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Biomedical subjects

Richard Lee

Publications and source records attributed to Richard Lee.

15 recordsLinked to original sources
PubMed2026

Comprehensive transcriptomics and proteomics analysis of neointima formation in human saphenous vein: implications for bypass graft disease.

Human saphenous veins (SVs) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima formation. Little is known, however, regarding the cellular, transcriptomic, and proteomic dynamics of neointima formation in human veins. Here, we performed transcriptomics and proteomics analysis in an ex vivo tissue culture model of neointima formation in human SVs procured for CABG surgery. Histological examination demonstrated significant elastin degradation and neointima formation (indicated by increased neointima area and neointima-to-media ratio) in SVs subjected to tissue culture. Analysis of data from 72 patients suggests that the progression of SV remodeling and neointima formation differs according to sex and body mass index, which is negatively associated with neointima formation in males only. RNA sequencing demonstrated upregulation of proinflammatory and proliferation-related genes during neointima formation and identified novel processes, including increased cellular stress and DNA damage responses, reflecting tissue trauma associated with vein harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics, used to infer regionally enriched gene expression, suggested dynamic alterations in fibroblast and vascular smooth muscle cell (VSMC) states during neointima formation. Specifically, we identified the emergence of HES1+ and matrix metalloproteinase 2- and 14-positive (MMP2+/MMP14+) expression in VSMCs and fibroblasts, respectively, during neointima formation. Furthermore, our data suggest that MIR647, identified through screening, maintains VSMC contractile gene expression. Our findings suggest dynamic transcriptomic and proteomic changes during neointima formation in human veins and provide useful mechanistic information for the pathogenesis of SV graft disease.NEW & NOTEWORTHY Using multiomics and spatial transcriptomics, we uncover dynamic molecular and cellular changes driving neointima proliferation in human saphenous veins, the most common conduit for bypass surgery. Our study highlights sex- and body mass index-associated differences, novel fibroblast and smooth muscle cell states, and a role for microRNA-647 in preserving vascular contractile phenotype. These findings provide new insight into the mechanisms of vein graft failure and may guide future strategies to improve coronary bypass outcomes.

Humans↗
PubMed2003

Transcatheter closure of recurrent postmyocardial infarction ventricular septal defects utilizing the Amplatzer postinfarction VSD device: a case series.

The initial therapy for postmyocardial infarction ventricular septal defects is surgical repair of the defect. Unfortunately, a significant number of patients develop recurrent ventricular septal defects (VSDs) following operative repair. Transcatheter closure offers an alternative to reoperation in these critically ill patients. We present a series of four patients in whom recurrent ventricular septal defects were closed using an Amplatzer VSD device.

Aged↗
PubMed2003

Postgrafting immunosuppression with sirolimus and cyclosporine facilitates stable mixed hematopoietic chimerism in dogs given sublethal total body irradiation before marrow transplantation from DLA-identical littermates.

We studied the value of postgrafting immunosuppression with sirolimus (SRL) and cyclosporine (CSP) in enhancing engraftment of dog leukocyte antigen-identical littermate marrow after nonmyeloablative conditioning in a canine model. Dogs received either 2 Gy (n=7) or 1 Gy (n=5) total body irradiation (TBI), followed by postgrafting immunosuppression with SRL and CSP. In the first cohort, all 7 dogs showed rapid initial engraftment. One engrafted dog died on day 21 due to hemorrhagic pneumonitis. Durable engraftment was seen in 5 of 6 remaining dogs, with a median follow-up of >48 (range, >32 to >56) weeks. The sixth dog rejected the marrow graft (as assessed by variable number of tandem repeats) at 11 weeks; however, a subsequent skin graft from the same marrow donor did not undergo acute cellular rejection, suggesting donor-specific tolerance. In the second cohort, all 5 dogs rejected the marrow graft at a median of 9 weeks (range, 3-11 weeks). We conclude that SRL/CSP is as effective as a previously studied combination of mycophenolate mofetil and CSP at establishing durable marrow engraftment after sublethal conditioning.

