Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, ... more Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, and other important diseases. Here, we report the inhibitory activity of a series of 76 dihydro-beta-agarofuran sesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter, to establish quantitative comparisons of their respective abilities to block the drug transport activity. The screening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulation of the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity and guide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The most salient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions, which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.
To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to re... more To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to report health states and estimate preference weights. Survey materials were mailed to 748 patients. Factor analysis, an item response theory-based model, and an internal consistency test were used to identify attributes and evaluate items. Two multiattribute preference weight functions (MAPWF) were constructed. Construct validity of the new measures was then tested. Four hundred eighty-seven patients returned the survey; 24 items on 6 health attributes were selected to form the new outcomes measure. Two MAPWF were derived with preference weights measured with time tradeoff and visual analog scales as dependent variables. All validity test results were statistically significant. Our results reveal that the new measures are reliable and valid in assessing health states and associated preference weights of patients with RA.
This chapter contains sections titled: The Iron and Arsenic Redox Cycles: A Microbial Perspective... more This chapter contains sections titled: The Iron and Arsenic Redox Cycles: A Microbial Perspective Microbial Diversity of Iron and Arsenic Reducers Genetics of Arsenic Geochemistry Genetics of Iron Reduction Iron Reduction and Arsenic Mobilization: A Molecular Perspective Microbiological Mechanisms Underpinning Arsenic Mobilization in Sediments Future Perspectives References
Griffiths, R., Gleeson, M., Reyes, C., Knopf, K. and Danese, M.(2010), Survival in elderly follic... more Griffiths, R., Gleeson, M., Reyes, C., Knopf, K. and Danese, M.(2010), Survival in elderly follicular lymphoma patients who receive frontline chemo-immunotherapy. American Journal of Hematology, 85: 963–967. doi: 10.1002/ajh. 21878
Brain metastases are a common and serious complication among patients with metastatic melanoma. T... more Brain metastases are a common and serious complication among patients with metastatic melanoma. The selective BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases (MBM). We examined the real-world application and clinical outcomes of vemurafenib in this patient population. Demographic, treatment patterns, response, and survival data were collected from medical charts. Clinical data on 283 patients with active BRAF V600E-mutant MBM treated with vemurafenib were provided by 70 US oncologists. Mean age was 57.2 years, 60.8% were male, 67.5% had ECOG performance status of 0-1, and 43.1% used corticosteroids at vemurafenib initiation. Median follow-up was 5.7 months. Following vemurafenib initiation, 48.1% of patients experienced intracranial response and 45.6% experienced extracranial response. The Kaplan-Meier estimate for overall survival was 59% at 12 months. Multivariate analyses showed associations between intracranial response and both corticosteroid use and vemurafenib as initial therapy after MBM diagnosis. Larger size (5-10 mm vs. <5 mm) and number of brain metastases (≥5 vs. <2) and progressive extracranial disease at treatment initiation were associated with decreased intracranial response and increased risk of disease progression. Multiple extracranial sites (2 vs. <2) and the absence of local treatments were also associated with increased risk of progression. Increased risk of death was associated with ≥2 extracranial disease sites, progressive extracranial disease, and ≥5 brain metastases. Subgroups of MBM patients may derive more benefit with vemurafenib, warranting prospective investigation.
Recent advances have increased treatment options for, and improved clinical outcomes in, metastat... more Recent advances have increased treatment options for, and improved clinical outcomes in, metastatic melanoma (mM). Using a large claims database, this retrospective study compared healthcare and adverse event (AE) costs in a US managed care population of mM patients initiating vemurafenib (VEM), ipilimumab (IPI), dacarbazine (DTIC), paclitaxel (PAC), or temozolomide (TMZ) from July 2009 to September 2012. Treatment episodes were identified from the start of study drugs (index date) to a switch to a different study drug, or a gap greater than 45 days (>112 days for IPI). Grade 3/4 adverse events occurring ≥5% from study drug package inserts were selected for this analysis. All-cause costs for treatment episodes and AEs were normalized as monthly costs. Generalized estimating equation models with log link and gamma distribution provided adjusted monthly treatment episode and AE costs. A total of 809 treatment episodes were identified in 541 mM patients, with a mean (SD) age of 57.5...
Annual review of biophysics and biomolecular structure, 2001
Computer modeling has been developed and widely applied in studying molecules of biological inter... more Computer modeling has been developed and widely applied in studying molecules of biological interest. The force field is the cornerstone of computer simulations, and many force fields have been developed and successfully applied in these simulations. Two interesting areas are (a) studying enzyme catalytic mechanisms using a combination of quantum mechanics and molecular mechanics, and (b) studying macromolecular dynamics and interactions using molecular dynamics (MD) and free energy (FE) calculation methods. Enzyme catalysis involves forming and breaking of covalent bonds and requires the use of quantum mechanics. Noncovalent interactions appear ubiquitously in biology, but here we confine ourselves to review only noncovalent interactions between protein and protein, protein and ligand, and protein and nucleic acids.
