Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. <br></br> EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. <br></br> RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.<br></br> CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.<br></br&gt

Characterization of a genomic signature of pregnancy identified in the breast.

The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer

Characterization of a genomic signature of pregnancy identified in the breast.

The objective of this study was to comprehensively compare the genomic profiles in the breast of parous and nulliparous postmenopausal women to identify genes that permanently change their expression following pregnancy. The study was designed as a two-phase approach. In the discovery phase, we compared breast genomic profiles of 37 parous with 18 nulliparous postmenopausal women. In the validation phase, confirmation of the genomic patterns observed in the discovery phase was sought in an independent set of 30 parous and 22 nulliparous postmenopausal women. RNA was hybridized to Affymetrix HG_U133 Plus 2.0 oligonucleotide arrays containing probes to 54,675 transcripts, scanned and the images analyzed using Affymetrix GCOS software. Surrogate variable analysis, logistic regression, and significance analysis of microarrays were used to identify statistically significant differences in expression of genes. The false discovery rate (FDR) approach was used to control for multiple comparisons. We found that 208 genes (305 probe sets) were differentially expressed between parous and nulliparous women in both discovery and validation phases of the study at an FDR of 10% and with at least a 1.25-fold change. These genes are involved in regulation of transcription, centrosome organization, RNA splicing, cell-cycle control, adhesion, and differentiation. The results provide initial evidence that full-term pregnancy induces long-term genomic changes in the breast. The genomic signature of pregnancy could be used as an intermediate marker to assess potential chemopreventive interventions with hormones mimicking the effects of pregnancy for prevention of breast cancer

Changing the Face of an Institution: Creative Partnerships for Women’s Professional Development

Purpose of program/study/research:To accelerate the advancement of women professionals at an academic medical center through creative collaboration. Methodology (including study design, analysis, and evaluation):The UMass Medical School Women’s Faculty Committee (WFC) initiated a partnership with the medical library to compete successfully to host the traveling exhibition “Changing the Face of Medicine: Celebrating America’s Women Physicians.” Concurrent with the 6-week exhibition, fifteen events brought local and nationally prominent women together for mentoring activities, an original dramatic production, and an awards luncheon for women faculty. Women featured in the exhibit as well as its Visiting Curator spoke at UMMS about their research and career challenges, read from their published works, and were featured at graduation and a regional medical society event. Results:Application-writing and event planning sessions forged robust working relationships among top-ranking administrators, senior and junior faculty, and staff. The exhibition increased opportunities for administration, faculty, and students to understand the impact of women in medicine, their leadership potential, and historical contributions. It also generated new mentor/mentee relationships and grant-writing collaborations. The exhibition’s national recognition helped draw a larger, more diverse and gender-balanced audience (575+ people) to the events enhancing the visibility of the WFC, as evidenced by institutional funding for women faculty to attend the AAMC WIM professional development workshops and ELAM for the first time. Conclusion(s):Creative partnerships, motivated by the opportunity to host “Changing the Face of Medicine,” produced greater than expected gains for women faculty, generating new awareness and understanding of women’s accomplishments and leadership potential. This partnership allowed for a wide range of multi-disciplinary efforts, strengthening networking across silos, and advancing the goals of women in an academic medical center. Presented October 29, 2006 at AAMC 2006 Annaul Meeting, Seattle, WA

On the design of mesostructured acidic catalysts for the one-pot dimethyl ether production from CO2

Dimethyl ether (DME) production from hydrogenation of CO2 based on two-function (redox and acidic) catalysts is receiving increasing attention due to the high demand for alternative and green fuels. In this work, we propose different mesostructured acidic metal oxides as methanol dehydration catalysts to be used as physical mixtures in combination with a commercial Cu-based redox catalyst (CZA) for the CO2-to-DME one-pot production. Al-MCM41, TiO2 and TiO2-ZrO2 mixed oxides, obtained through Sol-Gel methods, either in a conventional or Evaporation-Induced Self-Assembly approach were selected as mesostructured acidic systems and compared with a commercial zeolite (ferrierite). The regular mesoporous structure should render the active sites of the acidic catalyst easily accessible for CO2 and H2 and allow a homogeneous dispersion of the redox phase inside the mesopores in view of a possible development of bifunctional catalysts (redox + acidic). With the aim of understanding how the textural and acidic properties can be correlated with the performances and eventually design efficient dehydration catalysts, a careful study on the acidic sites was performed by both adsorption microcalorimetry with ammonia and FTIR-monitored adsorption of pyridine. The results of the performances highlighted a higher activity toward methanol dehydration for catalysts featured by Bronsted sites (zeolite and Al-MCM-41); as for catalysts with Lewis sites only (TiO2, Ti0.77Zr0.23O2) better performances were shown in case of systems presenting sites of moderate strength (Ti0.77Zr0.23O2). In the light of the above, Al-MCM-41 and TiO2ZrO2 demonstrated to be the most promising mesostructured dehydration catalysts in terms of selectivity to DME

