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Biomedical subjects

David Wu

Publications and source records attributed to David Wu.

18 recordsLinked to original sources
PubMed2026

Generation of two homozygous iPSC lines carrying variants of uncertain significance in LMNA associated with cardiomyopathy.

Variants of uncertain significance (VUS) in the LMNA gene represent a major challenge in clinical genetics, as insufficient functional evidence limits their interpretation and clinical decision-making in laminopathies, including dilated cardiomyopathy (DCM). Here, we generated two isogenic induced pluripotent stem cell (iPSC) lines carrying homozygous LMNA variants, c.293A > G (p.Glu98Gly) and c.439G > A (p.Ala147Thr) by prime editing of a healthy donor iPSC line. Both variants are located within Coil 1B domain of lamin A. The edited iPSC lines retain normal morphology, pluripotency, genomic integrity, and trilineage differentiation capacity, providing a valuable platform for functional characterization and potential clinical reclassification of LMNA VUS.

Humans↗
PubMed2025

FDA-approved drug repurposing in zebrafish identifies thyroid hormone and other compounds as potential antithrombotics.

Venous thromboembolism (VTE) is a highly prevalent medical condition with limited therapeutic options and an incomplete understanding of its acquired and inherited subtypes. The zebrafish is a model with the benefits of external development, fecundity, optical transparency, and hemostasis that demonstrates conservation with mammals. We utilized zebrafish as a phenotypic screening tool to identify novel therapeutic options for preventing VTE. A library of FDA-approved compounds was screened for suppression of acquired (elevated estrogen) and spontaneous (protein C deficiency) thrombosis. We found that thyroid hormone, receptor tyrosine kinase (RTK) inhibitors, and proton-pump inhibitors (PPIs) effectively modulated levels of thrombosis, particularly in the estrogen-induced model. These also showed a more favorable hemostatic profile than standard therapies, suggesting alternative mechanisms. Genome editing of thyroid hormone receptor proved that thyroid hormone action is on target. A retrospective electronic health record (EHR) analysis found that thyroid-hormone prescriptions in hormonal contraceptive users correlated with a higher VTE risk, potentially limiting direct repurposing but highlighting thyroid signaling as a pathway involved in estrogen-induced thrombosis. Together, these data identify several drug classes that can be tailored to specific subtypes of VTE and help elucidate distinct pathways driving thrombosis.

FDA-approved compounds↗
PubMed2006

Surveillance for World Trade Center disaster health effects among survivors of collapsed and damaged buildings.

PROBLEM/CONDITION: Survivors of collapsed or damaged buildings from the attack on the World Trade Center (WTC) were among those most exposed to injury hazards, air pollution, and traumatic events. REPORTING PERIOD: This report summarizes data from health outcomes collected during interviews conducted from September 5, 2003, to the close of the World Trade Center Health Registry (WTCHR) enrollment on November 20, 2004. DESCRIPTION OF SYSTEM: WTCHR will be used to monitor periodically the mental and physical health of 71,437 enrollees for 20 years. The analysis is limited to 8,418 adult survivors of collapsed buildings (n = 5,095) and buildings with major or moderate damage (n = 3,323), excluding those who were involved in rescue and recovery. RESULTS: A total of 62.4% of survivors of collapsed or damaged buildings were caught in the dust and debris cloud that resulted from the collapse of the WTC towers, and 63.8% experienced three or more potentially psychologically traumatizing events. Injuries were common (43.6%), but few survivors reported injuries that would have required extensive treatment. More than half (56.6%) of survivors reported experiencing new or worsening respiratory symptoms after the attacks, 23.9% had heartburn/reflux, and 21.0% had severe headaches. At the time of the interview, 10.7% of building survivors screened positive for serious psychological distress (SPD) using the K6 instrument. After multiple adjustments, data indicated that survivors caught in the dust and debris cloud were more likely to report any injuries (adjusted odds ratio [AOR] = 3.9; p< or =0.05); any respiratory symptom (AOR = 2.7; p< or =0.05); severe headaches (AOR = 2.0; p< or =0.05); skin rash/irritation (AOR = 1.7; p< or =0.05); hearing problems or loss (AOR = 1.7; p< or =0.05); heartburn (AOR = 1.7; p< or =0.05); diagnosed stroke (AOR = 5.6; p< or =0.05); self-reported depression, anxiety, or other emotional problem (AOR = 1.4; p< or =0.05); and current SPD (AOR = 2.2; p< or =0.05). Adjustment for SPD did not diminish the observed associations between dust cloud exposure and physical health outcomes. Building type and time of evacuation were associated with injuries on September 11, 2001 and reported symptoms; building type (collapsed versus damaged) also was associated with mental distress. INTERPRETATION: Two to three years after September 11, survivors of buildings that collapsed or that were damaged as a result of the WTC attack reported substantial physical and mental health problems. The long-term ramifications of these effects are unknown. Many survivors were caught directly in the dust and debris of collapsing towers, a dense cloud of particulate matter that might have produced or exacerbated these health effects. PUBLIC HEALTH ACTION RECOMMENDED: Long-term follow-up of building survivors and all other persons enrolled in WTCHR should be maintained, with particular attention to those persons exposed to the dust cloud. Some of these findings might lead to building designs that can minimize injury hazards.