To estimate weights for health states comprising American College of Rheumatology (ACR) response ... more To estimate weights for health states comprising American College of Rheumatology (ACR) response and different levels of adverse events associated with rheumatoid arthritis (RA) treatments. A survey was mailed to 748 patients with RA from southern California. In addition to several questionnaires commonly used for patients with RA, patients were instructed to evaluate 10 hypothetical health states, in which they could have an ACR response and/or adverse events due to new treatments, with a visual analog scale (VAS). Patients also evaluated their current health with a VAS question and a time tradeoff (TTO) question. Linear extrapolation was used to derive 6 more health states. The Pearson correlation coefficient was used to validate VAS and TTO results. A total of 487 (65%) patients returned the survey. Among the 10 health states evaluated with VAS directly, the health state in which a patient has ACR70 with no adverse events had the highest VAS weight (0.84), followed by the one hav...
To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to re... more To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to report health states and estimate preference weights. Survey materials were mailed to 748 patients. Factor analysis, an item response theory-based model, and an internal consistency test were used to identify attributes and evaluate items. Two multiattribute preference weight functions (MAPWF) were constructed. Construct validity of the new measures was then tested. Four hundred eighty-seven patients returned the survey; 24 items on 6 health attributes were selected to form the new outcomes measure. Two MAPWF were derived with preference weights measured with time tradeoff and visual analog scales as dependent variables. All validity test results were statistically significant. Our results reveal that the new measures are reliable and valid in assessing health states and associated preference weights of patients with RA.
Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, ... more Multidrug resistance (MDR) is one of the main challenges in the chemotherapy of cancer, malaria, and other important diseases. Here, we report the inhibitory activity of a series of 76 dihydro-beta-agarofuran sesquiterpenes, tested on NIH-3T3 cells expressing the human P-glycoprotein (Pgp) multidrug transporter, to establish quantitative comparisons of their respective abilities to block the drug transport activity. The screening was performed on the basis of the ability of sesquiterpenes to modulate the intracellular accumulation of the classical Pgp substrate daunorubicin. To understand the structural basis for inhibitory activity and guide the design of more potent Pgp inhibitors, we have performed a three-dimensional quantitative structure-activity relationship model using the comparative molecular similarity indices analysis (CoMSIA). The most salient features of these requirements are in the region of the substituents at the C-2, C-3, and C-8 positions, which seem to be critical for determining the overall effectiveness of sesquiterpenes as Pgp inhibitors.
To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to re... more To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to report health states and estimate preference weights. Survey materials were mailed to 748 patients. Factor analysis, an item response theory-based model, and an internal consistency test were used to identify attributes and evaluate items. Two multiattribute preference weight functions (MAPWF) were constructed. Construct validity of the new measures was then tested. Four hundred eighty-seven patients returned the survey; 24 items on 6 health attributes were selected to form the new outcomes measure. Two MAPWF were derived with preference weights measured with time tradeoff and visual analog scales as dependent variables. All validity test results were statistically significant. Our results reveal that the new measures are reliable and valid in assessing health states and associated preference weights of patients with RA.
