Biomedical subjects

David Chen

Publications and source records attributed to David Chen.

At least 19 recordsLinked to original sources

PubMed2025

Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.

The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.

Humans↗

PubMed2006

Human neural stem cell grafts ameliorate motor neuron disease in SOD-1 transgenic rats.

BACKGROUND: Experimental therapeutics for degenerative and traumatic diseases of the nervous system have been recently enriched with the addition of neural stem cells (NSCs) as alternatives to fetal tissues for cell replacement. Neurodegenerative diseases present the additional problem that cell death signals may interfere with the viability of grafted cells. The adult spinal cord raises further challenges for NSC differentiation because of lack of intrinsic developmental potential and the negative outcomes of several prior attempts. METHOD: NSCs from human fetal spinal cord were grafted into the lumbar cord of SOD1 G93A rats. The differentiation fate of grafted NSCs and their effects on motor neuron number, locomotor performance, disease onset, and survival trends/longevity were assessed. Trophic mechanisms of observed clinical effects were explored with molecular and cellular methodologies. RESULT: Human NSCs showed extensive differentiation into neurons that formed synaptic contacts with host nerve cells and expressed and released glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor. NSC grafts delayed the onset and progression of the fulminant motor neuron disease typical of the rat SOD1 G93A model and extended the lifespan of these animals by more than 10 days, despite the restricted grafting schedule that was limited to the lumbar protuberance. CONCLUSION: NSC grafts can survive well in a neurodegenerative environment and exert powerful clinical effects; at least a portion of these effects may be related to the ability of these grafts to express and release motor neuron growth factors delivered to host motor neurons via graft-host connections.

Animals↗

PubMed2006

Automatic document classification of biological literature.

BACKGROUND: Document classification is a wide-spread problem with many applications, from organizing search engine snippets to spam filtering. We previously described Textpresso, a text-mining system for biological literature, which marks up full text according to a shallow ontology that includes terms of biological interest. This project investigates document classification in the context of biological literature, making use of the Textpresso markup of a corpus of Caenorhabditis elegans literature. RESULTS: We present a two-step text categorization algorithm to classify a corpus of C. elegans papers. Our classification method first uses a support vector machine-trained classifier, followed by a novel, phrase-based clustering algorithm. This clustering step autonomously creates cluster labels that are descriptive and understandable by humans. This clustering engine performed better on a standard test-set (Reuters 21578) compared to previously published results (F-value of 0.55 vs. 0.49), while producing cluster descriptions that appear more useful. A web interface allows researchers to quickly navigate through the hierarchy and look for documents that belong to a specific concept. CONCLUSION: We have demonstrated a simple method to classify biological documents that embodies an improvement over current methods. While the classification results are currently optimized for Caenorhabditis elegans papers by human-created rules, the classification engine can be adapted to different types of documents. We have demonstrated this by presenting a web interface that allows researchers to quickly navigate through the hierarchy and look for documents that belong to a specific concept.

Abstracting and Indexing↗

PubMed2006

Neuronal ensemble control of prosthetic devices by a human with tetraplegia.

Neuromotor prostheses (NMPs) aim to replace or restore lost motor functions in paralysed humans by routeing movement-related signals from the brain, around damaged parts of the nervous system, to external effectors. To translate preclinical results from intact animals to a clinically useful NMP, movement signals must persist in cortex after spinal cord injury and be engaged by movement intent when sensory inputs and limb movement are long absent. Furthermore, NMPs would require that intention-driven neuronal activity be converted into a control signal that enables useful tasks. Here we show initial results for a tetraplegic human (MN) using a pilot NMP. Neuronal ensemble activity recorded through a 96-microelectrode array implanted in primary motor cortex demonstrated that intended hand motion modulates cortical spiking patterns three years after spinal cord injury. Decoders were created, providing a 'neural cursor' with which MN opened simulated e-mail and operated devices such as a television, even while conversing. Furthermore, MN used neural control to open and close a prosthetic hand, and perform rudimentary actions with a multi-jointed robotic arm. These early results suggest that NMPs based upon intracortical neuronal ensemble spiking activity could provide a valuable new neurotechnology to restore independence for humans with paralysis.

