RESUMO
BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; â¼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Progressão da Doença , Mutação , Diarreia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (â¼5.6 months) versus 16.2 weeks (â¼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fulvestranto/efeitos adversos , Pirrolidinas/uso terapêutico , Inibidores da Aromatase , Mutação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismoRESUMO
OBJECTIVE: The purpose of this study was to evaluate if the cognitive benefit of rivastigmine is affected by the presence of orthostatic hypotension (OH) in patients with Parkinson's disease dementia (PDD). METHODS: We conducted a post hoc analysis on 1,047 patients with PDD from 2 randomized controlled trials comparing rivastigmine versus placebo at week 24 (n = 501) and rivastigmine patch versus capsule at week 76 (n = 546). A drop ≥ 20 mm Hg in systolic blood pressure (SBP) or ≥ 10 in diastolic blood pressure (DBP) upon standing classified subjects as OH positive (OH+); otherwise, OH negative (OH-). The primary end point was the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) at week 24 and the Mattis Dementia Rating Scale (MDRS) at week 76, using intention-to-treat with retrieved dropout at week 24 and observed cases at week 76, consistent with the original analyses. RESULTS: Overall safety was comparable between OH+ (n = 288, 27.5%) and OH- (n = 730, 69.7%), except for higher frequency of syncope (9.2%) in the OH+ placebo arm. The placebo-adjusted effect of rivastigmine on ADAS-Cog at week 24 was 5.6 ± 1.2 for OH+ and 1.9 ± 0.9 in OH- (p = 0.0165). Among subjects with OH, the MDRS change from baseline at week 76 was higher for rivastigmine capsules versus patch (10.6 ± 2.9 vs -1.5 ± 3.0, p = 0.031). The overall prevalence of OH was lower for rivastigmine than placebo at week 24 (28.3% vs 44.6%, p = 0.0476). INTERPRETATION: The cognitive benefit from rivastigmine is larger in patients with PDD with OH, possibly mediated by a direct antihypotensive effect. ANN NEUROL 2021;89:91-98.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Hipotensão/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Rivastigmina/uso terapêutico , Idoso , Inibidores da Colinesterase/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Testes NeuropsicológicosRESUMO
BACKGROUND: In both acute graft-versus-host disease (GVHD) and lupus erythematosus (LE), the patient's own tissues are subjected to immunological assault via complex mechanisms influenced by interferon (IFN) and other cytokines. Although not typically confused clinically, these entities have overlapping histopathological findings in the skin. AIM: To assess whether GVHD can be differentiated from LE using molecular methods on skin specimens. METHODS: We developed a quantitative reverse transcription PCR assay based on previously identified tissue-based biomarkers of cutaneous GVHD, and compared gene expression in GVHD with that in LE. RESULTS: Both entities showed robust expression of IFN-induced genes and of genes encoding proteins involved in antigen presentation, cell signalling and tissue repair. Levels of gene expression differed significantly in GVHD compared with LE, particularly those of IFN-induced genes such as MX1, OAS3, TAP1 and STAT3 (P < 0.01). Three logistic regression models could differentiate the two entities with a high degree of certainty (receiver operating characteristic area under the curve of 1.0). CONCLUSION: The study demonstrates the feasibility of distinguishing between microscopically similar inflammatory dermatoses using tissue-based molecular techniques.
Assuntos
Expressão Gênica/genética , Doença Enxerto-Hospedeiro/metabolismo , Interferons/genética , Lúpus Eritematoso Sistêmico/metabolismo , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Citocinas/metabolismo , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Dermatopatias/patologiaRESUMO
The yellow color of Cheddar cheese whey arises from a residual amount of annatto that partitions into the whey during Cheddar cheese manufacture. Bleaching of the color using hydrogen peroxide or benzoyl peroxide is often a prerequisite to produce an acceptable neutral-colored whey protein concentrate and isolate. However, the use of these strong oxidizing agents often generates off-flavors as a result of lipid oxidation and results in loss of nutritive value due to protein oxidation. The objective of this study was to determine the extent of partitioning of annatto between protein, milk fat globule membrane (MFGM), and aqueous (serum) phases of cheese whey so that a simple method can be developed to remove annatto from cheese whey. The MFGM was separated from Cheddar cheese whey using a recently developed novel method. Quantitative analysis of the distribution of annatto in the fat-free whey protein isolate (WPI), the MFGM fractions, and the serum phase revealed that annatto was not bound to the protein fraction but was mostly distributed between the serum phase and the MFGM fraction. The results showed that a colorless WPI or whey protein concentrate could be produced from Cheddar cheese whey by separation of MFGM from the whey, followed by diafiltration. This approach will negate the need for using bleaching agents.
