognosis: coactivators increase SDF-1alpha expression whereas her2/neu stabilize CXCR4 protein.

Breast Neoplasms↗
PubMed2005

Abdominal computed tomography scans in the selection of patients with malignant peritoneal mesothelioma for comprehensive treatment with cytoreductive surgery and perioperative intraperitoneal chemotherapy.

BACKGROUND: Malignant peritoneal mesothelioma is a rare and fatal disease. Until recently, the treatment options were very limited and ineffective. The new comprehensive approach of cytoreductive surgery with perioperative intraperitoneal chemotherapy offers improved survival rates at a cost of considerable morbidity and mortality as in other peritoneal surface malignancies. The outcome after these treatments is predominantly dependent on adequate cytoreduction. The aim of the current study was to identify computed tomography (CT) scan images that are useful in patient selection for this comprehensive approach. METHODS: An analysis of the preoperative CT scans of 30 patients with peritoneal mesothelioma treated with cytoreductive surgery and perioperative intraperitoneal chemotherapy at a single institution was performed. Based on the size of residual tumor nodules after cytoreductive surgery, patients were divided into 2 groups: those with residual lesions 2.5 cm (suboptimal cytoreduction). The CT scans for each patient were evaluated by a standardized scoring system with the reader blinded to the operative findings. Thirty-nine CT scan parameters were obtained and statistically analyzed to determine their association with the study outcome variables, namely, adequacy of cytoreduction. RESULTS: Seven patients (64%) in the suboptimal cytoreduction group and 2 patients (11%) in the adequate cytoreduction group had a >5-cm tumor mass in the epigastric region (P=0.004). Nine patients (82%) in the suboptimal group and 2 patients (11%) in the adequate cytoreduction group had CT scans that showed loss of normal architecture of the small bowel and its mesentery (P<0.001). In a composite analysis of these 2 radiologic features, none of the patients with a >5-cm tumor mass in the epigastric region and loss of normal architecture of the small bowel and its mesentery had an adequate cytoreduction. Patients who lacked these two preoperative CT scan findings had a 94% probability of an adequate cytoreduction. CONCLUSIONS: CT scans effectively identified large peritoneal mesothelioma tumors at crucial anatomic sites. Because adequate cytoreduction is necessary to achieve prolonged survival, CT scans became an accurate prognostic radiologic test for patient selection for comprehensive treatment.

Adult↗
PubMed2005

Can we improve the cytologic examination of malignant pleural effusions using molecular analysis?

BACKGROUND: Currently, 40% of patients remain undiagnosed after routine cytologic examination for malignant pleural effusions. Deoxyribonucleic acid (DNA) methylation is a robust strategy for detecting cancer early in tissue. We hypothesized that DNA methylation would be more sensitive in diagnosing patients with malignant pleural effusions than cytology. METHODS: We conducted a prospective cohort study of 31 inpatients with pleural effusions (24 malignant pleural effusions metastatic from 10 different organs and 7 benign) over 18 months. Aspirated pleural fluid underwent cytologic examination and DNA extraction for nested methylation-specific polymerase chain reaction (PCR). We assayed for promoter hypermethylation in 8 genes known to be methylated in many cancers. Pleural fluid was considered positive if 2 or more genes were methylated by methylation-specific PCR. RESULTS: Cytology alone confirmed malignant pleural effusions in 15 of 24 patients (sensitivity 63%), whereas methylation alone positively identified 16 of 24 patients (sensitivity 67%). Both tests had 100% specificity in predicting benign effusions. If cytology and methylation were considered together, they exhibited 88% sensitivity and 100% specificity in discriminating benign and malignant effusions. Combined, the two assays were more sensitive than either test alone. Although the positive predictive value of each test was 100%, the negative predictive value of cytology and methylation combined was 78%, better than 47% and 44% for methylation and cytology alone, respectively. CONCLUSIONS: Epigenetic analysis of pleural fluid can detect malignant DNA from a variety of neoplasms, provide complementarity with cytology, and improve the diagnostic yield of the current standard examination of pleural fluid.

