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1.
Crit Care ; 28(1): 132, 2024 04 22.
Article in English | MEDLINE | ID: mdl-38649920

ABSTRACT

BACKGROUND: Rapidly improving acute respiratory distress syndrome (RIARDS) is an increasingly appreciated subgroup of ARDS in which hypoxemia improves within 24 h after initiation of mechanical ventilation. Detailed clinical and biological features of RIARDS have not been clearly defined, and it is unknown whether RIARDS is associated with the hypoinflammatory or hyperinflammatory phenotype of ARDS. The purpose of this study was to define the clinical and biological features of RIARDS and its association with inflammatory subphenotypes. METHODS: We analyzed data from 215 patients who met Berlin criteria for ARDS (endotracheally intubated) and were enrolled in a prospective observational cohort conducted at two sites, one tertiary care center and one urban safety net hospital. RIARDS was defined according to previous studies as improvement of hypoxemia defined as (i) PaO2:FiO2 > 300 or (ii) SpO2: FiO2 > 315 on the day following diagnosis of ARDS (day 2) or (iii) unassisted breathing by day 2 and for the next 48 h (defined as absence of endotracheal intubation on day 2 through day 4). Plasma biomarkers were measured on samples collected on the day of study enrollment, and ARDS phenotypes were allocated as previously described. RESULTS: RIARDS accounted for 21% of all ARDS participants. Patients with RIARDS had better clinical outcomes compared to those with persistent ARDS, with lower hospital mortality (13% vs. 57%; p value < 0.001) and more ICU-free days (median 24 vs. 0; p value < 0.001). Plasma levels of interleukin-6, interleukin-8, and plasminogen activator inhibitor-1 were significantly lower among patients with RIARDS. The hypoinflammatory phenotype of ARDS was more common among patients with RIARDS (78% vs. 51% in persistent ARDS; p value = 0.001). CONCLUSIONS: This study identifies a high prevalence of RIARDS in a multicenter observational cohort and confirms the more benign clinical course of these patients. We report the novel finding that RIARDS is characterized by lower concentrations of plasma biomarkers of inflammation compared to persistent ARDS, and that hypoinflammatory ARDS is more prevalent among patients with RIARDS. Identification and exclusion of RIARDS could potentially improve prognostic and predictive enrichment in clinical trials.


Subject(s)
Biomarkers , Respiration, Artificial , Respiratory Distress Syndrome , Humans , Respiratory Distress Syndrome/therapy , Respiratory Distress Syndrome/blood , Respiratory Distress Syndrome/physiopathology , Male , Female , Middle Aged , Prospective Studies , Aged , Biomarkers/blood , Biomarkers/analysis , Respiration, Artificial/methods , Respiration, Artificial/statistics & numerical data , Adult , Cohort Studies , Hypoxia/blood
4.
Agric For Meteorol ; 342: 109735, 2023 Nov 15.
Article in English | MEDLINE | ID: mdl-38020492

ABSTRACT

Common bean (Phaseolus vulgaris L.) is the second most important source of dietary protein and the third most important source of calories in Africa, especially for the poor. In East Africa, drought is an important constraint to bean production. Therefore, breeding programs in East Africa have been trying to develop drought resistant varieties of common bean. To do this, breeders need information about seasonal drought stress patterns including their onset, intensity, and duration in the target area of the breeding program, so that they can mimic this pattern during field trials. Using the Decision Support for Agrotechnology Transfer (DSSAT) v4.7 model together with historical and future (Coupled Model Inter-comparison Project 6, CMIP6) climate data, this study categorized Ethiopia, Tanzania, and Uganda into different target population of environments (TPEs) based on historical and future seasonal drought stress patterns. We find that stress-free conditions generally dominate across the three countries under historical conditions (50-80% frequency). These conditions are projected to increase in frequency in Ethiopia by 2-10% but the converse is true for Tanzania (2-8% reduction) and Uganda (17-20% reduction) by 2050 depending on the Shared Socioeconomic Pathway (SSP). Accordingly, by 2050, terminal drought stresses of various intensities (moderate, severe, extreme) are prevalent in 34% of Uganda, around a quarter of Ethiopia, and 40% of the bean growing environments in Tanzania. The TPEs identified in each country serve as a basis for prioritizing breeding activities in national programs. However, to optimize resource use in international breeding programs to develop genotypes that are resilient to future projected stress patterns, we argue that common bean breeding programs should focus primarily on identifying genotypes with tolerance to severe terminal drought, with co-benefits in relation to adaptation to moderate and extreme terminal drought. Little to no emphasis on heat stress is warranted by 2050s.

