6516 M D Anderson Blvd Suite 352
Houston TX 77030
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Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits. - eLife
Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance.
A digital assessment and documentation tool evaluated for daily podiatric wound practice. - Wounds : a compendium of clinical research and practice
Foot ulcers are a common complication of diabetes. Regular screening of patients with ulcers enables better treatment and reduces the number of amputations. The lack of wound specialists, especially in nonurban areas, drove the development of an IT-based system for analyzing wounds, the Wound Healing Analyzing Tool (WHAT). Digital images are scored and documented using software that runs on a laptop computer. The aim of this study was to evaluate WHAT's use in daily podiatry practice.Eighteen ambulant patients presenting with diabetic foot ulcers at the participating podiatric clinic were recruited to the study. Digital ulcer images were obtained. To measure size and assess wound bed condition, the evaluated software recognizes the square mark, which is printed on a sticker and placed next to the ulcer. A trained, blinded physician assessed the same digital images and results were compared.Fifteen of the 18 results obtained with the digital tool for ulcer area and wound bed condition were in line with the visual assessment conducted by the blinded physician. Eighty-seven percent of the images were correctly scored, with the main problem being a missing or partially visible square mark in the photograph (n = 3/18).The results indicate that WHAT showed sufficient accuracy to be considered for use in clinical settings for determination of wound area and wound bed characteristics. The tool also seems to be an attractive option for digital consulting.
Abscess penetration of cefpirome: concentrations and simulated pharmacokinetic profiles in pus. - European journal of clinical pharmacology
Abscess patients frequently receive antibiotic therapy when incision cannot be performed or in addition to incision. However, antibiotic concentrations in human abscesses are widely unknown.Pharmacokinetics of cefpirome in 12 human abscesses located in different body regions was studied. Cefpirome (2Â g) was administered as an intravenous short infusion, and concentrations were measured in plasma over an 8-h period and in abscesses at incision. A pharmacokinetic two-stage model was applied.At abscess incision performed 158â€‰Â±â€‰112Â min after the start of the infusion, the cefpirome concentrations in the abscess fluid varied markedly, ranging from â‰¤0.1 (limit of quantification) to 47 (mean 8.4â€‰Â±â€‰14.1Â ) mg/L. Cefpirome was detectable in nine of 12 abscesses. Maximum concentrations were calculated to be 183â€‰Â±â€‰106Â mg/L in plasma and 12â€‰Â±â€‰16Â mg/L in the abscess. A cefpirome concentration of 2Â mg/L, which is the minimum concentration inhibiting growth of 90% of the most relevant bacterial pathogens, was exceeded spontaneously in six of 12 abscesses after a single dose. Cefpirome concentrations in the abscess did not correlate with either the pH or the ratio of surface area to volume of the abscesses, nor with plasma pharmacokinetics.Cefpirome may be useful to treat abscess patients because it was detectable in most abscesses after a single dose. However, the penetration of cefpirome into abscesses is extremely variable and cannot be predicted by measuring other available covariates.
Biogenesis of multisubunit RNA polymerases. - Trends in biochemical sciences
Gene transcription in the nucleus of eukaryotic cells is carried out by three related multisubunit RNA polymerases, Pol I, Pol II and Pol III. Although the structure and function of the polymerases have been studied extensively, little is known about their biogenesis and their transport from the cytoplasm (where the subunits are synthesized) to the nucleus. Recent studies have revealed polymerase assembly intermediates and putative assembly factors, as well as factors required for Pol II nuclear import. In this review, we integrate the available data into a model of Pol II biogenesis that provides a framework for future analysis of the biogenesis of all RNA polymerases.Copyright Â© 2011 Elsevier Ltd. All rights reserved.
Eradication of methicillin-resistant Staphylococcus aureus in pressure ulcers comparing a polyhexanide-containing cellulose dressing with polyhexanide swabs in a prospective randomized study. - Advances in skin & wound care
The study evaluated eradication of methicillin-resistant Staphylococcus aureus (MRSA) from pressure ulcers comparing swabs containing polyhexanide with a cellulose dressing + polyhexanide. After receiving approval from the ethics committee and informed consent, patients from the centers were recruited.Prospective randomized study. Thirty patients (n = 15/n = 15), not responding to wound disinfection after a washout period of 2 weeks, were included in the intention-to-treat analysis.This study was performed on hospital patients.Patients had pressure ulcers containing MRSA.For the control group, cleansing was performed with polyhexanide swabs (20 minutes), after which a foam dressing was applied. The study group received a polyhexanide-containing cellulose dressing. For bacterial analysis, semiquantitative swab cultures (Robert Koch Institute recommendations) were taken on days 0, 7, and 14 and during 3 consecutive days.The groups were comparable at baseline. At day 7, in the control group, 6 of 15 (40%) MRSA eradication. For the study group, there were 13 of 15 (86.67%) who showed MRSA eradication. At day 14, in the control group, there were 10 of 15 (66.67%) who had MRSA eradication, compared with the study group, where 15 of 15 (100%; P < .05) had the MRSA eradicated.Wound disinfection with polyhexanide was shown to be successful in both groups, showing superior results for the study group.
Machine learning improves the precision and robustness of high-content screens: using nonlinear multiparametric methods to analyze screening results. - Journal of biomolecular screening
Imaging-based high-content screens often rely on single cell-based evaluation of phenotypes in large data sets of microscopic images. Traditionally, these screens are analyzed by extracting a few image-related parameters and use their ratios (linear single or multiparametric separation) to classify the cells into various phenotypic classes. In this study, the authors show how machine learning-based classification of individual cells outperforms those classical ratio-based techniques. Using fluorescent intensity and morphological and texture features, they evaluated how the performance of data analysis increases with increasing feature numbers. Their findings are based on a case study involving an siRNA screen monitoring nucleoplasmic and nucleolar accumulation of a fluorescently tagged reporter protein. For the analysis, they developed a complete analysis workflow incorporating image segmentation, feature extraction, cell classification, hit detection, and visualization of the results. For the classification task, the authors have established a new graphical framework, the Advanced Cell Classifier, which provides a very accurate high-content screen analysis with minimal user interaction, offering access to a variety of advanced machine learning methods.