Breast Neoplasms↗
PubMed2005

Prevalence of blood-borne pathogens in an urban, university-based general surgical practice.

OBJECTIVE: To measure the current prevalence of blood-borne pathogens in an urban, university-based, general surgical practice. SUMMARY BACKGROUND DATA: Human immunodeficiency virus (HIV), hepatitis B, and hepatitis C represent significant occupational hazards to the surgeon. While the incidence of these blood-borne pathogens is increasing in the general population, little is known about the current prevalence of these exposures among patients presenting for surgery. METHODS: We studied 709 consecutive operative cases (July 2003 to June 2004) in a university practice that provides all inpatient, emergency department, and outpatient consultative general surgical services. Trauma cases and bedside procedures were excluded. Data collected included HIV, hepatitis B and C test results, type of operation, age, sex, and history of intravenous drug use. RESULTS: Testing for blood-borne pathogens was performed in 53% (N = 373) of 709 patients based on abnormal liver function tests, neutropenia, history of IV drug use, or patient request. Thirty-eight percent of all operations (142/373) were found to involve a blood-borne pathogen when tested: HIV (26%), hepatitis B (4%), hepatitis C (35%), and coinfection with HIV and hepatitis C (17%). Forty-seven percent of men tested positive for at least 1 blood-borne pathogen. Seventy-three different types of operations were performed, ranging from Whipple procedures to amputations. Soft-tissue abscess procedures 48% (34/71) and lymph node biopsies 67% (10/15) (P < 0.01) were most often associated with blood-borne pathogens. Infections were more common among men (P < 0.01), patients 41 to 50 years of age (P < 0.01), and patients with a history of intravenous drug use (P < 0.01). CONCLUSIONS: HIV and hepatitis C infections are common in an urban university general surgical practice, while hepatitis B is less common. In addition, certain operations are associated with significantly increased exposure rates. Given the high incidence of these infections, strategies such as sharpless surgical techniques should be evaluated and implemented to protect surgeons from blood-borne pathogens.

Adult↗
PubMed2005

Readiness to change and the role of inpatient counseling for alcohol/substance abusing youth with major trauma.

BACKGROUND: The data regarding trauma recidivism among youth suggest that alcohol and/or substance abuse counseling should be an integral part of an injury prevention program in Level I trauma centers. Analysis of attitudes and motivation toward changing substance use is an important part of counseling. This study explores the willingness of a patient population at risk for recurrent injury to address their alcohol or substance use habits. METHODS: Young patients (ages 15-24) admitted with major trauma and positive alcohol/toxicology screens to a Level I trauma center were offered a previously described "readiness-to-change" interview tool. Responses were analyzed using a modified methodology to identify those patients motivated toward curtailing subsequent use. RESULTS: From February 2002 to August 2003, 120 patients (study group) consented to be interviewed. Within the study group, 109 (91%) were male patients, 110 (92%) were black, 85 (71%) suffered penetrating trauma injuries, and 75 (63%) had dropped out of high school. According to their interview tool responses, 61 (87%) of those patients using alcohol and 63 (85%) of those patients using drug were either "contemplative" or "action oriented" toward addressing their substance use behaviors. Furthermore, 35 patients (29%) in the study group indicated an absolute willingness to address their alcohol/drug use. No patient accessed treatment resources provided once discharged. CONCLUSION: Although findings regarding the assessment of attitudes toward readiness to change among young drug/alcohol-using patients experiencing penetrating trauma were initially very encouraging, facilitating and engaging these patients in actual behavior changing activities was far more challenging. Further exploration into the existing barriers to accessing treatment services and cultivating attitudes toward changing substance use behaviors is necessary.