Adult↗

PubMed2006

Size effects under a strong magnetic field: Hall effect induced by electron-surface scattering on thin gold films deposited onto mica substrates under high vacuum.

We report measurements of the Hall effect performed on 4 gold films evaporated onto mica substrates where the signal arises primarily from electron-surface scattering. The measurements were performed at low temperatures T (4 K < or = T < or = 50 K) under high magnetic field strengths B (1.5 T < or = B < or = 9 T), with B oriented perpendicular to the films.

Journal Article↗

PubMed2006

Combined immunosuppressive agents or CD4 antibodies prolong survival of human neural stem cell grafts and improve disease outcomes in amyotrophic lateral sclerosis transgenic mice.

Amyotrophic lateral sclerosis (ALS) is a target for cell-replacement therapies, including therapies based on human neural stem cells (NSCs). These therapies must be first tested in the appropriate animal models, including transgenic rodents harboring superoxide dismutase (SOD1) mutations linked to familial ALS. However, these rodent subjects reject discordant xenografts. In the present investigation, we grafted NSCs from human embryonic spinal cord into the ventral lumbar cord of 2-month-old SOD1-G93A transgenic mice. Animals were immunosuppressed with FK506, FK506 plus rapamycin, FK506 plus rapamycin plus mycophenolate mofetil, or CD4 antibodies. With FK506 monotherapy, human NSC grafts were rejected within 1 week, whereas combinations of FK506 with one or two of the other agents or CD4 antibodies protected grafts into end-stage illness (i.e., more than 2 months after grafting). The combination of FK506 with rapamycin appeared to be optimal with respect to efficacy and simplicity of administration. Graft protection was achieved via the blockade of CD4- and CD8-cell infiltration and attenuation of the microglial phagocytic response from the host. Surviving NSCs differentiated extensively into neurons that began to establish networks with host nerve cells, including alpha-motor neurons. Immunosuppressed animals with live cells showed later onset and a slower progression of motor neuron disease and lived longer compared with immunosuppressed control animals with dead NSC grafts. Our findings indicate that combined immunosuppression promotes the survival of human NSCs grafted in the spinal cord of SOD1-G93A mice and, in doing so, allows the differentiation of NSCs into neurons and leads to the improvement of key parameters of motor neuron disease.

Amyotrophic Lateral Sclerosis↗

PubMed2006

Prevalence of Clostridium difficile colonization at admission to rehabilitation.

OBJECTIVES: To assess the prevalence of intestinal colonization with Clostridium difficile (C. difficile) at admission to acute rehabilitation and to identify risk factors associated with colonization. DESIGN: Case-control study. PARTICIPANTS: Consecutive admissions to 2 rehabilitation units (spinal cord injury, brain injury and stroke). SETTING: Free-standing acute rehabilitation facility. INTERVENTIONS: Rectal swabs for culture for C. difficile were obtained at admission and cytotoxin assay performed on all culture positive specimens. Rates of colonization with cytotoxic C. difficile were calculated. Charts were reviewed for medical and demographic factors that may have predisposed patients to colonization, and for possible symptoms at the time of admission. MAIN OUTCOME MEASURES: Percentage of patients with culture and cytotoxin assay positive for C. difficile. Frequency of specific patient characteristics that could predispose to C. difficile colonization. RESULTS: Of admission stool samples, 16.4% tested positive for C. difficile; none of these patients had been identified as colonized before admission. No patients were discordant for C. difficile positivity on culture and presence of a toxigenic strain. No medical or demographic factors were associated with increased risk of colonization, including age (t(52)=-.748, P=.458, not significant [NS]), diarrhea within 24 hours of admission (chi(1)(2) test=.001, P=.973 [NS]), or use of oral or intravenous antibiotics at admission (chi(1)(2) test=.044, P=.834 [NS]). CONCLUSIONS: Patients admitted to acute rehabilitation may have an elevated rate of intestinal colonization with C. difficile without having clinical symptoms. No medical or demographic characteristics were found to be predictive of colonization, however, most of the patients admitted had more than 1 factor that may have increased their susceptibility to infection with this organism. Inadvertent transfer of this organism within the rehabilitation setting may occur because asymptomatic colonization is not recognized.