5.
Dalton Trans ; 52(31): 10855-10868, 2023 Aug 08.
Article in English | MEDLINE | ID: mdl-37486008

ABSTRACT

The discovery of new coordination compounds with anticancer properties is an active field of research due to the severe side effects of platinum-based compounds currently used in chemotherapy. In the search for new agents for the treatment of cancer, unsymmetrical N2O2-tetradentate ligand (H2L1 and H2L2) and their Ni(II) and Zn(II) asymmetric complexes (NiII-L1-2 and ZnII-L1-2) have been synthesized and fully characterized. 1H NMR studies revealed that the ligands and complexes were stable in mixtures of DMSO : D2O (9 : 1). Complementary UV-Vis studies confirmed that ZnII derivatives also exhibit high stability in mixtures DMSO : buffer (6 : 4) after 24 h. Single-crystal X-ray diffraction studies confirmed the molecular structures of H2L1, H2L2, NiII-L1, and NiII-L2. At the molecular level, complexes were completely planar without significant distortions of the square-planar geometry according to τ4 parameter. Furthermore, the crystalline structures revealed non-classical intermolecular interactions of the C-H⋯O and the Ni⋯Ni type. The ligands and complexes were screened against the human osteosarcoma (MG-63), human colon cancer (HCT-116), breast cancer (MDA-MB-231) cell lines, and non-cancerous cells (L929). H2L1 and H2L2 ligands not caused cytotoxic effects at a concentration of 100 µM, while NiII-L2, ZnII-L1, and ZnII-L2 complexes induce cytotoxic effects in all cell lines. NiII-L2 was a more active complex against MG-63 (3.9 ± 1.5) and HCT-116 (3.4 ± 1.7) cell lines with IC50 values in the low micromolar range. In addition, this compound was 10-, 5-, and 11-fold more potent than cisplatin in MG-63 (39 ± 1.8), HCT-116 (17.2), and MDA-MB-231 (131 ± 18), respectively. Three complexes exhibited great selectivity for tumoral cells with SI values ranging from 1.6 to 7.4.


Subject(s)
Antineoplastic Agents , Coordination Complexes , Humans , Coordination Complexes/chemistry , Ligands , Dimethyl Sulfoxide , X-Ray Diffraction , Antineoplastic Agents/chemistry , Zinc/chemistry , Crystallography, X-Ray
6.
J Biol Inorg Chem ; 28(6): 549-558, 2023 09.
Article in English | MEDLINE | ID: mdl-37462740

ABSTRACT

A series of new ferrocenyl nitroheterocyclic sulfonylhydrazones (1a-4a and 1b-2b) were prepared by the reaction between formyl (R = H) or acetyl (R = CH3) nitroheterocyclic precursors [4/5-NO2(C5H2XCOR), where X = O, S)] and ferrocenyl tosyl hydrazine [(η5-C5H5)Fe(η5-C5H4SO2-NH-NH2)]. All compounds were characterized by conventional spectroscopic techniques. In the solid state, the molecular structures of compounds 1a, 2b, and 3a were determined by single-crystal X-ray diffraction. The compounds showed an E-configuration around the C=N moiety. Evaluation of trypanocidal activity, measured in vitro against the Trypanosoma cruzi and Trypanosoma brucei strains, indicated that all organometallic tosyl hydrazones displayed activity against both parasite species with a higher level of potency toward T. brucei than T. cruzi. Moreover, the biological evaluation showed that the 5-nitroheterocyclic derivatives were more efficient trypanocidal agents than their 4-nitroheterocyclic counterparts.