Adolescent↗
PubMed2004

Utility of CEA and CA 19-9 tumor markers in diagnosis and prognostic assessment of mucinous epithelial cancers of the appendix.

BACKGROUND AND OBJECTIVES: Tumor markers are a clinical tool frequently used in oncology in association with other clinical and radiologic information. For gastrointestinal cancer, carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9) tumor markers have found selected clinical application. The use of these tumor markers in mucinous epithelial tumors of the appendix has not been previously determined. METHODS: In patients with peritoneal dissemination of a mucinous epithelial malignancy of the appendix, tumor markers CEA and CA 19-9 were prospectively recorded preoperatively within 1 week prior to definitive treatment. Also, if the appendiceal tumor recurred, the tumor marker was determined. The accuracy of these two tumor markers in the management of this disease was determined for these two specific clinical situations. RESULTS: CEA was elevated in 56% of 532 patients and CA 19-9 was elevated in 67.1% of these patients. Although the absolute level of tumor marker did not correlate with prognosis, a normal value indicated an improved survival. CEA was elevated in 35.2% of 110 patients determined to have recurrent disease; CA 19-9 was elevated in 62.9% and at least one of the tumor markers was elevated in 68.2% of patients. An elevated CEA tumor marker at the time of recurrence indicated a reduced prognosis. CONCLUSIONS: Both CEA and CA 19-9 tumor markers were elevated in a majority of these patients and should be a valuable diagnostic tool previously underutilized in this group of patients. These tumor markers were also of benefit in the assessment of prognosis in that a normal level indicated an improved prognosis. At the time of a reoperative procedure, CEA and CA 19-9 tumor markers gave information regarding the progression of disease. These tumor markers have practical value in the management of epithelial appendiceal malignancy with peritoneal dissemination.

Adenocarcinoma, Mucinous↗
PubMed2004

Structural requirements for additional N-linked carbohydrate on recombinant human erythropoietin.

N-Linked glycosylation is a post-translational event whereby carbohydrates are added to secreted proteins at the consensus sequence Asn-Xaa-Ser/Thr, where Xaa is any amino acid except proline. Some consensus sequences in secreted proteins are not glycosylated, indicating that consensus sequences are necessary but not sufficient for glycosylation. In order to understand the structural rules for N-linked glycosylation, we introduced N-linked consensus sequences by site-directed mutagenesis into the polypeptide chain of the recombinant human erythropoietin molecule. Some regions of the polypeptide chain supported N-linked glycosylation more effectively than others. N-Linked glycosylation was inhibited by an adjacent proline suggesting that sequence context of a consensus sequence could affect glycosylation. One N-linked consensus sequence (Asn123-Thr125) introduced into a position close to the existing O-glycosylation site (Ser126) had an additional O-linked carbohydrate chain and not an additional N-linked carbohydrate chain suggesting that structural requirements in this region favored O-glycosylation over N-glycosylation. The presence of a consensus sequence on the protein surface of the folded molecule did not appear to be a prerequisite for oligosaccharide addition. However, it was noted that recombinant human erythropoietin analogs that were hyperglycosylated at sites that were normally buried had altered protein structures. This suggests that carbohydrate addition precedes polypeptide folding.

Carbohydrates↗
PubMed2004

Spinal injuries in children.

BACKGROUND/PURPOSE: Traumatic spinal injury (TSI) is an uncommon source of morbidity and mortality in children. The aim of this study was to describe childhood TSI in a single level 1 urban pediatric trauma center. METHODS: The authors retrospectively analyzed all children younger than 14 years with TSI, treated at a level I pediatric trauma center between 1991 and 2002 (n = 406, 4% total registry). All children were stratified according to demographics, mechanisms, type and level of injury, radiologic evaluations, associated injuries, and mortality. RESULTS: The mean age was 9.48 +/- 3.81 years. The most common overall mechanism of injury was motor vehicle crash (MVC; 29%) and ranked highest for infants. Falls ranked highest for ages 2 to 9 years. Sports ranked highest in the 10 to 14 year age group. Paravertebral soft tissue injuries were 68%. The most common injury level was the high cervical spine (O-C4). The incidence of spinal cord injury without radiologic abnormality (SCIWORA) was 6%. Traumatic brain injury (37%) was the most common associated injury. Overall mortality rate was 4% in this urban catchment. CONCLUSIONS: TSI in children requires a different preventive and therapeutic logarithm compared with that of adults. The potential devastating nature of TSI warrants that the health care team always maintains a high index of suspicion for injury. Future prospective studies are needed to further elucidate injury patterns.