Animals↗
PubMed2003

Ethics seminars: health care proxies and suicidal patients.

Advance directives, health care proxies, and living wills are forms of advance planning that permit patients to make decisions regarding their health care and are used when the patient becomes incapacitated. The ethics of allowing these forms of advance planning are questioned when the patient has attempted suicide. The authors present an ethical analysis of a case of an elder patient who overdosed on sustained-release diltiazem and had a health care proxy who wanted all treatments stopped.

Advance Directives↗
PubMed2002

Reoperative transmyocardial laser revascularization for late recurrent angina.

Transmyocardial laser revascularization (TMR) reduces anginal class and is indicated for severely symptomatic patients who are not candidates for conventional revascularization. This report describes a 72-year-old man who presented 4 years following initially successful TMR with recurrent angina refractory to maximal medical management. Reoperative TMR was performed with substantial improvement in angina and functional class.

Aged↗
PubMed2002

PDE7A is expressed in human B-lymphocytes and is up-regulated by elevation of intracellular cAMP.

PDE7A is a recently described 3',5'-cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase (PDE) whose expression has been detected in T-cells. As treatment with the methylxanthine theophylline, a nonspecific PDE inhibitor, induces apoptosis in leukemic cells from patients with the B-lineage malignancy chronic lymphocytic leukemia (CLL), we sought to determine if PDE7A was a target of theophylline therapy in such cells. Western analysis revealed expression of PDE7A in normal human splenic B-cells, primary CLL cells, and in a CLL-derived cell line (WSU-CLL). Among the six cAMP PDEs (PDE1B, PDE3B, PDE4A, PDE4B, PDE4D, and PDE7) examined in WSU-CLL, only PDE7A levels were augmented by treatment with methylxanthines. The activity of PDE7A isolated from the WSU-CLL cell line by immunoprecipitation was inhibited by theophylline and IBMX with IC50 values of 343.5 and 8.6 microM, respectively. WSU-CLL PDE7A was also up-regulated by a novel specific inhibitor (IC242), which inhibits PDE7A from WSU-CLL cells with an IC50 value of 0.84 microM. IC242-mediated up-regulation of PDE7A was blocked by the protein kinase A (PKA) inhibitor H-89.

1-Methyl-3-isobutylxanthine↗
PubMed2002

Treatment outcomes in localized prostate cancer: a patient-oriented approach.

Although there are many treatment options available to patients with localized prostate cancer, it remains unclear which is superior in terms of overall survival. Patients, therefore, consider a number of other less traditional outcomes when choosing therapy for newly diagnosed disease. In particular, because each treatment can have a unique and highly individual impact on various aspects of the patient's health and daily life, there is a need for a patient-oriented approach to outcomes that accounts for both quantity and quality of life after therapy. Although all therapies can result in some degree of sexual, urinary, or bowel dysfunction, the degree of bother patients experience does not always correlate with the objective degree of symptoms present. Providers must, therefore, make the important distinction between function and bother when presenting the risks for each therapy to patients. Patients should also be aware that if they experience particular bother from their sexual or urinary dysfunction, there are therapies available that will improve erectile function or lower urinary tract voiding dysfunction and result in better quality of life. Finally, when discussing the probability of unwanted outcomes, such as urinary, sexual, or bowel dysfunction after treatment for localized prostate cancer, providers should strive to present risks by using a number of different styles, facilitating understanding, and leading to a truly informed decision that best fits the patient's goals.

Brachytherapy↗
PubMed2002

Iterative normalization of cDNA microarray data.

This paper describes a new approach to normalizing microarray expression data. The novel feature is to unify the tasks of estimating normalization coefficients and identifying control gene set. Unification is realized by constructing a window function over the scatter plot defining the subset of constantly expressed genes and by affecting optimization using an iterative procedure. The structure of window function gates contributions to the control gene set used to estimate normalization coefficients. This window measures the consistency of the matched neighborhoods in the scatter plot and provides a means of rejecting control gene outliers. The recovery of normalizational regression and control gene selection are interleaved and are realized by applying coupled operations to the mean square error function. In this way, the two processes bootstrap one another. We evaluate the technique on real microarray data from breast cancer cell lines and complement the experiment with a data cluster visualization study.