Subject(s)
Chagas Disease , Trypanocidal Agents , Trypanosoma cruzi , Humans , Metallocenes , Chagas Disease/drug therapy , Chagas Disease/parasitology
7.
Eur Clin Respir J ; 10(1): 2174640, 2023.
Article in English | MEDLINE | ID: mdl-36815942

ABSTRACT

Background: Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. Methods: We retrospectively identified 185 patients hospitalized with severe COVID-19 who underwent lower respiratory culture; 85 had evidence of bacterial superinfection. Receiver operating characteristic curve and area under the curve (AUC) analyses were performed to assess the utility of procalcitonin for diagnosing superinfection. Results: This approach demonstrated that procalcitonin measured at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). The AUC not affected by exposure to antibiotics, treatment with immunomodulatory agents, or timing of procalcitonin measurement. Conclusion: Static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

8.
Curr Med Chem ; 30(5): 573-600, 2023.
Article in English | MEDLINE | ID: mdl-35670351

ABSTRACT

BACKGROUND: Since the 1980s, cancer research has focused primarily on developing new therapeutic agents targeting DNA alterations rather than understanding cancer as an integrated system composed of several modules. In this sense, G-quadruplex (G4) nucleic acids are a promising target for drug development for cancer therapy since they exist in the chromosomal telomeric sequences and the promoter regions of numerous genes. The G4 structures within telomeric DNA can inhibit telomerase activity and prevent the proliferation and immortalization of cancer cells. Furthermore, such G4 systems within the promoter regions of oncogenes can inhibit the transcription and expression of the oncogene. OBJECTIVE: The rational design of small molecules such as organic ligands and their metal- organic derivative compounds can stabilize G4 structures through different binding modes on several G4 DNA topologies. Metal-based compounds have demonstrated their competitiveness compared to organic molecules to distinguish G4 over the DNA duplex owing to their convenient coordination features, positive charge, and electron density promoted by organic ligand. RESULTS: This article is a comprehensive review of metal compounds G4-binders and their structural features that confer them the ability to recognize G-quartets and stabilize several DNA G4s. CONCLUSION: This stabilization can be achieved through extended square aromatic surfaces, increased hydrophobicity, different auxiliary ligands, axially coordinated ligands, and the nature of the metal center.


Subject(s)
Antineoplastic Agents , G-Quadruplexes , Neoplasms , Humans , Ligands , Antineoplastic Agents/pharmacology , Antineoplastic Agents/metabolism , DNA/chemistry , Neoplasms/drug therapy , Organic Chemicals , Metals , Telomere/metabolism
9.
medRxiv ; 2022 Apr 05.
Article in English | MEDLINE | ID: mdl-35411344

ABSTRACT

Patients hospitalized with COVID-19 are at significant risk for superimposed bacterial pneumonia. However, diagnosing superinfection is challenging due to its clinical resemblance to severe COVID-19. We therefore evaluated whether the immune biomarker, procalcitonin, could facilitate the diagnosis of bacterial superinfection. To do so, we identified 185 patients with severe COVID-19 who underwent lower respiratory culture; 85 had superinfection. Receiver operating characteristic curve analysis showed that procalcitonin at the time of culture was incapable of distinguishing patients with bacterial infection (AUC, 0.52). We conclude that static measurement of procalcitonin does not aid in the diagnosis of superinfection in severe COVID-19.