Assuntos
Carotenoides/análise , Queijo/análise , Glicolipídeos/análise , Glicoproteínas/análise , Proteínas do Leite/análise , Extratos Vegetais/análise , Animais , Bixaceae , Bovinos , Tecnologia de Alimentos/métodos , Gotículas Lipídicas , Oxirredução , Proteínas do Soro do LeiteRESUMO
Clomiphene citrate (CC) has been widely used for ovulation induction since the 1960s, due to its ease of administration and minimal side-effects. We conducted a retrospective study of 565 women who attended the infertility clinic at a district general hospital (Victoria Hospital, Kirkcaldy) between January 2004 and October 2008. The database was analysed for age, pregnancy rates, type of infertility and pregnancy outcomes. The conception rate with clomiphene citrate was 25%. The drug was well tolerated in 97.5% of women. The miscarriage rate with CC was 4.3%. We believe that these data give useful insights on CC therapy to gynaecologists involved in infertility clinics in a district general hospital setting.
Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Infertilidade Feminina/tratamento farmacológico , Adulto , Feminino , Humanos , Gravidez , Taxa de Gravidez , Estudos RetrospectivosRESUMO
The effect of solvent conditions on the refolding of bovine serum albumin was studied. The rate and extent of refolding was affected by the type of monovalent salt used in the medium. While NaCl and NaBr promoted refolding, NaClO4 and NaSCN decreased the rate and extent of refolding at 0.2 M concentration. In this respect the relative order in which various anions influenced the refolding process followed the lyotropic series Cl-, Br-, I-, ClO4-, SCN-. Urea exhibited two opposite effects on the refolding of albumin: whereas at low concentrations urea increased the extent of refolding, at concentrations above 2.0 M the rate and extent of refolding were dramatically decreased. Addition of ethanol to the medium greatly decreased the refolding even at concentrations as low as 4% (v/v). The effects of these various additives on the refolding behavior of serum albumin is interpreted in terms of subtle changes in the structure of water. It is also shown that, while such changes in the solvent structure affected the rate and extent of refolding, they did not affect the pathway of refolding.
Assuntos
Soroalbumina Bovina , Etanol/farmacologia , Cinética , Concentração Osmolar , Conformação Proteica , Desnaturação Proteica , Soroalbumina Bovina/metabolismo , Solventes , Espectrometria de FluorescênciaRESUMO
To elucidate the role of protein conformation in the kinetics of adsorption at interfaces, seven structural intermediates of bovine serum albumin were prepared and their adsorption at the air/water interface was studied. Molecular area calculations indicated two distinct molecular processes, the first being the creation of an area, delta A1, for anchoring the molecule during the initial phase of adsorption and the second being the delta A2 cleared during subsequent reorientation and rearrangement of adsorbed molecules at the interface. The delta A1 values for all the albumin intermediates were the same, indicating that the initial work pi delta A1 needed to anchor the molecule at the interface was independent of solution conformation of the protein. Unlike delta A1, delta A2 exhibited a bell-shaped relationship with the extent of refolded state of the intermediates. Calculation of diffusion coefficients indicated that greater the unfolded state of the albumin intermediate, the greater was the diffusion coefficient. It is shown that the simple diffusion theory is inadequate to explain quantitatively the kinetics of protein adsorption. Specific, conformation-dependent, solute-solvent and solute-interface interactions also seem to influence the kinetics of adsorption of proteins.
Assuntos
Conformação Proteica , Albumina Sérica , Adsorção , Ar , Difusão , Cinética , Relação Estrutura-Atividade , Termodinâmica , ÁguaRESUMO
OBJECTIVE: The authors' goal was to conduct a prospective study comparing the rate of occurrence of neuroleptic-induced dystonia in a group of consecutively admitted manic and schizophrenic patients receiving typical inpatient treatment from several clinicians. METHOD: All patients met the following criteria: 1) male sex, 2) age between 17 and 45 years, 3) definite diagnosis of mania or schizophrenia according to Research Diagnostic Criteria, 4) no exposure to neuroleptics during the past month, 5) absence of past or family history of a neurodegenerative disorder with extrapyramidal symptoms. All treatment decisions were left to the treating clinicians. Fifty patients with mania and 33 with schizophrenia were included in the study. Most of these patients received high-potency neuroleptics, but the specific neuroleptic used varied in the two groups. RESULTS: Twelve (24%) of the patients with mania and five (15%) of the patients with schizophrenia developed acute dystonia. Manic patients received significantly higher peak doses of neuroleptics during the risk period for dystonia. Stepwise multiple regression analysis revealed that the peak neuroleptic dose and age were most strongly related to the occurrence of dystonia. CONCLUSIONS: This prospective study failed to support the retrospective finding of another study that acute dystonia occurred more often in manic patients than in patients with nonparanoid schizophrenia. The authors conclude that there is a need for carefully controlled prospective studies with larger groups of patients.