Adult↗

PubMed2005

Novel function of the flap endonuclease 1 complex in processing stalled DNA replication forks.

Restarting stalled replication forks partly depends on the break-induced recombination pathway, in which a DNA double-stranded break (DSB) is created on the stalled replication fork to initiate the downstream recombination cascades. Single-stranded DNA gaps accumulating on stalled replication forks are potential targets for endonucleases to generate DSBs. However, it is unclear how this process is executed and which nucleases are involved in eukaryotic cells. Here, we identify a novel gap endonuclease (GEN) activity of human flap endonuclease 1 (FEN-1), critical in resolving stalled replication fork. In response to replication arrest, FEN-1 interacts specifically with Werner syndrome protein for efficient fork cleavage. Replication protein A facilitates FEN-1 interaction with DNA bubble structures. Human FEN-1, but not the GEN-deficient mutant, E178A, was shown to rescue the defect in resistance to UV and camptothecin in a yeast FEN-1 null mutant.

Cell Extracts↗

PubMed2004

Differential effects of equiaxial and uniaxial strain on mesenchymal stem cells.

Bone marrow mesenchymal stem cells (MSCs) can differentiate into a variety of cell types, including vascular smooth muscle cells (SMCs), and have tremendous potential as a cell source for cardiovascular regeneration. We postulate that specific vascular environmental factors will promote MSC differentiation into SMCs. However, the effects of the vascular mechanical environment on MSCs have not been characterized. Here we show that mechanical strain regulated the expression of SMC markers in MSCs. Cyclic equiaxial strain downregulated SM alpha-actin and SM-22alpha in MSCs on collagen- or elastin-coated membranes after 1 day, and decreased alpha-actin in stress fibers. In contrast, cyclic uniaxial strain transiently increased the expression of SM alpha-actin and SM-22alpha after 1 day, which subsequently returned to basal levels after the cells aligned in the direction perpendicular to the strain direction. In addition, uniaxial but not equiaxial strain induced a transient increase of collagen I expression. DNA microarray experiments showed that uniaxial strain increased SMC markers and regulated the expression of matrix molecules without significantly changing the expression of the differentiation markers (e.g., alkaline phosphatase and collagen II) of other cell types. Our results suggest that uniaxial strain, which better mimics the type of mechanical strain experienced by SMCs, may promote MSC differentiation into SMCs if cell orientation can be controlled. This study demonstrates the differential effects of equiaxial and uniaxial strain, advances our understanding of the mechanical regulation of stem cells, and provides a rational basis for engineering MSCs for vascular tissue engineering and regeneration.

Biomarkers↗

PubMed2004

Native osteoprotegerin gene transfer inhibits the development of murine osteolytic bone disease induced by tumor xenografts.

OBJECTIVE: Multiple myeloma is a plasma cell malignancy characterized by the development of osteolytic lesions leading to bone pain, pathologic fractures, and hypercalcemia. Osteoprotegerin (OPG) is a potent inhibitor of osteoclast differentiation and activation, but is limited as a therapeutic agent due to its short circulating half-life. In order to overcome these limitations, the therapeutic effects of native OPG gene transfer are examined. MATERIALS AND METHODS: We used replication-incompetent lentiviral vectors to transfer the unmodified, native human OPG gene ex vivo into human ARH-77 cells injected into severe combined immunodeficient (SCID) mice, to determine gene transfer efficiency as well as the impact on disease progression in this in vivo model. RESULTS: We can efficiently transfer and express either the LacZ marker gene or the native human OPG gene into human ARH-77 cells. Moreover, transfer of the OPG gene into ARH-77 cells reduces the development of osteolytic bony lesions when these cells are injected into SCID mice, compared to mice injected with either unmodified ARH-77 cells or ARH-77 cells transduced with the OPG gene in the antisense orientation. This therapeutic effect was manifested as a reduction in vertebral compression deformities and in the number and size of long-bone osteolytic lesions on skeletal radiographs, as well as a decrease in osteoclast surface on histologic analysis. CONCLUSIONS: A lentiviral vector can efficiently transfer the native human OPG gene to myeloma cells ex vivo and inhibit myeloma-induced bone destruction, thereby suggesting a therapeutic potential for unmodified, native OPG gene transfer for osteoclast-dependent skeletal disorders.