10.
Eur J Ophthalmol ; 32(5): 3064-3073, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35075918

ABSTRACT

Describe drug utilisation and clinical outcomes of intravitreal anti-VEGF drug and dexamethasone use in the real-world setting in Southern Italy using data from multi-centre study of retinal disease. Clinical data of retinal disease patients treated with anti-VEGF drugs and dexamethasone implant in 6 out-patient ophthalmology centres from Southern Italy were collected by means of an electronic case report form. Patients receiving at least one intravitreal injection/implant of the study drugs were followed for up to two years and described in terms of demographics and clinical characteristics. Drug utilisation patterns were described. A sign-rank test was used to compare clinical data on visual acuity and other ophthalmic parameters from baseline at different follow-up times for each indication. Data from 1327 patients was collected. Most patients were diagnosed with age-related macular degeneration (AMD) (660, 49.7%), followed by diabetic macular oedema (423, 31.9%), retinal vein occlusion (164, 12.3%), and myopic choroidal neovascularization (80, 6.0%). Patients were followed for a median of 10.3 months (interquartile range: 3.6 - 24.7 months). Mean patient age was 69.7 (±10.9) years and 54.2% were males. Ranibizumab (55.4%) and aflibercept (27.5%) were the most commonly used drugs. Baseline visual acuity significantly improved by about 0.05 to 0.1 logMAR at all follow-up times for AMD and RVO but less consistently for the other diseases. Intravitreal ranibizumab use accounted for half of all treatment for retinal diseases in a Southern Italian out-patient setting. Patients treated with anti-VEGF drugs for AMD and RVO in Southern Italy experienced significant improvement in VA.


Subject(s)
Macular Degeneration , Retinal Diseases , Retinal Vein Occlusion , Aged , Aged, 80 and over , Angiogenesis Inhibitors/therapeutic use , Bevacizumab/therapeutic use , Dexamethasone/therapeutic use , Female , Humans , Intravitreal Injections , Macular Degeneration/drug therapy , Male , Middle Aged , Prospective Studies , Ranibizumab/therapeutic use , Retinal Diseases/chemically induced , Retinal Diseases/diagnosis , Retinal Diseases/drug therapy , Retinal Vein Occlusion/diagnosis , Retinal Vein Occlusion/drug therapy , Vascular Endothelial Growth Factor A
11.
J Inorg Biochem ; 219: 111428, 2021 06.
Article in English | MEDLINE | ID: mdl-33774450

ABSTRACT

Four N-acylhydrazones of general formulae [R1-C(O)-NH-N=C(R2)(5-nitrofuryl)] with (R1 = ferrocenyl or cyrhetrenyl and R2 = H or Me) are synthesized and characterized in solution and in the solid-state. Comparative studies of their stability in solution under different experimental conditions and their electrochemical properties are reported. NMR studies reveal that the four compounds are stable in DMSO­d6 and complementary UV-Vis studies confirm that they also exhibit high stability in mixtures DMSO:H2O at 37 °C. Electrochemical studies show that the half-wave potential of the nitro group of the N-acylhydrazones is smaller than that of the standard drug nifurtimox and the reduction process follows a self-protonation mechanism. In vitro studies on the antiparasitic activities of the four complexes and the nifurtimox against Trypanosoma cruzi and Trypanosoma brucei reveal that: i) the N-acylhydrazones have a potent inhibitory growth activity against both parasites [EC50 in the low micromolar (in T. cruzi) or even in the nanomolar (in T. brucei) range] and ii) cyrhetrenyl derivatives are more effective than their ferrocenyl analogs. Parallel studies on the L6 rat skeletal myoblast cell line have also been conducted, and the selectivity indexes determined. Three of the four N-acylhydrazones showed higher selectivity towards T. brucei than the standard drug nifurtimox. Additional studies suggest that the organometallic compounds are bioactivated by type I nitroreductase enzymes.