This chapter contains sections titled: The Iron and Arsenic Redox Cycles: A Microbial Perspective... more This chapter contains sections titled: The Iron and Arsenic Redox Cycles: A Microbial Perspective Microbial Diversity of Iron and Arsenic Reducers Genetics of Arsenic Geochemistry Genetics of Iron Reduction Iron Reduction and Arsenic Mobilization: A Molecular Perspective Microbiological Mechanisms Underpinning Arsenic Mobilization in Sediments Future Perspectives References
Griffiths, R., Gleeson, M., Reyes, C., Knopf, K. and Danese, M.(2010), Survival in elderly follic... more Griffiths, R., Gleeson, M., Reyes, C., Knopf, K. and Danese, M.(2010), Survival in elderly follicular lymphoma patients who receive frontline chemo-immunotherapy. American Journal of Hematology, 85: 963–967. doi: 10.1002/ajh. 21878
Brain metastases are a common and serious complication among patients with metastatic melanoma. T... more Brain metastases are a common and serious complication among patients with metastatic melanoma. The selective BRAF inhibitor vemurafenib has demonstrated clinical efficacy in patients with BRAF V600E-mutant melanoma brain metastases (MBM). We examined the real-world application and clinical outcomes of vemurafenib in this patient population. Demographic, treatment patterns, response, and survival data were collected from medical charts. Clinical data on 283 patients with active BRAF V600E-mutant MBM treated with vemurafenib were provided by 70 US oncologists. Mean age was 57.2 years, 60.8% were male, 67.5% had ECOG performance status of 0-1, and 43.1% used corticosteroids at vemurafenib initiation. Median follow-up was 5.7 months. Following vemurafenib initiation, 48.1% of patients experienced intracranial response and 45.6% experienced extracranial response. The Kaplan-Meier estimate for overall survival was 59% at 12 months. Multivariate analyses showed associations between intracranial response and both corticosteroid use and vemurafenib as initial therapy after MBM diagnosis. Larger size (5-10 mm vs. <5 mm) and number of brain metastases (≥5 vs. <2) and progressive extracranial disease at treatment initiation were associated with decreased intracranial response and increased risk of disease progression. Multiple extracranial sites (2 vs. <2) and the absence of local treatments were also associated with increased risk of progression. Increased risk of death was associated with ≥2 extracranial disease sites, progressive extracranial disease, and ≥5 brain metastases. Subgroups of MBM patients may derive more benefit with vemurafenib, warranting prospective investigation.
Recent advances have increased treatment options for, and improved clinical outcomes in, metastat... more Recent advances have increased treatment options for, and improved clinical outcomes in, metastatic melanoma (mM). Using a large claims database, this retrospective study compared healthcare and adverse event (AE) costs in a US managed care population of mM patients initiating vemurafenib (VEM), ipilimumab (IPI), dacarbazine (DTIC), paclitaxel (PAC), or temozolomide (TMZ) from July 2009 to September 2012. Treatment episodes were identified from the start of study drugs (index date) to a switch to a different study drug, or a gap greater than 45 days (>112 days for IPI). Grade 3/4 adverse events occurring ≥5% from study drug package inserts were selected for this analysis. All-cause costs for treatment episodes and AEs were normalized as monthly costs. Generalized estimating equation models with log link and gamma distribution provided adjusted monthly treatment episode and AE costs. A total of 809 treatment episodes were identified in 541 mM patients, with a mean (SD) age of 57.5...
Annual review of biophysics and biomolecular structure, 2001
Computer modeling has been developed and widely applied in studying molecules of biological inter... more Computer modeling has been developed and widely applied in studying molecules of biological interest. The force field is the cornerstone of computer simulations, and many force fields have been developed and successfully applied in these simulations. Two interesting areas are (a) studying enzyme catalytic mechanisms using a combination of quantum mechanics and molecular mechanics, and (b) studying macromolecular dynamics and interactions using molecular dynamics (MD) and free energy (FE) calculation methods. Enzyme catalysis involves forming and breaking of covalent bonds and requires the use of quantum mechanics. Noncovalent interactions appear ubiquitously in biology, but here we confine ourselves to review only noncovalent interactions between protein and protein, protein and ligand, and protein and nucleic acids.
To estimate weights for health states comprising American College of Rheumatology (ACR) response ... more To estimate weights for health states comprising American College of Rheumatology (ACR) response and different levels of adverse events associated with rheumatoid arthritis (RA) treatments. A survey was mailed to 748 patients with RA from southern California. In addition to several questionnaires commonly used for patients with RA, patients were instructed to evaluate 10 hypothetical health states, in which they could have an ACR response and/or adverse events due to new treatments, with a visual analog scale (VAS). Patients also evaluated their current health with a VAS question and a time tradeoff (TTO) question. Linear extrapolation was used to derive 6 more health states. The Pearson correlation coefficient was used to validate VAS and TTO results. A total of 487 (65%) patients returned the survey. Among the 10 health states evaluated with VAS directly, the health state in which a patient has ACR70 with no adverse events had the highest VAS weight (0.84), followed by the one hav...
To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to re... more To develop and validate multiattribute measures for patients with rheumatoid arthritis (RA) to report health states and estimate preference weights. Survey materials were mailed to 748 patients. Factor analysis, an item response theory-based model, and an internal consistency test were used to identify attributes and evaluate items. Two multiattribute preference weight functions (MAPWF) were constructed. Construct validity of the new measures was then tested. Four hundred eighty-seven patients returned the survey; 24 items on 6 health attributes were selected to form the new outcomes measure. Two MAPWF were derived with preference weights measured with time tradeoff and visual analog scales as dependent variables. All validity test results were statistically significant. Our results reveal that the new measures are reliable and valid in assessing health states and associated preference weights of patients with RA.
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