Tuning the activity of cobalt 2-hydroxyphosphonoacetates-derived electrocatalysts for water splitting and oxygen reduction: insights into the local order by pair distribution function analysis

Pyrophosphate- or phosphide-based iron/cobalt electrocatalysts were prepared from the metal (R,S)−2-hydroxyphosphonoacetates to evaluate the effects of metal composition, N-doping and P-enrichment on the electrocatalytic activity. Rietveld and Pair Distribution Function analysis were used to determine phase composition. Irrespectively of the amorphous or crystalline nature, all pyrolyzed solids transformed under OER operation into biphasic Fe/CoO(OH), composed of discrete clusters (size ≤ 20 Å). Carbon paper-supported Fe0.2Co0.8O(OH) electrocatalysts displayed the best OER performances (overpotentials of 270–279 mV at 10 mA·cm−2), attributable to the formation of highly active bimetallic intermediate species. For HER, increased concentration of o-CoP in phosphide-based electrocatalysts resulted in improved performance, up to an overpotential of 140 mV. Employed as anode in alkaline water splitting, amorphous Fe-doped cobalt pyrophosphate and phosphide-derived electrocatalysts showed a cell voltage of 1.58 V at 10 mA·cm−2, with comparable stability to that of RuO2 and requiring lower voltage demand at high current densities.This work was funded by the PID2019-110249RB-I00/AEI/10.13039/501100011033; TED2021–129836B-I00/AEI/10.13039/501100011033/Unión Europea NextGenerationEU/PRTR (MICIU, Spain) and P20-00416 (Junta de Andalucia, Spain/FEDER) research projects. Synchrotron X-ray powder diffraction studies were performed at MSPD04 beamline at ALBA Synchrotron Light with the collaboration of ALBA staff. A.V.C. thanks MICIU for PRE2020-094459 student grant. R.M.P.C. acknowledges funding by project acknowledges B1_2022-23 (Plan Propio UMA). M.B.G. thanks PAIDI2020-DOC_00272 research grant (Junta de Andalucia, Spain). Funding for open access charge: Universidad de Málaga / CBUA

Blocking Zika virus vertical transmission.

The outbreak of the Zika virus (ZIKV) has been associated with increased incidence of congenital malformations. Although recent efforts have focused on vaccine development, treatments for infected individuals are needed urgently. Sofosbuvir (SOF), an FDA-approved nucleotide analog inhibitor of the Hepatitis C (HCV) RNA-dependent RNA polymerase (RdRp) was recently shown to be protective against ZIKV both in vitro and in vivo. Here, we show that SOF protected human neural progenitor cells (NPC) and 3D neurospheres from ZIKV infection-mediated cell death and importantly restored the antiviral immune response in NPCs. In vivo, SOF treatment post-infection (p.i.) decreased viral burden in an immunodeficient mouse model. Finally, we show for the first time that acute SOF treatment of pregnant dams p.i. was well-tolerated and prevented vertical transmission of the virus to the fetus. Taken together, our data confirmed SOF-mediated sparing of human neural cell types from ZIKV-mediated cell death in vitro and reduced viral burden in vivo in animal models of chronic infection and vertical transmission, strengthening the growing body of evidence for SOF anti-ZIKV activity

Microwave-assisted coating of carbon nanostructures with titanium dioxide for the catalytic dehydration of D-xylose into furfural

Titanium dioxide was selectively grown on reduced graphene oxide (TiO2/RGO) and carbon black (TiO2/CB) by a microwave-assisted synthesis in benzyl alcohol to produce nanocomposite catalysts (consisting of 8-9 nm anatase nanoparticles dispersed on the carbon surface) with interesting properties for the production of furfural from renewable carbohydrate biomass. The materials efficiently catalyze the aqueous-phase dehydration of xylose into furfural at 170 degrees C with high furfural yields (67-69%) at high conversions (95-97%). The catalytic performance was not significantly affected by the type of carbon support, suggesting that cheap amorphous carbons can be used to support the titania nanoparticles. Additionally, the catalysts were found to be stable under hydrothermal conditions and outstandingly stable towards coke formation in comparison to other solid acid catalysts reported in the literature. Both composites were reused after a simple wash and drying procedure without any detectable loss of catalytic activity in consecutive batch runs