Subject(s)
Ferrous Compounds/chemistry , Hydrazones/chemistry , Hydrazones/pharmacology , Nitrofurans/chemistry , Trypanocidal Agents/pharmacology , Animals , Cell Line , Electrochemistry/methods , Humans , Nifurtimox/pharmacology , Nitroreductases/metabolism , Organometallic Compounds/chemistry , Rats , Trypanosoma brucei brucei/drug effects , Trypanosoma cruzi/drug effects
12.
Photochem Photobiol ; 97(1): 61-70, 2021 01.
Article in English | MEDLINE | ID: mdl-32627201

ABSTRACT

The new cyrhetrenyl acylhydrazone [(CO)3 Re(η5 -C5 H4 )-C(O)-NH-N = C(CH3 )-(2-C4 H2 S-5-NO2 )] (E-CyAH) has been designed, synthesized and fully characterized to study the effect of having a cyrhetrenyl fragment (sensitizer) covalently bonded to an acylhydrazone moiety (switch), on its photophysical and photochemical properties. The crystal structure reveals that E-CyAH adopts an E-configuration around the iminic moiety [-N = C(CH3 )]. The absorption spectrum of E-CyAH displays two bands at 270 and 380 nm, which are mainly ascribed to π â†’ π* intraligand (IL) and dπ  â†’ π* metal-to-ligand charge transfer (MLCT) transitions, being consistent with DFT/TD-DFT calculations. Upon 365 nm irradiation, E-CyAH photoisomerizes to Z-CyAH, as evidenced by UV-Vis and 1 H-NMR spectral changes, with a quantum yield value ΦE -CyAH → Z -CyAH of 0.30. Z-CyAH undergoes a first-order thermal back-isomerization process, with a relatively short half-life τ1/2 of 277 min. Consequently, E-CyAH was quantitatively recovered after 24 h, making it a fully reversible T-type molecular photoswitch. This remarkable behavior allows us to measure the individual photophysical properties for both isomers. In addition, E-CyAH and Z-CyAH efficiently photosensitize the generation of singlet oxygen (O2 (1 Δg )) with good yield (ΦΔ  = 0.342).

13.
Thorax ; 75(11): 974-981, 2020 11.
Article in English | MEDLINE | ID: mdl-32826284

ABSTRACT

INTRODUCTION: Procalcitonin expression is thought to be stimulated by bacteria and suppressed by viruses via interferon signalling. Consequently, during respiratory viral illness, clinicians often interpret elevated procalcitonin as evidence of bacterial coinfection, prompting antibiotic administration. We sought to evaluate the validity of this practice and the underlying assumption that viral infection inhibits procalcitonin synthesis. METHODS: We conducted a retrospective cohort study of patients hospitalised with pure viral infection (n=2075) versus bacterial coinfection (n=179). The ability of procalcitonin to distinguish these groups was assessed. In addition, procalcitonin and interferon gene expression were evaluated in murine and cellular models of influenza infection. RESULTS: Patients with bacterial coinfection had higher procalcitonin than those with pure viral infection, but also more severe disease and higher mortality (p<0.001). After matching for severity, the specificity of procalcitonin for bacterial coinfection dropped substantially, from 72% to 61%. In fact, receiver operating characteristic curve analysis showed that procalcitonin was a better indicator of multiple indices of severity (eg, organ failures and mortality) than of coinfection. Accordingly, patients with severe viral infection had elevated procalcitonin. In murine and cellular models of influenza infection, procalcitonin was also elevated despite bacteriologic sterility and correlated with markers of severity. Interferon signalling did not abrogate procalcitonin synthesis. DISCUSSION: These studies reveal that procalcitonin rises during pure viral infection in proportion to disease severity and is not suppressed by interferon signalling, in contrast to prior models of procalcitonin regulation. Applied clinically, our data suggest that procalcitonin represents a better indicator of disease severity than bacterial coinfection during viral respiratory infection.