Adult↗
PubMed2006

Perceptually lossless medical image coding.

A novel perceptually lossless coder is presented for the compression of medical images. Built on the JPEG 2000 coding framework, the heart of the proposed coder is a visual pruning function, embedded with an advanced human vision model to identify and to remove visually insignificant/irrelevant information. The proposed coder offers the advantages of simplicity and modularity with bit-stream compliance. Current results have shown superior compression ratio gains over that of its information lossless counterparts without any visible distortion. In addition, a case study consisting of 31 medical experts has shown that no perceivable difference of statistical significance exists between the original images and the images compressed by the proposed coder.

Algorithms↗
PubMed2005

Chemical colloids versus biological colloids: a comparative study for the elucidation of the mechanism of protein fiber formation.

Fiber formation from murine serum amyloid A1 (SAA) was compared to the linear aggregation and fiber formation of colloidal gold particles. Here we report the similarities of these processes. Upon incubation with acetic acid, SAA misfolds and adopts a new conformation, which we termed saa. saa apparently is less soluble than SAA in aqueous solution; it aggregates and forms nucleation units and then fibers. The fibers appear as a string of the nucleation units. Additionally, an external electric field promotes saa fiber formation. These properties of saa are reminiscent of colloidal gold formation from gold ions and one-dimensional aggregation of the gold colloids. Colloidal gold particles were also found to be capable of aggregating one-dimensionally under an electric field or in the presence of polylysine. These gold fibers resembled in structure that of saa fibers. In summary, protein aggregation and formation of fibers appear to follow the generalized principles derived in colloidal science for the aggregation of atoms and molecules, including polymers such as polypeptides. The analysis of colloidal gold formation and of one-dimensional aggregation provides a simple model system for the elucidation of some aspects of protein fiber formation.

Animals↗
PubMed2005

An open-label, randomized study comparing efficacy and safety of intravenous piperacillin/tazobactam and ampicillin/sulbactam for infected diabetic foot ulcers.

BACKGROUND: Soft tissue and bone infections of the lower limb continue to be a frequent and serious complication in patients with diabetes mellitus. The best choice of antimicrobial for the empiric treatment of moderate to severe diabetic foot infections has not been established clearly. METHODS: We conducted a prospective, randomized, open-label, multicenter trial comparing piperacillin/tazobactam (P/T) (4 g/0.5 g q8h) and ampicillin/sulbactam (A/S) (2 g/1 g q6h) as a parenteral treatment for 314 adult patients with moderate-to-severe infected diabetic foot ulcers. Patients with polymicrobial infections involving methicillin-resistant Staphylococcus aureus also received vancomycin 1 g q12h. RESULTS: Clinical efficacy rates (cure or improvement) were statistically equivalent overall (81% for P/T vs. 83.1% for A/S), and median duration of treatment was similar in the clinically evaluable populations (nine days for P/T, 10 days for A/S). Drug-related adverse events for both study drugs were comparable in frequency and type. CONCLUSIONS: Although both study drugs provide safe and effective empiric treatment for moderate-to-severe infected diabetic foot ulcers, piperacillin/tazobactam has the advantage of covering Pseudomonas aeruginosa (bacteriologic success rate of 85.7%), the most commonly isolated gram-negative pathogen in this study.

Ampicillin↗
PubMed2004

Nanometer-localized multiple single-molecule fluorescence microscopy.

Fitting the image of a single molecule to the point spread function of an optical system greatly improves the precision with which single molecules can be located. Centroid localization with nanometer precision has been achieved when a sufficient number of photons are collected. However, if multiple single molecules reside within a diffraction-limited spot, this localization approach does not work. This paper demonstrates nanometer-localized multiple single-molecule (NALMS) fluorescence microscopy by using both centroid localization and photobleaching of the single fluorophores. Short duplex DNA strands are used as nanoscale "rulers" to validate the NALMS microscopy approach. Nanometer accuracy is demonstrated for two to five single molecules within a diffraction-limited area. NALMS microscopy will greatly facilitate single-molecule study of biological systems because it covers the gap between fluorescence resonance energy transfer-based (<10 nm) and diffraction-limited microscopy (>100 nm) measurements of the distance between two fluorophores. Application of NALMS microscopy to DNA mapping with <10-nm (i.e., 30-base) resolution is demonstrated.