Successful bridging treatment and healing of enteric fistulae by vacuum-assisted closure (VAC) therapy and targeted drainage in patients with open abdomen. - International journal of colorectal disease
The object of this study was to investigate the bridging treatment of enteric fistulae by vacuum-assisted closure (VAC) therapy in patients with open abdomen.We retrospectively analyzed patients who have been treated between 1 January 2007 and 31 December 2008 at the intensive care unit of the Department of General Surgery, Medical University Vienna. Control of the fistula was established by VAC therapy to bridge the patients to the time of the fistula resection.In the period of investigation, we treated nine (six men/three women) patients suffering from enteric fistulae with VAC therapy. The median age of the patients was 48 (range, 37-67) years. The median duration of VAC therapy was 76 (range, 53-128) days. The median length of stay in the intensive care unit was 44 (range, 25-127) days. The median APACHE II score was 23 (range, 18-25). The predicted mortality was 40%; the actual mortality was 11% (one patient). Primary fascial closure was achieved after median 91 (range, 89-92) days in three patients (33%) and secondary fascial closure after median 292 (range, 252-546) days in another three patients (33%). Fistulae were cured with VAC (five patients, 56%) and surgical resection (three patients, 33%). None of the patients developed a refistulation at the time of follow-up.Control of enteric fistulae by VAC therapy can lead to spontaneous fistula closure and is associated with a low mortality.
A protein inventory of human ribosome biogenesis reveals an essential function of exportin 5 in 60S subunit export. - PLoS biology
The assembly of ribosomal subunits in eukaryotes is a complex, multistep process so far mostly studied in yeast. In S. cerevisiae, more than 200 factors including ribosomal proteins and trans-acting factors are required for the ordered assembly of 40S and 60S ribosomal subunits. To date, only few human homologs of these yeast ribosome synthesis factors have been characterized. Here, we used a systematic RNA interference (RNAi) approach to analyze the contribution of 464 candidate factors to ribosomal subunit biogenesis in human cells. The screen was based on visual readouts, using inducible, fluorescent ribosomal proteins as reporters. By performing computer-based image analysis utilizing supervised machine-learning techniques, we obtained evidence for a functional link of 153 human proteins to ribosome synthesis. Our data show that core features of ribosome assembly are conserved from yeast to human, but differences exist for instance with respect to 60S subunit export. Unexpectedly, our RNAi screen uncovered a requirement for the export receptor Exportin 5 (Exp5) in nuclear export of 60S subunits in human cells. We show that Exp5, like the known 60S exportin Crm1, binds to pre-60S particles in a RanGTP-dependent manner. Interference with either Exp5 or Crm1 function blocks 60S export in both human cells and frog oocytes, whereas 40S export is compromised only upon inhibition of Crm1. Thus, 60S subunit export is dependent on at least two RanGTP-binding exportins in vertebrate cells.
Basics in nutrition and wound healing. - Nutrition (Burbank, Los Angeles County, Calif.)
Wound healing is a process that can be divided into three different phases (inflammatory, proliferative, and maturation). Each is characterized by certain events that require specific components. However, wound healing is not always a linear process; it can progress forward and backward through the phases depending on various intrinsic and extrinsic factors. If the wound-healing process is affected negatively, this can result in chronic wounds. Chronic wounds demand many resources in the clinical daily routine. Therefore, local wound management and good documentation of the wound is essential for non-delayed wound healing and prevention of the development of chronic wounds. During the wound-healing process much energy is needed. The energy for the building of new cells is usually released from body energy stores and protein reserves. This can be very challenging for undernourished and malnourished patients. Malnutrition is very common in geriatric patients and patients in catabolic phases of stress such as after injury or surgery. For that reason a close survey of the nutritional status of patients is necessary to start supplementation quickly, if applicable. Wound healing is indeed a very complex process that deserves special notice. There are some approaches to develop guidelines but thus far no golden standard has evolved. Because wounds, especially chronic wounds, cause also an increasing economic burden, the development of guidelines should be advanced.(c) 2010 Elsevier Inc. All rights reserved.
Distinct cytoplasmic maturation steps of 40S ribosomal subunit precursors require hRio2. - The Journal of cell biology
During their biogenesis, 40S ribosomal subunit precursors are exported from the nucleus to the cytoplasm, where final maturation occurs. In this study, we show that the protein kinase human Rio2 (hRio2) is part of a late 40S preribosomal particle in human cells. Using a novel 40S biogenesis and export assay, we analyzed the contribution of hRio2 to late 40S maturation. Although hRio2 is not absolutely required for pre-40S export, deletion of its binding site for the export receptor CRM1 decelerated the kinetics of this process. Moreover, in the absence of hRio2, final cytoplasmic 40S maturation is blocked because the recycling of several trans-acting factors and cytoplasmic 18S-E precursor ribosomal RNA (rRNA [pre-rRNA]) processing are defective. Intriguingly, the physical presence of hRio2 but not its kinase activity is necessary for the release of hEnp1 from cytoplasmic 40S precursors. In contrast, hRio2 kinase activity is essential for the recycling of hDim2, hLtv1, and hNob1 as well as for 18S-E pre-rRNA processing. Thus, hRio2 is involved in late 40S maturation at several distinct steps.
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6516 M D Anderson Blvd Suite 352 Houston, TX 77030
6624 Fannin St Suite 2180
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