Animals↗

PubMed2004

Syndecan-1 expression in locally invasive and metastatic prostate cancer.

OBJECTIVES: To determine the significance of syndecan-1 expression, a cell-surface heparan sulfate proteoglycan in localized and metastatic prostate cancer. METHODS: We performed a retrospective analysis of 76 men with Gleason sum 6 or 7 prostate cancer treated by radical prostatectomy and a separate cohort of 75 men with metastatic prostate cancer. Syndecan-1 immunoreactivity was measured in primary prostate specimens or in samples from metastatic sites and correlated with patient outcome. RESULTS: Syndecan-1 was expressed in normal basal and secretory epithelial cells, 26% of radical prostatectomy specimens, and 35% of metastatic disease. No association was found between syndecan-1 positivity and prostate-specific antigen recurrence in the collective cohort of Gleason sum 6 and 7 cancers. However, when stratified by Gleason sum, syndecan-1 immunoreactivity (immunoreactivity score 150 or greater) was associated with a greater recurrence rate in Gleason sum 7 cancers. Expression of syndecan-1 was significantly greater in soft tissue than in bone metastasis (P = 0.048, Fisher's exact test). CONCLUSIONS: Consistent with a possible biochemical role for syndecan-1 in prostate cancer progression and metastasis, syndecan-1 expression correlated with serologic recurrence in Gleason sum 7 prostate cancer and was highly expressed in soft-tissue metastases.

Adenocarcinoma↗

PubMed2004

Daily vs twice daily enoxaparin in the prevention of venous thromboembolic disorders during rehabilitation following acute spinal cord injury.

BACKGROUND: Subcutaneous administration of low molecular weight heparin (eg, enoxaparin) has been shown to be safe and effective in the prevention of acute venous thromboembolic (TE) disease following acute spinal cord injury (SCI) in the rehabilitation setting. However, emerging evidence suggests that different dosing strategies may be equivalent. OBJECTIVE: To determine whether subcutaneous enoxaparin, 40 mg once daily, when compared with subcutaneous enoxaparin, 30 mg twice daily, is equally safe and effective in the prevention of venous TE disease in patients with SCI. DESIGN: Retrospective chart review. SETTING: A freestanding, inpatient, acute, rehabilitation hospital. PATIENTS: One hundred and twenty-nine patients admitted from June 2000 through June 2002 for inpatient rehabilitation following an acute SCI who received either enoxaparin, 40 mg once daily, or enoxaparin, 30 mg twice daily, for prophylaxis for TE disease. RESULTS: Equivalent prophylaxis efficacy was seen in both enoxaparin groups. Symptomatic venous thromboembolism did not differ, with deep vein thromboses occurring in 1 of 49 (2.0%) patients receiving twice-daily enoxaparin, and 1 of 80 (1.25%) patients receiving once-daily enoxaparin (chi2 = 0.125, NS). Pulmonary embolism was seen in 1 of 49 (2.0%) patients treated with twice-daily enoxaparin and in none of the patients in the once-daily group (chi2 = 1.64, NS). Bleeding complications also did not differ between the 2 treatment groups; these were observed in 2 of 49 (4.1%) patients receiving twice-daily enoxaparin and in 5 of 80 (6.3%) patients receiving once-daily enoxaparin (chi2 = 0.228, NS). CONCLUSION: Subcutaneous enoxaparin administered once or twice daily is equally effective for the prevention of venous TE disease. Both dosing strategies are associated with a low incidence of bleeding in patients with SCI who are undergoing rehabilitation.

