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Carboxymethyl Hyaluronan-Stabilized Nanoparticles for Anticancer Drug Delivery. - International journal of cell biology
Carboxymethyl hyaluronic acid (CMHA) is a semisynthetic derivative of HA that is recognized by HA binding proteins but contains an additional carboxylic acid on some of the 6-hydroxyl groups of the N-acetyl glucosamine sugar units. These studies tested the ability of CMHA to stabilize the formation of calcium phosphate nanoparticles and evaluated their potential to target therapy resistant, CD44(+)/CD24(-/low) human breast cancer cells (BT-474EMT). CMHA stabilized particles (nCaP(CMHA)) were loaded with the chemotherapy drug cis-diamminedichloroplatinum(II) (CDDP) to form nCaP(CMHA)CDDP. nCaP(CMHA)CDDP was determined to be poorly crystalline hydroxyapatite, 200â€‰nm in diameter with a -43â€‰mV zeta potential. nCaP(CMHA)CDDP exhibited a two-day burst release of CDDP that tapered resulting in 86% release by 7 days. Surface plasmon resonance showed that nCaP(CMHA)CDDP binds to CD44, but less effectively than CMHA or hyaluronan. nCaP(CMHA-AF488) was taken up by CD44(+)/CD24(-) BT-474EMT breast cancer cells within 18 hours. nCaP(CMHA)CDDP was as cytotoxic as free CDDP against the BT-474EMT cells. Subcutaneous BT-474EMT tumors were more reproducibly inhibited by a near tumor dose of 2.8â€‰mg/kg CDDP than a 7â€‰mg/kg dose nCaP(CMHA)CDDP. This was likely due to a lack of distribution of nCaP(CMHA)CDDP throughout the dense tumor tissue that limited drug diffusion.
Epithelial-mesenchymal transition induces similar metabolic alterations in two independent breast cancer cell lines. - Cancer letters
Epithelial-mesenchymal transition (EMT) induces invasive properties in epithelial tumors and promotes metastasis. Although EMT-mediated cellular and molecular changes are well understood, very little is known about EMT-induced metabolic changes. HER2-positive BT-474 breast cancer cells were induced to undergo a stable EMT using mammosphere culture, as previously described by us for the ERÎ±-positive MCF-7 breast cancer cells. Two epithelial breast cancer cell lines (BT-474 and MCF-7) were compared to their respective EMT-derived mesenchymal progeny (BT-474(EMT) and MCF-7(EMT)) for changes in metabolic pathways including glycolysis, glycogen metabolism, anabolic pathways and gluconeogenesis. Both EMT-derived cells displayed enhanced aerobic glycolysis along with the overexpression of specific glucose transporters, lactate dehydrogenase isoforms, monocarboxylate transporters and glycogen phosphorylase isoform. In contrast, both EMT-derived cells suppressed the expression of crucial enzymes in anabolic pathways and gluconeogenesis. STAT3, a transcription factor involved in tumor initiation and progression, plays a role in the EMT-related changes in the expression of specific enzymes and transporters. This study provides a broad overview of similar metabolic changes induced by EMT in two independent breast cancer cell lines. These metabolic changes may provide novel therapeutic targets for metastatic breast cancer.Copyright Â© 2015 Elsevier Ireland Ltd. All rights reserved.
Higher-than-predicted saltation threshold wind speeds on Titan. - Nature
Titan, the largest satellite of Saturn, exhibits extensive aeolian, that is, wind-formed, dunes, features previously identified exclusively on Earth, Mars and Venus. Wind tunnel data collected under ambient and planetary-analogue conditions inform our models of aeolian processes on the terrestrial planets. However, the accuracy of these widely used formulations in predicting the threshold wind speeds required to move sand by saltation, or by short bounces, has not been tested under conditions relevant for non-terrestrial planets. Here we derive saltation threshold wind speeds under the thick-atmosphere, low-gravity and low-sediment-density conditions on Titan, using a high-pressure wind tunnel refurbished to simulate the appropriate kinematic viscosity for the near-surface atmosphere of Titan. The experimentally derived saltation threshold wind speeds are higher than those predicted by models based on terrestrial-analogue experiments, indicating the limitations of these models for such extreme conditions. The models can be reconciled with the experimental results by inclusion of the extremely low ratio of particle density to fluid density on Titan. Whereas the density ratio term enables accurate modelling of aeolian entrainment in thick atmospheres, such as those inferred for some extrasolar planets, our results also indicate that for environments with high density ratios, such as in jets on icy satellites or in tenuous atmospheres or exospheres, the correction for low-density-ratio conditions is not required.