Subject(s)
Biomarkers/metabolism , Pneumonia, Viral/metabolism , Procalcitonin/metabolism , Aged , Aged, 80 and over , Animals , Coinfection , Female , Humans , Male , Mice , Mice, Inbred C57BL , Middle Aged , Pneumonia, Bacterial/metabolism , Pneumonia, Bacterial/mortality , Pneumonia, Viral/mortality , Retrospective Studies , Severity of Illness Index
14.
PLoS One ; 15(4): e0231071, 2020.
Article in English | MEDLINE | ID: mdl-32243471

ABSTRACT

At present, our ability to comprehend the dynamics of food systems and the consequences of their rapid 'transformations' is limited. In this paper, we propose to address this gap by exploring the interactions between the sustainability of food systems and a set of key drivers at the global scale. For this we compile a metric of 12 key drivers of food system from a globally-representative set of low, middle, and high-income countries and analyze the relationships between these drivers and a composite index that integrates the four key dimensions of food system sustainability, namely: food security & nutrition, environment, social, and economic dimensions. The two metrics highlight the important data gap that characterizes national systems' statistics-in particular in relation to transformation, transport, retail and distribution. Spearman correlations and Principal Component Analysis are then used to explore associations between levels of sustainability and drivers. With the exception of one economic driver (trade flows in merchandise and services), the majority of the statistically significant correlations found between food system sustainability and drivers appear to be negative. The fact that most of these negative drivers are closely related to the global demographic transition that is currently affecting the world population highlights the magnitude of the challenges ahead. This analysis is the first one that provides quantitative evidence at the global scale about correlations between the four dimensions of sustainability of our food systems and specific drivers.


Subject(s)
Food Supply , Internationality , Food Supply/economics , Humans , Principal Component Analysis , Statistics, Nonparametric
15.
Biomed Res Int ; 2020: 7582763, 2020.
Article in English | MEDLINE | ID: mdl-31998798

ABSTRACT

PURPOSE: To describe intravitreal anti-VEGF drug and dexamethasone use in four Italian regions. METHODS: Four regional claims databases were used to measure drug prevalence, compare dosing intervals to those recommended in the summary of product characteristics (SPC), and identify switchers. Bilateral treatment and diabetic macular edema (DME) coding algorithms were validated, linking claims with a sample of prospectively collected ophthalmological data. RESULTS: Overall, 41,836 patients received ≥1 study drug in 2010-2016 (4.8 per 10,000 persons). In 2016, anti-VEGF drug use ranged from 0.8 (Basilicata) to 5.7 (Lombardy) per 10,000 persons while intravitreal dexamethasone use ranged from 0.2 (Basilicata) to 1.4 (Lombardy) per 10,000 persons. Overall, 40,815 persons were incident users of study drugs. Among incident users with ≥1 year of follow-up (N = 30,745), 16.0% (N = 30,745), 16.0% (N = 30,745), 16.0% (. CONCLUSION: Study drug use increased over time in Lombardy, Basilicata, Calabria, and Sicily, despite a large heterogeneity in prevalence of use across regions. Drug treatment appeared to be partly in line with SPC, suggesting that improvement in clinical practice may be needed to maximize drug benefits.


Subject(s)
Angiogenesis Inhibitors/administration & dosage , Dexamethasone/administration & dosage , Diabetic Retinopathy/drug therapy , Macular Edema/drug therapy , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Aged , Aged, 80 and over , Diabetic Retinopathy/epidemiology , Drug Implants/administration & dosage , Female , Humans , Insurance Claim Review , Italy/epidemiology , Macular Edema/epidemiology , Male , Middle Aged
16.
Sci Data ; 6(1): 279, 2019 11 25.
Article in English | MEDLINE | ID: mdl-31767866

ABSTRACT

This paper presents the first global map of food systems sustainability based on a rigorous protocol. The choice of the metric dimensions, as well as the individual indicators included in the metric, were initially identified from a thorough review of the existing literature. A rigorous inclusion/exclusion protocol was then used to refine the list and shorten it to a sub-set of 27 indicators. An aggregate sustainability score was then computed based on those 27 indicators organized into four dimensions: environment, social, food security & nutrition and economic. The paper shows how the availability of data (or lack therefore) results in an unavoidable trade-off between number of indicators and number of countries, and highlights how optimization can be used to present the most robust metric possible given the existence of this trade-offs in the data space. The process results in the computation of a global sustainability map covering 97 countries and 20 indicators. The sustainability scores obtained for each country are made available over the entire range of indicators.