Drug Administration Schedule↗

PubMed2004

Perceived quality of care and outcomes following spinal cord injury: minority status in the context of multiple predictors.

OBJECTIVE: To determine whether patients with spinal cord injury (SCI) who are members of minority groups experience a disadvantage with regard to quality of care, and investigate predictors of perceived quality of care and indicators of outcome. DESIGN: Correlational analysis of longitudinal data. SAMPLE: One hundred and forty-three individuals with SCI in the first year following injury (43.3% tetraplegia, 56.7% paraplegia; 53.6% of total had complete injuries). SETTING: Hospital and postdischarge (usually outpatient) care at 3 SCI model systems. MAIN OUTCOME MEASURES: Perceived quality of acute, rehabilitative, and continuing care rated by patients according to standard format. Objective indicators of amount of care (eg, length of stay [LOS], charges) and outcomes (eg, medical complications, Functional Independence Measure [FIM] scores, a life satisfaction measure [the Diener Scale], and the Craig Handicap and Reporting Technique [CHART; a community participation scale]). RESULTS: Minorities did not report statistically significant differences in perceived quality of care or other indicators (eg, amount of care, medical complications, FIM gain, life satisfaction, and CHART scores) compared with other groups. Severity of injury affected LOS and activity outcomes. Satisfaction with medical care before the injury significantly predicted perceived quality of acute hospital care, inpatient rehabilitation, and continuing care (P < 0.03, 0.02, and 0.02, respectively). CONCLUSION: A number of factors may affect variations in perceived quality of care and outcomes, but ethnicity is not always the most important predictor. Asking patients about their satisfaction with previous care can assist in distinguishing satisfaction with current care from pre-existing biases.

Adult↗

PubMed2004

Management of the anophthalmic socket in pediatric patients.

PURPOSE OF REVIEW: The management of the pediatric anophthalmic socket is distinguished from adult anophthalmia, because normal socket and facial development is dependent on orbital growth. Recent literature on managing anophthalmic sockets is discussed with a focus on the pediatric patient. RECENT FINDINGS: There are many studies discussing the management of the anophthalmic socket, but few are randomized clinical studies. Although the management of anophthalmia in the child is fraught with challenges and nuances, the principal aim is to encourage socket growth. SUMMARY: Both congenital and acquired pediatric anophthalmia are discussed. Surgical decisions, choice of orbital implants, various methods of socket expansion, and socket reconstructions are examined.

Anophthalmos↗

PubMed2004

A new XRCC1-containing complex and its role in cellular survival of methyl methanesulfonate treatment.

DNA single-strand break repair (SSBR) is important for maintaining genome stability and homeostasis. The current SSBR model derived from an in vitro-reconstituted reaction suggests that the SSBR complex mediated by X-ray repair cross-complementing protein 1 (XRCC1) is assembled sequentially at the site of damage. In this study, we provide biochemical data to demonstrate that two preformed XRCC1 protein complexes exist in cycling HeLa cells. One complex contains known enzymes that are important for SSBR, including DNA ligase 3 (DNL3), polynucleotide kinase 3'-phosphatase, and polymerase beta; the other is a new complex that contains DNL3 and the ataxia with oculomotor apraxia type 1 (AOA) gene product aprataxin. We report the characterization of the new XRCC1 complex. XRCC1 is phosphorylated in vivo and in vitro by CK2, and CK2 phosphorylation of XRCC1 on S518, T519, and T523 largely determines aprataxin binding to XRCC1 though its FHA domain. An acute loss of aprataxin by small interfering RNA renders HeLa cells sensitive to methyl methanesulfonate treatment by a mechanism of shortened half-life of XRCC1. Thus, aprataxin plays a role to maintain the steady-state protein level of XRCC1. Collectively, these data provide insights into the SSBR molecular machinery in the cell and point to the involvement of aprataxin in SSBR, thus linking SSBR to the neurological disease AOA.