Structuring a written examination to assess ASBH health care ethics consultation core knowledge competencies. - The American journal of bioethics : AJOB
As clinical ethics consultants move toward professionalization, the process of certifying individual consultants or accrediting programs will be discussed and debated. With certification, some entity must be established or ordained to oversee the standards and procedures. If the process evolves like other professions, it seems plausible that it will eventually include a written examination to evaluate the core knowledge competencies that individual practitioners should possess to meet peer practice standards. The American Society for Bioethics and Humanities (ASBH) has published core knowledge competencies for many years that are accepted by experts as the prevailing standard. Probably any written examination will be based upon the ASBH core knowledge competencies. However, much remains to be done before any examination may be offered. In particular, it seems likely that a recognized examining board must create and validate examination questions and structure the examination so as to establish meaningful, defensible parameters after dealing with such challenging questions as: Should the certifying examination be multiple choice or short-answer essay? How should the test be graded? What should the pass rate be? How may the examination be best administered? To advance the field of health care ethics consultation, thought leaders should start to focus on the written examination possibilities, to date unaddressed carefully in the literature. Examination models-both objective and written-must be explored as a viable strategy about how the field of health care ethics consultations can grow toward professionalization.
Using a theoretical predictive tool for the analysis of recent health department inspections at outbreak restaurants and relation of this information to foodborne illness likelihood. - Journal of food protection
Because U.S. restaurants are inspected at least annually against criteria in the U.S. Food and Drug Administration Model Food Code, large amounts of data are generated and should be systematically reviewed. The purpose of this study was to determine the relationships among the data obtained through health department inspections, the contributing factors to foodborne illness identified by the Centers for Disease Control and Prevention, and the risks of outbreaks of norovirus, Salmonella, and Clostridium perfringens infection associated with a specific restaurant. These agents were chosen for the analysis because they cause the majority of foodborne illnesses. A theoretical predictive assessment tool was built that extracts data from routine health department inspection reports for specific restaurants to establish a risk profile for each restaurant and identify the likelihood of a norovirus, Salmonella, or C. perfringens outbreak at that restaurant. The tool was used to examine inspection reports from restaurants known to have had confirmed norovirus, Salmonella, and C. perfringens outbreaks. Although evaluation of an extensive data set revealed lack of an overall association between outbreak inspection scores and routine inspection scores obtained at outbreak restaurant locations, certain specific violations were significantly more likely to be recorded. Significant differences in types of violations recorded during outbreak and routine inspections were determined. When risks based on violation type can be identified, targeted actions may be able to be prioritized and implemented to help decrease illnesses.
Health department inspection criteria more likely to be associated with outbreak restaurants in Minnesota. - Journal of food protection
Millions of routine restaurant inspections are performed each year in the United States, and the Centers for Disease Control and Prevention has reported that a majority of foodborne illness outbreaks occur in restaurant settings. In an attempt to relate the data collected during inspections in Minnesota to illness likelihood, data from routine inspections conducted at outbreak restaurants were compared with data from routine inspections conducted at nonoutbreak restaurants. The goal was to identify differences in recorded violations. Significantly more violations were recorded at restaurants that had outbreaks. The majority of these violations were related to contamination in the facility and environment and to food handling procedures. Relative risks also were calculated for violations significantly more likely to occur at locations that had outbreaks of norovirus infection, Clostridium perfringens infection or toxin-type illness, and Salmonella infection. These three pathogens are estimated to cause the majority of foodborne illnesses in the United States. Meta-analysis of composited data for the three pathogens revealed 11 violations significantly more likely (Î± < 0.05) to be identified during routine inspections at outbreak restaurants than during inspections at nonoutbreak restaurants. Application of this information permits assessment of health department inspection data in a consistent fashion. This approach can help identify criteria more likely to be associated with outbreak locations and allow operators to focus on interventions that will have the most significant impact in higher risk establishments.