Accidental Falls↗
PubMed2004

Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology.

Alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH2) are responsible for metabolizing the bulk of ethanol consumed as part of the diet and their activities contribute to the rate of ethanol elimination from the blood. They are expressed at highest levels in liver, but at lower levels in many tissues. This pathway probably evolved as a detoxification mechanism for environmental alcohols. However, with the consumption of large amounts of ethanol, the oxidation of ethanol can become a major energy source and, particularly in the liver, interferes with the metabolism of other nutrients. Polymorphic variants of the genes for these enzymes encode enzymes with altered kinetic properties. The pathophysiological effects of these variants may be mediated by accumulation of acetaldehyde; high-activity ADH variants are predicted to increase the rate of acetaldehyde generation, while the low-activity ALDH2 variant is associated with an inability to metabolize this compound. The effects of acetaldehyde may be expressed either in the cells generating it, or by delivery of acetaldehyde to various tissues by the bloodstream or even saliva. Inheritance of the high-activity ADH beta2, encoded by the ADH2*2 gene, and the inactive ALDH2*2 gene product have been conclusively associated with reduced risk of alcoholism. This association is influenced by gene-environment interactions, such as religion and national origin. The variants have also been studied for association with alcoholic liver disease, cancer, fetal alcohol syndrome, CVD, gout, asthma and clearance of xenobiotics. The strongest correlations found to date have been those between the ALDH2*2 allele and cancers of the oro-pharynx and oesophagus. It will be important to replicate other interesting associations between these variants and other cancers and heart disease, and to determine the biochemical mechanisms underlying the associations.

Alcohol Dehydrogenase↗
PubMed2003

Passively driven integrated microfluidic system for separation of motile sperm.

This paper describes a self-contained integrated microfluidic system that can separate motile sperm from small samples that are difficult to handle using conventional sperm-sorting techniques. The device isolates motile sperm from nonmotile sperm and other cellular debris, based on the ability of motile sperm to cross streamlines in a laminar fluid stream. The device is small, simple, and disposable yet is an integrated system complete with sample inlets, outlets, sorting channel, and a novel passively driven pumping system that provides a steady flow of liquid; it requires no external power source or controls. The device fulfills a need in clinical settings where small amounts of sperm need to be sorted. It also opens the way for convenient bioassays based on sperm motility including at-home motile sperm tests.

Cell Separation↗
PubMed2003

Enhancement of therapeutic protein in vivo activities through glycoengineering.

Delivery of protein therapeutics often requires frequent injections because of low activity or rapid clearance, thereby placing a burden on patients and caregivers. Using glycoengineering, we have increased and prolonged the activity of proteins, thus allowing reduced frequency of administration. Glycosylation analogs with new N-linked glycosylation consensus sequences introduced into the protein were screened for the presence of additional N-linked carbohydrates and retention of in vitro activity. Suitable consensus sequences were combined in one molecule, resulting in glycosylation analogs of rHuEPO, leptin, and Mpl ligand. All three molecules had substantially increased in vivo activity and prolonged duration of action. Because these proteins were of three different classes (rHuEPO is an N-linked glycoprotein, Mpl ligand an O-linked glycoprotein, and leptin contains no carbohydrate), glycoengineering may be generally applicable as a strategy for increasing the in vivo activity and duration of action of proteins. This strategy has been validated clinically for glycoengineered rHuEPO (darbopoetin alfa).