Amino Acids↗

PubMed2004

Optimizing genetic circuits by global sensitivity analysis.

Artificial genetic circuits are becoming important tools for controlling cellular behavior and studying molecular biosystems. To genetically optimize the properties of complex circuits in a practically feasible fashion, it is necessary to identify the best genes and/or their regulatory components as mutation targets to avoid the mutation experiments being wasted on ineffective regions, but this goal is generally not achievable by current methods. The Random Sampling-High Dimensional Model Representation (RS-HDMR) algorithm is employed in this work as a global sensitivity analysis technique to estimate the sensitivities of the circuit properties with respect to the circuit model parameters, such as rate constants, without knowing the precise parameter values. The sensitivity information can then guide the selection of the optimal mutation targets and thereby reduce the laboratory effort. As a proof of principle, the in vivo effects of 16 pairwise mutations on the properties of a genetic inverter were compared against the RS-HDMR predictions, and the algorithm not only showed good consistency with laboratory results but also revealed useful information, such as different optimal mutation targets for optimizing different circuit properties, not available from previous experiments and modeling.

Algorithms↗

PubMed2003

A model to predict the development of mental status changes of unclear cause after liver transplantation.

Postoperative mental status changes are common after liver transplantation (LT). A clear cause of these mental status changes cannot be identified in a significant proportion of patients. In adult liver transplant recipients, our goals are to: (1) identify independent predictors for the development of post-LT mental status changes of unclear cause and (2) derive a practical formula to predict the risk for developing this complication by using simple clinical parameters. Eligible patients had documented mental status changes of at least 3 days' duration, occurring within 1 month of LT. Exclusion criteria were known structural brain disorders, major organ dysfunction, or metabolic causes of altered mentation. Age- and sex-matched controls were liver transplant recipients without post-LT neurological sequelae. Data were collected on preoperative, intraoperative, and postoperative variables. Univariate and multivariate analyses were performed to detect factors predictive of the development of post-LT mental status of unclear cause. There were 40 cases and 40 controls. Independent predictors of mental status changes of unclear cause included alcoholic and metabolic liver diseases; pre-LT mechanical ventilation; Model for End-Stage Liver Disease (MELD) score greater than 15; and nonelective LT. Using these four preoperative factors, a simple predictive rule was developed. Risk for developing altered mental status of unclear cause after LT was 78% to 89% if all four predictors were present versus 0.8% to 2.4% if no predictors were present. In conclusion, alcoholic and metabolic liver diseases, pre-LT mechanical ventilation, MELD score greater than 15, and nonelective LT are independent predictive factors for post-LT altered mental status changes of unclear cause. A simple model can be used to calculate the risk for developing altered mental status post-LT.

Case-Control Studies↗

PubMed2003

Hypothesis for a common basis for neuroprotection in glaucoma and Alzheimer's disease: anti-apoptosis by alpha-2-adrenergic receptor activation.

Recent studies have suggested glaucomatous loss of retinal ganglion cells and their axons in Alzheimer's disease. Amyloid beta peptides and phosphorylated tau protein have been implicated in the selective regional neuronal loss and protein accumulations characteristic of Alzheimer's disease. Similar protein accumulations are not present on glaucomatous retinal ganglion cells. Neurons die in both Alzheimer's disease and glaucoma by apoptosis, although the signaling pathways for neuronal degradation appear to differ in the two diseases. Alzheimer's disease features a loss of locus ceruleus noradrenergic neurons, which send axon terminals to the brain regions suffering neuronal apoptosis and results in reductions in noradrenaline in those regions. Activation of alpha-2 adrenergic receptors reduces neuronal apoptosis, in part through a protein kinase B (Akt)-dependent signaling pathway. Loss of noradrenaline innervation facilitates neuronal apoptosis in Alzheimer's disease models and may act similarly in glaucoma. Alpha-2 adrenergic receptor agonists offer the potential to slow the neuronal loss in both diseases by compensating for lost noradrenaline innervation.

Adrenergic alpha-Agonists↗