Algorithms↗
PubMed2002

An investigation of a new amorphous silicon electronic portal imaging device for transit dosimetry.

The relationship between the pixel value and exit dose was investigated for a new commercially available amorphous silicon electronic portal imaging device. The pixel to dose mapping function was established to be linear for detector distances between 116.5 cm to 150 cm from the source, radiation field sizes from 5 x 5 cm2 to 20 x 20 cm2 and beam energies of 6 to 18 MV. Coefficients in the mapping function were found to be dependent on beam energy and field size. Open and wedged field profiles measured with the device showed agreement to a maximum of 5% and 8%, respectively, as compared to film. A comparison of relative transmission measurements between the EPID and ion chamber indicate a maximum deviation of 6% and 2% at 6 and 18 MV, respectively, for an attenuator thickness of 21 cm and SDD > or = 130 cm. It was found that accuracies of better than 1% could be obtained if detector position and field size specific fitting parameters were used to generate unique mapping functions for each configuration.

Models, Statistical↗
PubMed2002

Inhibition of PDE3B augments PDE4 inhibitor-induced apoptosis in a subset of patients with chronic lymphocytic leukemia.

PURPOSE: cAMP phosphodiesterase (PDE) 4 is a family of enzymes the inhibition of which induces chronic lymphocytic leukemia (CLL) apoptosis. However, leukemic cells from a subset of CLL patients are relatively resistant to treatment with the PDE4 inhibitor rolipram, particularly when this drug is used in the absence of an adenylate cyclase stimulus such as forskolin. Elevated cAMP levels induce compensatory up-regulation of several cyclic nucleotide PDE families in other model systems. We here examine the hypothesis that CLL cells that survive treatment with rolipram do so as a result of residual PDE activity that is not inhibited by this drug. EXPERIMENTAL DESIGN: We examined by Western analysis the effect of rolipram treatment on CLL expression of PDE3B, PDE4A, PDE4B, PDE4D, and PDE7A. We also examined the ability of rolipram (PDE4 inhibitor) or cilostamide (PDE3 inhibitor), alone or together, to induce apoptosis or elevate cyclic AMP in leukemic cells from patients with CLL. RESULTS: Rolipram increased levels of PDE4B and, to a variable extent, PDE4D. When combined with forskolin, rolipram also increased levels of a second family of PDEs, PDE3B. Addition of the specific PDE3 inhibitor, cilostamide, modestly augmented rolipram-induced apoptosis in five of seven "rolipram-resistant" CLL samples. CONCLUSIONS: Although this work confirms that PDE4 appears to be the most important PDE target for induction of apoptosis in CLL, combination therapy with PDE3 and PDE4 inhibitors or use of dual-selective drugs may be of benefit in a subset of relatively PDE4-inhibitor resistant CLL patients.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMedDate not supplied

Percutaneous central dual-lumen catheter for apheresis in the canine.

The dog model has been used extensively for preclinical hematopoietic stem-cell transplantation (HSCT) research. Apheresis of granulocyte colony-stimulating factor mobilized peripheral blood donor stem cells is increasingly being used for transplantation. We investigated the use of a percutaneous dual-lumen central venous catheter (DLC) for large-volume apheresis in the dog model. Fifteen dogs undergoing apheresis for HSCT had catheters placed percutaneously. Apheresis was performed in all 15 dogs without complications. In comparison to the previous techniques of arteriovenous shunts for apheresis, the DLC demonstrates comparable efficacy, is more efficient and cost-effective, and is associated with a lower complication rate. We demonstrate that the percutaneous DLC is the preferable method for apheresis in the dog model.

Animals↗