Anemia↗
PubMed2003

Community characteristics and demographic information as determinants for a hospital-based injury prevention outreach program.

HYPOTHESIS: To focus the efforts of a hospital-based injury prevention outreach program, information on patient demographics, community characteristics, and catchment area must be known. DESIGN AND SETTING: Evaluation of prospectively collected data maintained in the Trauma Registry of a level I university-based trauma center. PATIENTS AND MAIN OUTCOME MEASURES: Demographics, mechanism of injury, mortality, and home ZIP codes of patients admitted to the Adult Trauma Service, The Johns Hopkins Medical Institution, Baltimore, Md, were compared for 2 separate calendar years, at 2 years before (1995) and at 2 years after (2000) the implementation of a dedicated trauma program that includes an injury prevention outreach program. RESULTS: The list of common patient ZIP codes varied minimally from 1995 to 2000. The 18 most common ZIP codes represent (1) 80% of patients, (2) total area of 99 square miles (257.4 km2) (5.7-mile [9.1-km] radius), and (3) a region with a mean household income that is 67% of the statewide median. An increasingly disproportionate percentage of patients with gunshot wounds (GSWs) were the youngest patients (ages 15-24 years) treated by the Adult Trauma Service. While overall survival of trauma patients improved in 2000, no improvement was seen among patients with GSWs. Over half of the nonsurviving patients (37/65 [57%]) seen in 2000 and more than two thirds of patients with lethal GSWs (25/37 [67.6%]) were declared dead in the emergency department, suggesting nonpreventability from a clinical care standpoint. CONCLUSIONS: The catchment area represented by the bulk of patients admitted to a level I urban trauma center is compact and economically disadvantaged. While overall trauma mortality has decreased, GSWs are more lethal and prevalent in teenagers and young men. This identifies violence prevention as an area of emphasis.

Adolescent↗
PubMed2003

Third look surgery and beyond for appendiceal malignancy with peritoneal dissemination.

BACKGROUND AND OBJECTIVES: Second look surgery has been previously studied in patients with recurrent peritoneal dissemination from appendiceal malignancy. However, selection criteria for third, fourth, and subsequent reoperations are not available. METHODS: Five hundred and one patients with epithelial peritoneal surface malignancy of appendiceal origin underwent treatment with cytoreductive surgery and intraperitoneal chemotherapy during an 18-year period. Forty-five of these patients (8.9%) underwent three or more operative interventions. A critical statistical analysis of the impact of selected clinical features on survival was performed from a prospective database. RESULTS: Overall 5-year survival of these 45 patients was 70%. Five- and ten-year survival rates for patients with three interventions were 60 and 48%, for four interventions were 78 and 36%, and for five or more interventions were 100 and 80%. Sites of recurrent disease, histopathologic type of tumor, and lymph node status had no impact on survival. A complete second and third cytoreduction was associated with an improved 5-year survival rate. CONCLUSIONS: Prolonged survival in patients with three or more reoperations was significantly associated with a complete cytoreduction. However, after four or more interventions, the effects of tumor biology may predominate. Although 5-year survival is likely with multiple reoperations, prolonged follow-up shows that cancer cure is a rare event.

Adenocarcinoma, Mucinous↗
PubMed2003

Blood-donor perceptions of health history screening with a computer-assisted self-administered interview.