The effect of completing a surrogacy information and decision-making tool upon admission to an intensive care unit on length of stay and charges. - The Journal of clinical ethics
Many critically ill patients in intensive care units (ICUs) are unable to communicate their wishes about goals of care, particularly about the use of life-sustaining treatments. Surrogates and clinicians struggle with medical decisions because of a lack of clarity regarding patients' preferences, leading to prolonged hospitalizations and increased costs. This project focused on the development and implementation of a tool to facilitate a better communication process by (1) assuring the early identification of a surrogate if indicated on admission and (2) clarifying the decision-making standards that the surrogate was to use when participating in decision making. Before introducing the tool into the admissions routine, the staff were educated about its use and value to the decision-making process. PROJECT AND METHODS: The study was to determine if early use of a simple method of identifying a patient's surrogate and treatment preferences might impact length of stay (LOS) and total hospital charges. A pre- and post-intervention study design was used. Nurses completed the surrogacy information tool for all patients upon admission to the neuroscience ICU. Subjects (total N = 203) were critically ill patients who had been on a mechanical ventilator for 96 hours or longer, or in the ICU for seven days or longer.The project included staff education on biomedical ethics, critical communication skills, early identification of families and staff in crisis, and use of a simple tool to document patients' surrogates and previously expressed care wishes. Data on hospital LOS and hospital charges were collected through a retrospective review of medical records for similar four-month time frames pre- and post-implementation of the assessment tool.Significant differences were found between pre- and post-groups in terms of hospital LOS (F = 6.39, p = .01) and total hospital charges (F = 7.03, p = .009).Project findings indicate that the use of a simple admission assessment tool, supported by staff education about its completion, use, and available resources, can decrease LOS and lower total hospital charges. The reasons for the difference between the pre- and post-intervention groups remain unclear. Further research is needed to evaluate if the quality of communications between patients, their legally authorized representatives, and clinicians--as suggested in the literature--may have played a role in decreasing LOS and total hospital charges.
ERÎ±, microRNAs, and the epithelial-mesenchymal transition in breast cancer. - Trends in endocrinology and metabolism: TEM
The most common form of breast cancer, luminal A, is estrogen receptor Î± (ERÎ±)-positive and epithelial, but nevertheless can metastasize. The process of epithelial-mesenchymal transition (EMT) is probably the first step in the metastasis of epithelial cancers. We discuss the characteristics of EMT, including factors that induce EMT, and the relationship of EMT to cancer stem cells (CSCs). Estrogen/ERÎ± signaling maintains an epithelial phenotype and suppresses EMT. An overview of microRNAs in breast cancer is presented, including how microRNA biogenesis is altered in cancer and regulated by ERÎ±. We also discuss the role of the miR-200 family in opposing EMT. Finally, we discuss specific microRNAs that target ERÎ± and regulate EMT in breast cancer, and the role of these microRNAs in breast cancer progression.Copyright Â© 2011 Elsevier Ltd. All rights reserved.
Precision across the analytical measuring range of a quantitative real-time PCR assay for cytomegalovirus detection among three clinical laboratories. - Journal of clinical microbiology
This study measured the precision of a quantitative laboratory-developed real-time PCR test for cytomegalovirus performed at three different clinical laboratories that use the same methodology. The overall standard deviation (adjusted for analyte level) was 0.18 log(10) copies/ml, and there was no significant relationship between standard deviation and analytical measuring range.
Coordinate regulation of FOXO1 by miR-27a, miR-96, and miR-182 in breast cancer cells. - The Journal of biological chemistry
The FOXO1 transcription factor orchestrates the regulation of genes involved in the apoptotic response, cell cycle checkpoints, and cellular metabolism. FOXO1 is a putative tumor suppressor, and the expression of this gene is dysregulated in some cancers, including prostate and endometrial cancers. However, the molecular mechanism resulting in aberrant expression of human FOXO1 in cancer cells is poorly understood. We show here that FOXO1 mRNA is down-regulated in breast tumor samples as compared with normal breast tissue. Silencing of the microRNA processing enzymes, Drosha and Dicer, led to an increase in FOXO1 expression. We also identified functional and specific microRNA target sites in the FOXO1 3'-untranslated region for miR-27a, miR-96, and miR-182, microRNAs that have previously been linked to oncogenic transformation. The three microRNAs, miR-27a, miR-96 and miR-182, were observed to be highly expressed in MCF-7 breast cancer cells, in which the level of FOXO1 protein is very low. Antisense inhibitors to each of these microRNAs led to a significant increase in endogenous FOXO1 expression and to a decrease in cell number in a manner that was blocked by FOXO1 siRNA. Overexpression of FOXO1 resulted in decreased cell viability because of inhibition of cell cycle traverse and induction of cell death. We have identified a novel mechanism of FOXO1 regulation, and targeting of FOXO1 by microRNAs may contribute to transformation or maintenance of an oncogenic state in breast cancer cells.
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