17.
Article in English | MEDLINE | ID: mdl-31131348

ABSTRACT

PURPOSE: Androgen receptor (AR) gene alterations, including ligand-binding domain mutations and copy number (CN) gain, have yet to be fully established as predictive markers of resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). The goal of this study was to validate AR gene alterations detected in cell-free DNA (cfDNA) as markers of enzalutamide and abiraterone resistance in patients with mCRPC. METHODS: Patients with mCRPC (N = 62) were prospectively enrolled between 2014 and 2018. Blood was collected before therapies-enzalutamide (n = 25), abiraterone (n = 35), or enzalutamide and abiraterone (n = 2)-and at disease progression. We used deep next-generation sequencing to analyze cfDNA for sequence variants and CN status in AR and 45 additional cancer-associated genes. Primary end points were prostate-specific antigen response, progression-free survival (PFS), and overall survival (OS). RESULTS: Elevated tumor-specific cfDNA (circulating tumor DNA) was associated with a worse prostate-specific antigen response (hazard ratio [HR], 3.17; 95% CI, 1.11 to 9.05; P = .031), PFS (HR, 1.76; 95% CI, 1.03 to 3.01; P = .039), and OS (HR, 2.92; 95% CI, 1.40 to 6.11; P = .004). AR ligand-binding domain missense mutations (HR, 2.51; 95% CI, 1.15 to 5.72; P = .020) were associated with a shorter PFS in multivariable models. AR CN gain was associated with a shorter PFS; however, significance was lost in multivariable modeling. Genetic alterations in tumor protein p53 (HR, 2.70; 95% CI, 1.27 to 5.72; P = .009) and phosphoinositide 3-kinase pathway defects (HR, 2.62; 95% CI, 1.12 to 6.10; P = .026) were associated with a worse OS in multivariable models. CONCLUSION: These findings support the conclusion that high circulating tumor DNA burden is associated with worse outcomes to enzalutamide and abiraterone in men with mCRPC. Tumor protein p53 loss and phosphoinositide 3-kinase pathway defects were associated with worse OS in men with mCRPC. AR status associations with outcomes were not robust, and additional validation is needed.

18.
Dalton Trans ; 48(3): 1023-1039, 2019 Jan 15.
Article in English | MEDLINE | ID: mdl-30604795

ABSTRACT

The syntheses, characterization, X-ray crystal structures, electrochemical properties and anticancer and antichagasic activities of the first examples of 2-substituted 2,4-dihydro-1H-3,1-benzoxazines with half-sandwich organometallic arrays, [M(η5-C5H4)(CO)3] (M = Re or Mn), at position-2 are described. Experimental and computational studies based on DFT calculations on the open forms [Schiff bases of general formulae R-CH[double bond, length as m-dash]N-C6H4-2-CH2OH] (5), with R = ferrocenyl (a), phenyl (b), cyrhetrenyl (c) or cymantrenyl (d), and their tautomeric forms (2-substituted 2,4-dihydro-1H-3,1 benzoxazines) have allowed us to establish the influence of substituents a-d and solvents on: (a) the extent of tautomeric equilibria (5a-5d) ↔ (6a-6d) and (b) their electrochemical properties and the electronic distribution on the open and closed forms. Despite the formal similarity between 6c and 6d, their anticancer and antiparasitic activities are markedly different. Compound 6d is inactive in the HCT116, MDA-MB231 and MCF7 cancer cell lines, but 6c shows moderate activity in the latter cell line, while the Mn(i) complex (6d) is a more potent anti-Trypanosoma cruzi agent than its Re(i) analogue (6c).