DNA↗
PubMed2004

Analysis of compartmental models of ligand-induced endocytosis.

Kinetic models have played a pivotal role in the study of ligand-induced endocytosis. However, an analysis that suggests a systematic way to validate such models is lacking. The current work analyses the base model of ligand-induced endocytosis for three widely used experimental protocols. In protocol I cells initially devoid of ligand are incubated in ligand solution, whereas protocols II and III are desorption experiments in which an initial pool of surface or internalized ligand-receptor complexes, respectively, are released into an elution medium that is initially devoid of ligand. A short-time analysis of protocol I using successive substitutions yielded a corrected pre-factor for the In/Sur plot introduced by Wiley and Cunningham (Cell 25 (1981) 433). In contrast, neglecting the variation in receptor numbers yielded an approximation of protocol I that is valid for long times (e.g. tens of minutes). Similarly, the low cell-concentration limits of protocols II and III are derived by neglecting the concentration of free ligand. The simplicity of these approximations provides a simple and reliable method for estimating the parameters governing ligand kinetics, while their definitive nature implies that they can be used to verify the validity of the base model. This analysis also provides insight on the fast endocytosis and recycling limit of protocol III.

Animals↗
PubMed2004

Resonance energy transfer for assessing the molecular integrity of proteins for local delivery.

It remains unclear whether the limitations to the therapeutic potential of angiogenic growth factors stem from pharmacokinetic concerns related to inadequate delivery or from a reduced sensitivity of target tissues. Here, we report a novel method using resonance energy transfer to assess the molecular integrity of proteins after local delivery. As an example, we labeled fibroblast growth factor-2 with a fluorescent donor and nonfluorescent acceptor pair, tetramethylrhodamine and QSY-7, and demonstrate in an ex vivo bovine carotid artery model that this growth factor is not limited by proteolytic constraints imposed by the tissue. Our data indicate that FGF-2 is unlikely to be degraded within the arterial wall and suggest that pharmacokinetic limitations alone cannot fully explain the muted response seen thus far in therapeutic angiogenesis. In general, resonance energy transfer may serve as a novel approach to assess the molecular integrity of protein-based therapies in local delivery.

Animals↗
PubMed2004

Window of opportunity of cerebral hypothermia for postischemic white matter injury in the near-term fetal sheep.

Postresuscitation cerebral hypothermia is consistently neuroprotective in experimental preparations; however, its effects on white matter injury are poorly understood. Using a model of reversible cerebral ischemia in unanesthetized near-term fetal sheep, we examined the effects of cerebral hypothermia (fetal extradural temperature reduced from 39.4 +/- 0.1 degrees C to between 30 and 33 degrees C), induced at different times after reperfusion and continued for 72 hours after ischemia, on injury in the parasagittal white matter 5 days after ischemia. Cooling started within 90 minutes of reperfusion was associated with a significant increase in bioactive oligodendrocytes in the intragyral white matter compared with sham cooling (41 +/- 20 vs 18 +/- 11 per field, P < 0.05), increased myelin basic protein density and reduced expression of activated caspase-3 (14 +/- 12 vs 91 +/- 51, P < 0.05). Reactive microglia were profoundly suppressed compared with sham cooling (4 +/- 6 vs 38 +/- 18 per field, P < 0.05) with no effect on numbers of astrocytes. When cooling was delayed until 5.5 hours after reperfusion there was no significant effect on loss of oligodendrocytes (24 +/- 12 per field). In conclusion, hypothermia can effectively protect white matter after ischemia, but only if initiated early after the insult. Protection was closely associated with reduced expression of both activated caspase-3 and of reactive microglia.

Animals↗
PubMed2003

Quantitation of apoptotic activity following castration in human prostatic tissue in vivo.