BACKGROUND: Computer-assisted self-interviewing (CASI) has been shown to promote disclosures of sensitive information. Using CASI to screen blood-donor candidates might encourage reports of deferrable risks without discouraging eligible donors. STUDY DESIGN AND METHODS: In 1998, an anonymous mail survey was sent to donors from eight blood centers. The relationship of donor demographics, donation history, and infectious risks (HIV test-seeking behavior, unreported deferrable risk, or reactive donor-screening test result) on attitudes toward CASI were assessed. RESULTS: Of 92,581 blood donors surveyed, 52,650 (57%) responded; of these, 4713 (7%) had an infectious risk. Among donors with risks, 29 percent felt they would be encouraged to reveal personal data, and 7 percent reported they would be discouraged from donating by CASI. Young, minority, female, and first-time donors were the most likely to report that CASI would encourage personal disclosures. Among donors without risks, 5 percent felt CASI would discourage them from donating. CONCLUSIONS: Although most donors felt their donation practices would not be influenced, CASI might reduce the proportion of donors with infectious risks by fostering personal disclosures and self-deferrals. The potential for CASI to improve donor screening and increase appropriate self-deferrals should be balanced against the possible loss of reluctant safe donors.

Adolescent↗
PubMed2003

Percutaneous repair of coronary artery bypass graft-related pseudoaneurysms using covered JOSTENTs.

Spontaneous rupture of a saphenous vein graft with pseudoaneurysm formation is a rare occurrence after coronary artery bypass grafting. Using polytetrafluoroethylene covered JOSTENTs (Jomed Inc., Rancho Cordova, California), we report the successful percutaneous repair of a large pseudoaneurysm emanating from a 23-year-old saphenous vein graft and pseudoaneurysm at the site of a radial artery graft to the circumflex coronary artery 18 days after bypass surgery. These are, respectively, the oldest saphenous vein graft-related and earliest radial artery graft-related pseudoaneurysms to have been reported in the literature to date, and illustrate the versatility of the JOSTENT in the treatment of these conditions.

Aged↗
PubMed2002

Transgenic overexpression of human IL-17E results in eosinophilia, B-lymphocyte hyperplasia, and altered antibody production.

We have identified and cloned a novel human cytokine with homology to cytokines of the interleukin-17 (IL-17) family, which we have termed human IL-17E (hIL-17E). With the identification of several IL-17 family members, it is critical to understand the in vivo function of these molecules. We have generated transgenic mice overexpressing hIL-17E using an apolipoprotein E (ApoE) hepatic promoter. These mice displayed changes in the peripheral blood, particularly, a 3-fold increase in total leukocytes consisting of increases in eosinophils, lymphocytes, and neutrophils. Splenomegaly and lymphoadenopathy were predominant and included marked eosinophil infiltrates and lymphoid hyperplasia. CCR3(+) eosinophils increased in the blood and lymph nodes of the transgenic mice by 50- and 300-fold, respectively. Eosinophils also increased 8- to 18-fold in the bone marrow and spleen, respectively. In the bone marrow, most of the eosinophils had an immature appearance. CD19(+) B cells increased 2- to 5-fold in the peripheral blood, 2-fold in the spleen, and 10-fold in the lymph nodes of transgenic mice, whereas CD4(+) T lymphocytes increased 2-fold in both blood and spleen. High serum levels of the cytokines IL-2, IL-4, IL-5, granulocyte colony-stimulating factor, eotaxin, and interferon gamma were observed. Consistent with B-lymphocyte increases, serum immunoglobulin (Ig) M, IgG, and IgE were significantly elevated. Antigenic challenge of the transgenic mice with keyhole limpet hemocyanin (KLH) resulted in a decrease in anti-KLH IgG accompanied by increases of anti-KLH IgA and IgE. In situ hybridization of transgenic tissues revealed that IL-17Rh1 (IL-17BR/Evi27), a receptor that binds IL-17E, is up-regulated. Taken together, these data indicate that IL-17E regulates hematopoietic and immune functions, stimulating the development of eosinophils and B lymphocytes. The fact that hIL-17E overexpression results in high levels of circulating eosinophils, IL-4, IL-5, eotaxin, and IgE suggests that IL-17E may be a proinflammatory cytokine favoring Th2-type immune responses.

Amino Acid Sequence↗