19.
Oncotarget ; 8(9): 15651-15662, 2017 Feb 28.
Article in English | MEDLINE | ID: mdl-28152506

ABSTRACT

Somatic genetic alterations including copy number and point mutations in the androgen receptor (AR) are associated with resistance to therapies targeting the androgen/AR axis in patients with metastatic castration resistant prostate cancer (mCRPC). Due to limitations associated with biopsying metastatic lesions, plasma derived cell-free DNA (cfDNA) is increasingly being used as substrate for genetic testing. AR mutations detected by deep next generation sequencing (NGS) of cfDNA from patients with mCRPC have been reported at allelic fractions ranging from over 25% to below 1%. The lower bound threshold for accurate mutation detection by deep sequencing of cfDNA has not been comprehensively determined and may have locus specific variability. Herein, we used NGS for AR mutation discovery in plasma-derived cfDNA from patients with mCRPC and then used droplet digital polymerase chain reaction (ddPCR) for validation. Our findings show the AR (tTC>cTC) F877L hotspot was prone to false positive mutations during NGS. The rate of error at AR (tTC>cTC) F877L during amplification prior to ddPCR was variable among high fidelity polymerases. These results highlight the importance of validating low-abundant mutations detected by NGS and optimizing and controlling for amplification conditions prior to ddPCR.


Subject(s)
DNA, Neoplasm/genetics , Mutation , Prostatic Neoplasms, Castration-Resistant/genetics , Receptors, Androgen/genetics , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , DNA, Neoplasm/blood , Genetic Testing/methods , High-Throughput Nucleotide Sequencing/methods , Humans , Male , Middle Aged , Polymerase Chain Reaction/methods , Prostatic Neoplasms, Castration-Resistant/blood , Prostatic Neoplasms, Castration-Resistant/diagnosis , Reproducibility of Results , Sensitivity and Specificity
20.
Rev. colomb. psicol ; 25(1): 155-173, ene.-jun. 2016. ilus, tab
Article in Spanish | LILACS | ID: lil-783637

ABSTRACT

Se exploraron las percepciones que tienen 300 docentes de la ciudad de Cali, acerca de los saberes y prácticas para la atención de población en situación de desplazamiento en contexto escolar. El estudio fue exploratorio descriptivo, vinculó investigación documental y el diseño, aplicación y análisis de una encuesta cualitativa (Jansen, 2012). En Colombia, desde 1995, inicia la regulación de marcos normativos y orientaciones para la atención de población en situación de desplazamiento; sin embargo, el estudio muestra que estas orientaciones aún no han sido de cobertura suficiente para impactar lo que los docentes requieren conocer y hacer al respecto. Desde la psicología política se invita a fomentar procesos de formación continua docente, que permitan mejorar la atención a las poblaciones en el ámbito educativo.


The paper explores the perceptions of 300 teachers from the city of Cali concerning knowledge and practices for the support of the displaced population in a school context. The descriptive exploratory study involved documentary, research and the application and analysis of a qualitative survey (Jansen, 2012). Since 1995 regulatory frameworks and orientations to assist the displaced population have existed in Colombia; nonetheless, the study shows that these orientations still have not had sufficient coverage to impact what teachers need to know and do in that respect. From a political psychology perspective, this article supports the need of continuous teacher training to improve the attention given to displaced populations in the educational environment.


Neste estudo, exploram-se as percepções que 300 docentes da cidade de Cali têm sobre os saberes e as práticas para o atendimento da população em situação de deslocamento forçado em contexto escolar. O estudo foi exploratório descritivo; vinculou pesquisa documental e o desenho, a aplicação e a análise de uma enquete qualitativa (Jansen, 2012). Na Colômbia, desde 1995, inicia a regulação de referenciais normativos e orientações para o atendimento da população em situação de deslocamento; contudo, o estudo mostra que essas orientações ainda não são de cobertura suficiente para impactar o que os docentes requerem conhecer e fazer a respeito. A partir da psicologia política, faz-se o convite para se fomentar processos de formação contínua docente que permitam melhorar o atendimento dessas populações no âmbito educativo.

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