BACKGROUND: Androgen deprivation induces apoptosis in the prostate. Representative data, quantitating apoptotic activity in human prostatic epithelium following androgen ablation, are lacking. METHODS: Human prostatic tissue was grafted beneath the renal capsule of intact male athymic mice and allowed to become established. The mice were castrated and specimens were harvested on post-castration day 0, 1, 2, 3, 4, 5, 7, 8, 9, 10, 14, 17, 18, and 21. Tissue was immediately fixed and apoptotic epithelial nuclei were identified. RESULTS: The percentage of terminal deoxynucleotidyl-transferase-mediated dUTP nick end-labeling (TUNEL) positive epithelial cells increased from a baseline of 0.026%, peaked on post-castration day 3 (1.54%), and returned to baseline by day 21. Mathematical analysis predicted that the observed apoptotic activity account for the loss of 87% of prostatic epithelial cells in 3 weeks. CONCLUSIONS: Post-castration apoptosis in human prostatic epithelium was low but was sufficient to account for the loss of nearly 90% of epithelial cells.

Androgens↗
PubMed2003

Impact of transport and drug properties on the local pharmacology of drug-eluting stents.

Drugs released from stents are driven by physiological transport forces, principally solvent-driven flow (convection) and random molecular agitation (diffusion). The relative strength of these two forces determines drug penetration and distribution in the arterial wall. Drug physicochemical factors can induce critical modulations to the primary distribution, both transiently and at steady state. Hydrophobic interactions and nonspecific binding, for example, can both result in tissue drug concentrations severalfold above administered concentration. Drug interaction with native proteins may also interfere with drug transfer at the stent-artery interface. These transport forces and tissue interactions can induce local drug concentrations even at steady state to vary by one or more orders of magnitude over the span of a few cells. To account for significant local variations in drug concentrations following stent-based delivery, rational design of vascular delivery systems requires consideration of drug distribution and tissue interactions on a local, continuum basis. Continuum analysis adapts traditional pharmacokinetics to the local environment by supplementing discrete global parameters of drug content with continuous local values of concentration, transport and binding. The interplay of these parameters with local flux conditions and drug and tissue properties defines the local drug distribution in space and over time. This type of analysis may well become increasingly relevant given the trend toward stent-based drug therapy in cardiovascular care.

Angioplasty, Balloon↗
PubMed2003

Insulin-like growth factor (IGF)-1 suppresses oligodendrocyte caspase-3 activation and increases glial proliferation after ischemia in near-term fetal sheep.

Insulin-like growth factor (IGF-1) markedly increases myelination and glial numbers in white matter after ischemia in near-term fetal sheep; however, it is unclear whether this is due to reduced cell loss or increased secondary proliferation. Brain injury was induced in near-term fetal sheep by 30 minutes of bilateral carotid artery occlusion. Ninety minutes after the occlusion, fetuses were given, intracerebroventricularly, either a single dose of IGF-1 (either 3 or 30 micro g), or 3 micro g followed by 3 micro g over 24 hours (3 + 3 micro g). White matter was assessed 4 days after reperfusion. Three micrograms, but not 30 micro g of IGF-1 prevented loss of oligodendrocytes and myelin basic protein density (P < 0.001) compared to the vehicle-treated ischemia controls. No additional effect was observed in the 3 + 3 micro g group. IGF-1 treatment was associated with reduced caspase-3 activation and increased glial proliferation in a similar dose-dependent manner. Caspase-3 was only expressed in oligodendrocytes that showed apoptotic morphology. Proliferating cell nuclear antigen co-localized with both oligodendrocytes and astrocytes and microglia. Thus, increased oligodendrocyte numbers after IGF-1 treatment is partly due to suppression of apoptosis, and partly to increased proliferation. In contrast, the increase in reactive glia was related only to proliferation. Speculatively, reactive glia may partly mediate IGF-1 white matter protection.

Animals↗
PubMed2003

Prion diseases: recent developments toward diagnostic tests.

Concerns about the large-scale European crisis of bovine spongiform encephalopathy, the finding of 1 infected cow in Alberta, Canada, in 2003, and the theoretical concern of prion transmissibility in blood have renewed interest in the development of rapid, minimally invasive diagnostic assays for prion diseases. Herein we review the pathologic features, clinical manifestations, diagnostic criteria, and recent developments that may lead to new diagnostic screening assays for prion diseases.

Activins↗
PubMed2002

Diagnostic accuracy and cost-effectiveness of contrast echocardiography on evaluation of cardiac function in technically very difficult patients in the intensive care unit.