Assuntos
Antipsicóticos/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Distonia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Antipsicóticos/administração & dosagem , Relação Dose-Resposta a Droga , Distonia/epidemiologia , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Projetos de Pesquisa/normas , Estudos RetrospectivosRESUMO
The effect of various anions in destabilizing yeast nucleoprotein complexes followed the order F- less than Cl- less than Br- less than ClO-4 congruent to Cl3CCOO-. Treatment of yeast nucleoproteins with 0.5 M NaClO4 resulted in removal of 80% of RNA. Based on the results, a simple method for effective separation of RNA from ribosomal particles is proposed and the mechanism of RNA dissociation by anions is also discussed.
Assuntos
Nucleoproteínas/isolamento & purificação , RNA Ribossômico/isolamento & purificação , Fenômenos Químicos , Química , Proteínas Fúngicas , RNA Fúngico , Saccharomyces cerevisiae/genética , SaisRESUMO
Competitive adsorption of proteins from several binary protein solutions to the air-water interface has been studied. With a few exceptions, the equilibrium composition of the saturated monolayer of mixed protein films at various bulk concentration ratios did not follow a Langmuir-type competitive adsorption model. The deviation from ideal behavior results from incompatibility of mixing of proteins in the film at the air-water interface. This immiscibility alters the ratio of the binding affinity of the proteins in a protein 1/protein 2/water ternary film compared to that in a protein 1/water and protein 2/water binary film. A method to determine the extent of incompatibility between two proteins in a mixed protein film has been developed. It is shown that the incompatibility index derived for 19 protein 1/water and protein 2/water systems studied show a linear relationship with the absolute difference between Flory-Huggins protein-solvent interaction parameters, that is, /chi(1s) - chi(2)/, of the constituent proteins. On the basis of the evidence, it is theorized that, because of incompatibility, proteins in a mixed protein film at interfaces may undergo two-dimensional phase separation.
Assuntos
Proteínas/química , Adsorção , Ar , Biofilmes , Modelos Teóricos , Soluções , Propriedades de Superfície , ÁguaRESUMO
Lateral phase separation in two-dimensional mixed films of soy 11S/beta-casein, acidic subunits of soy 11 (AS11S)/beta-casein, and alpha-lactalbumin/beta-casein adsorbed at the air-water interface has been studied using an epifluorescence microscopy method. No distinct lateral phase separation was observed in the mixed protein films when they were examined after 24 h of adsorption from the bulk phase. However, when the soy 11S/beta-casein and AS11S/beta-casein films were aged at the air-water interface for 96 h, phase-separated regions of the constituent proteins were evident, indicating that the phase separation process was kinetically limited by a viscosity barrier against lateral diffusion. In these films, beta-casein always formed the continuous phase and the other globular protein the dispersed phase. The morphology of the dispersed patches was affected by the protein composition in the film. In contrast with soy 11S/beta-casein and AS11S/beta-casein films, no lateral phase separation was observed in the alpha-lactalbumin/beta-casein film at both low and high concentration ratios in the film. The results of these studies proved that proteins in adsorbed binary films exhibit limited miscibility, and the deviation of competitive adsorption behavior of proteins at the air-water interface from that predicted by the ideal Langmuir model (Razumovsky, L.; Damodaran, S. J. Agric. Food Chem. 2001, 49, 3080-3086) is in fact due to thermodynamic incompatibility of mixing of the proteins in the binary film. It is hypothesized that phase separation in adsorbed mixed protein films at the air-water and possibly oil-water interfaces of foams and emulsions might be a source of instability in these dispersed systems.