Echocardiographic assessment of cardiac function can be quite difficult in the intensive care unit and may require transesophageal echocardiography (TEE). We therefore compared harmonic imaging alone or in combination with contrast to TEE in 32 consecutive patients in the intensive care units who were considered technically very difficult (> or =50% of the 16 segments not visualized from any view). Excellent or adequate endocardial visualization was achieved in 13% of segments with fundamental imaging, 34% with harmonic imaging, and 87% with contrast (p < 0.0001); the latter success rate was similar to TEE (87% vs 90%; p = NS). When TEE was used as the standard, agreement in exact interpretation of wall motion increased from 48% for fundamental imaging to 58% with harmonic imaging, and reached 70% with contrast (p <0.0001). Contrast had the best sensitivity (89%) for detecting wall motion abnormalities. Estimation of ejection fraction was possible in 31% with fundamental imaging, 50% with harmonic imaging, and in 97% with contrast. Ejection fraction quantitated by contrast enhancement correlated best with TEE (r = 0.91). Cost-effectiveness analysis revealed that contrast echo was cost-effective compared with TEE in determining regional and global ventricular function, with a cost saving of 3% and 17%, respectively. Thus, contrast echocardiography provides an accurate, safe, and cost-effective alternative to TEE for evaluating ventricular function in technically very difficult studies.

Albumins↗
PubMed2002

Sociodemographic characteristics and health related quality of life in men attending prostate cancer support groups.

PURPOSE: Prostate cancer can be associated with anxiety, depression and fears of recurrence and side effects of treatment. Support groups may help meet the needs of patients with cancer by providing treatment information and emotional support. We describe men in prostate cancer support groups and compare them to a national registry. METHODS AND METHODS: Men attending prostate cancer support groups in the San Francisco Bay area completed a questionnaire including sociodemographic and clinical characteristics, health related quality of life items, satisfaction with treatment, relief of prostate cancer symptoms and bother from perceived side effects of treatment. Patients in support groups were compared to men enrolled in a national prostate cancer registry (Cancer of the Prostate Strategic Urological Research Endeavor). RESULTS: Men attending support groups had higher annual income and education levels, lower median serum prostate specific antigen and higher cancer grades than men in Cancer of the Prostate Strategic Urological Research Endeavor. Clinical stage was comparable for the 2 groups. Men in support groups were satisfied with treatment and alleviation from symptoms. Adjusting for ethnicity, marital status, age and type of treatment, sexual function scores were higher in men who attended support groups (p = 0.001). There was no statistically significant difference in bowel and urinary function between groups, although urinary function approached statistical significance at p = 0.05. Sexual and bowel bother scores indicated less bother for men in support groups (p < or = 0.025). CONCLUSIONS: Men enrolled in support groups have unique sociodemographic characteristics. Their health related quality of life appears to be better than that of other men with prostate cancer. Whether this is related to support group participation is not known. Additional studies are required to determine whether routine support group participation improves outcomes in men with prostate cancer.

Aged↗
PubMed2002

Identification of potential prostate cancer preventive agents through induction of quinone reductase in vitro.

Human prostate cancer is characterized by an early and near-universal loss of expression of the phase 2 enzyme glutathione S-transferase-pi (GSTP1). We hypothesize that a mechanism-based prostate cancer preventive strategy could involve induction of phase 2 enzymes within the prostate to compensate for the loss of GSTP1 expression. NAD[P]H:(quinone-acceptor) oxidoreductase (quinone reductase or QR) enzymatic activity, a surrogate of phase 2 enzyme response, was measured after treating the human prostate cancer cell line LNCaP with known phase 2 enzyme-inducing agents from 10 distinct chemical classes. QR enzymatic activity was assayed in microtiter plates using the menadione-coupled reduction of tetrazolium dye. Degree of induction was expressed as fold-increase over control and corrected for toxicity. Compounds were also tested in LNCaP-5-aza-C, an LNCaP subline selected in 5-aza-cytidine that expresses GSTP1, and in the human liver cell line HepG2. LNCaP showed robust induction of QR enzymatic activity after treatment with a subset of the phase 2 enzyme-inducing agents. All Michael acceptors were effective at inducing QR activity in LNCaP. Some phenolic antioxidants, heavy metal salts, and quinones also significantly increased QR activity, although inducer potency varied widely within these classes of compounds. Some of the isothiocyanates, mercaptans, bifunctional inducers, and trivalent arsenicals also produced modest QR induction, but peroxides and dithiolethiones were inactive. LNCaP-5-aza-C and LNCaP responded similarly to all compounds, but the pattern of response for HepG2 differed significantly. The differences in QR responsiveness between the prostate cell lines and HepG2 suggest that prostate tissues may have a unique pattern of response to phase 2-inducing agents distinct from other tissue types. Our data suggest that measurement of QR induction in prostate cancer cell lines may help identify potential cancer chemopreventive agents effective in the prostate.

Anticarcinogenic Agents↗