Assuntos
Caseínas/química , Lactalbumina/química , Proteínas de Soja/química , Adsorção , Ar , Biofilmes , Microscopia de Fluorescência/métodos , Propriedades de Superfície , ÁguaRESUMO
beta-Casein was polymerized to various extents by the transglutaminase-catalyzed cross-linking reaction. Under the reaction conditions used, dimer, trimer, and tetramer of beta-casein were produced as predominant species at short reaction times (20-90 min) and large polymers at longer reaction times (3-24 h). Examination of the emulsifying properties of these cross-linked beta-casein polymers showed that although the emulsifying activity index decreased, the storage stability of the emulsions increased with increasing degree of polymerization. Experiments with mixtures of native and polymerized beta-casein also showed that increasing the fraction of polymerized beta-casein in the mixture increased the emulsion stability. This enhancement of emulsion stability might be due either to an enhancement in steric stabilization, attributable to the branched nature of the trasgutaminase-catalyzed polymers, or to stronger cohesive interactions between polymerized beta-casein molecules than between monomeric beta-casein molecules in the film.
Assuntos
Caseínas/química , Excipientes , Transglutaminases/metabolismo , Caseínas/metabolismo , Reagentes de Ligações Cruzadas , Emulsões , Cinética , Streptomyces/enzimologiaRESUMO
The emulsifying properties of the acidic subunits (AS11S) isolated from soy glycinin (11S) have been studied. The isolated AS11S existed in solution mainly as a dimer species. Circular dichroic analysis indicated only a slight increase in aperiodic structure and no significant difference in beta-sheet structure when compared with those of soy 11S. At similar experimental conditions, the emulsifying properties of AS11S were superior to those of soy 11S and heat-denatured 11S. Emulsions prepared with 1% AS11S remained very stable without any visible oil separation for more than a month under gentle agitating conditions, whereas those prepared with 1% 11S collapsed and separated into phases within 2-3 days. The AS11S-stabilized emulsions were very stable below 0.15 M ionic strength. Studies on the rate of adsorption and surface tension reduction at the air-water interface showed that AS11S was significantly more surface active than soy 11S. It is proposed that, because the mass fraction of acidic subunits in soy 11S is approximately 60% and it is relatively easy to separate the acidic subunits from soy 11S, it may be industrially feasible to develop an economical process to isolate functional acidic subunits for use in emulsion-based food products.
Assuntos
Excipientes/química , Globulinas/química , Proteínas de Soja/química , Cromatografia em Gel , Dicroísmo Circular , Eletroforese em Gel de Poliacrilamida , Emulsões , Excipientes/isolamento & purificação , Globulinas/isolamento & purificação , Concentração de Íons de Hidrogênio , Solubilidade , Propriedades de SuperfícieRESUMO
The thermostability of serum albumin and beta-lactoglobulin in various salt solutions was studied using differential scanning calorimetry. Below 1.0 M salt concentrations, the relative effectiveness of various sodium salts on increasing the thermostability of beta-lactoglobulin followed the classic Hofmeister or lyotropic series, i.e. SO2-(4) greater than Cl- greater than Br- greater than ClO-4 greater than SCN-; however, in the case of serum albumin the above order was reversed, i.e. ClO-4 greater than SCN- greater than Br- greater than Cl- greater than SO2-(4), indicating that the thermostability of serum albumin was higher in chaotropic solution conditions. Circular dichroic analysis of serum albumin in NaClO4 solutions revealed that the alpha-helical content of the protein increased from 59% to 73% in 1.0 M NaClO4; no similar increase in secondary structure was observed for beta-lactoglobulin. These observations contradicted the general notion that the chaotropic effect of neutral salts on the stability of macromolecules is independent of any details of the macromolecular conformation itself. The results presented here indicate that the predisposition of the native conformation of a protein per se might affect whether the protein would undergo stabilization or destabilization (i.e. conformational adaptability) under moderate chaotropic solution conditions.
Assuntos
Lactoglobulinas/química , Conformação Proteica , Albumina Sérica/química , Animais , Varredura Diferencial de Calorimetria , Bovinos , Dicroísmo Circular , Desnaturação Proteica , Sais , Sódio , TemperaturaRESUMO
The therapeutic efficacy of Cassia alata leaf extract against Pityriasis versicolor has been reported for the first time involving humans. For the collection of clinically effective antifungal compounds from the leaves of Cassia alata, a simple procedure has been devised. A 10-year human study indicates that the leaf extract can be reliably used as a herbal medicine to treat Pityriasis versicolor. The leaf extract has no side-effects.