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Cancer poses a significant risk to human well-being. Among the crucial characteristics of cancer is metabolic reprogramming. To meet the relentless metabolic needs, cancer cells enhance cholesterol metabolism within the adverse tumor microenvironment. Reprograming cholesterol metabolism includes a series of modifications in the synthesis, absorption, esterification, and metabolites associated with cholesterol. These adjustments have a strong correlation with the proliferation, invasion, metastasis, and other characteristics of malignant tumors. FDFT1, also known as farnesyl diphosphate farnesyltransferase 1, is an enzyme crucial in the process of cholesterol biosynthesis. Its significant involvement in tumor metabolism has garnered considerable interest. The significance of FDFT1 in cancer metabolism cannot be overstated, as it actively interacts with cancer cells. This paper aims to analyze and consolidate the mechanism of FDFT1 in cancer metabolism and explore its clinical application. The goal is to contribute new strategies and targets for the prevention and treatment of cancer metabolism.
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Farnesil Difosfato Farnesil Transferasa , Neoplasias , Humanos , Neoplasias/metabolismo , Neoplasias/patología , Farnesil Difosfato Farnesil Transferasa/metabolismo , Farnesil Difosfato Farnesil Transferasa/genética , Colesterol/metabolismo , Animales , Microambiente TumoralRESUMEN
Background: Colorectal cancer is a major cause of mortality among the prevalent malignant tumors of the gastrointestinal tract. Although chemotherapy is a standard treatment for colorectal cancer, its efficacy is limited by chemoresistance. Recent studies have investigated targeting tumor stem cells as a potential new therapeutic approach for addressing chemoresistance in colorectal cancer. Colorectal cancer frequently relapses, with tumor stem cells often representing one of the leading causes of treatment failure. Purpose: Understanding drug resistance in colorectal cancer stem cells is crucial for improving treatment outcomes. By focusing on developing targeted therapies that specifically address drug resistance in colorectal cancer stem cells, there is potential to make significant advancements in the treatment of colorectal cancer.This approach may lead to more effective and lasting outcomes in patients battling colorectal cancer. Research Design: In this review, a comprehensive overview of recent research on colorectal cancer stem cell treatment resistance is presented.Results: Elucidating the key underlying mechanisms. This review also highlights the potential benefits of targeted therapies in overcoming colorectal cancer resistance to treatment. Conclusions: CCSCs are key players in drug resistance of CRC, indicating their potential as targets for effective therapy. Elucidating their role in this process could aid in discovering tailored treatment strategies.The significance of signaling pathways, TME, and miRNA in regulating drug resistance in CCSCs is been highlighted.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Células Madre Neoplásicas , Humanos , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , MicroARNs/genética , Transducción de Señal/efectos de los fármacos , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
The mechanical stimulation of cells from the surrounding environment is an important life activity. However, there has been a lack of dynamically quantitative analysis of cell morphology under mechanical stimulations. A theoretical model for the evolution of cell morphology under stretching is proposed by analyzing the transformation between cell deformation energy and adhesion energy. The images of the evolution show that detachment of the adhesion membrane or re-adhesion of the cell, causes a decrease or increase of the adhesion area, respectively. In addition to the stretching amplitude and velocity, we found that the duration of the stretching stage and the no stretching stage can affect the cell morphology during cyclic stretching. The theoretical model explains some counter-intuitive experimental results and provides many quantitative insights into understanding the physical mechanisms of cell adhesion under stretching. This study can provide a useful guide to control cell adhesion under mechanical stimulations.
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Adhesión Celular , Modelos Biológicos , Forma de la Célula , Estrés Mecánico , Fenómenos Biomecánicos , HumanosRESUMEN
BACKGROUND: Individuals with transfusion-dependent ß-thalassemia (TDT) experience symptoms and functional impacts that reduce their health-related quality of life. However, EQ-5D-derived health utility index scores in TDT often indicate good HRQoL, suggesting the EQ-5D may not adequately capture the impact of TDT. This study explored the disease and treatment burden of TDT and examined the appropriateness of the EQ-5D-5L descriptive system (DS) in measuring HRQoL in TDT. METHODS: Adults with TDT in the United Kingdom, United States, and France completed a background questionnaire and EQ-5D-5L DS, followed by 60-minute semi-structured interviews on symptoms and HRQoL impacts of TDT (concept elicitation) and appropriateness of EQ-5D-5L DS (cognitive debrief). Transcribed interviews were analyzed using thematic and content analyses. The relationship between TDT symptoms and impacts were summarized in a conceptual model. EQ-5D-5L DS was mapped to concepts identified in the qualitative data to assess its capture of HRQoL concepts. Participants' EQ-5D-5L DS scores were compared to their qualitative descriptions for each dimension to assess their concordance. RESULTS: Thirty participants in the United States (n = 14 [46.7%]), United Kingdom. (n = 12 [40.0%]), and France (n = 4 [13.3%]) completed the study (73.3% female; mean age = 28.4 years [standard deviation (SD) = 5.1]; mean annual red blood cell transfusion [RBCT] frequency = 18.4 [SD = 7.6]). Participants reported TDT symptoms and impacts on HRQoL, all fluctuating across the RBCT cycle. EQ-5D-5L DS did not fully capture 11 of 16 (68.8%) HRQoL concepts reported. Most participants (n = 20/27 [74.1%]) reported that EQ-5D-5L DS did not capture important aspects of living with TDT, and 42.9% (n = 12/28) reported negative/neutral overall impressions of EQ-5D-5L DS. The highest degree of discordance between participants' qualitative data and EQ-5D-5L DS dimension scores was observed with mobility (42.3%) and self-care (34.6%), where the qualitative descriptions relating to these dimensions were worse than their quantitative scores. CONCLUSION: Current findings suggest that EQ-5D-5L DS lacks content validity and the derived health utility index score may not fully represent the burden of disease in TDT.
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Calidad de Vida , Talasemia beta , Humanos , Femenino , Masculino , Calidad de Vida/psicología , Adulto , Talasemia beta/psicología , Talasemia beta/terapia , Encuestas y Cuestionarios , Reino Unido , Estados Unidos , Francia , Persona de Mediana Edad , Transfusión Sanguínea/psicología , Entrevistas como Asunto , Adulto Joven , Investigación CualitativaRESUMEN
OBJECTIVE: Florfenicol(FF) is an excellent veterinary antibiotic, limited by poor solubility and poor bioavailability. SIGNIFICANCE: Here in, we aimed to explore the applicability of fast disintegrating tablets compressed from Florfenicol-loaded solid dispersions (FF-SD-FDTs) to improve the dissolution rate and oral bioavailability of Florfenicol. METHODS: Utilizing selecting appropriate preparation methods and carriers, the solid dispersions of Florfenicol (FF-SDs) were prepared by solvent evaporation and the fast disintegrating tablets (FF-SD-FDTs) were prepared by the direct compression (DC) method. RESULTS: The tablet properties including hardness, friability, disintegration time, weight variation, etc. all met the specifications of Chinese Veterinary Pharmacopeia(CVP). FF-SD-FDTs significantly improved drug dissolution and dispersion of FF in vitro compared to florfenicol conventional tablets (FF-CTs). A pharmacokinetics study in German shepherd dogs proved the AUC0-∞ and Cmax values of FF-SD-FDTs are 1.38 and 1.38 times more than FF-CTs, respectively. CONCLUSIONS: Overall, it can be concluded that FF-SD-FDTs with excellent disintegration and dissolution properties were successfully produced, which greatly improved the oral bioavailability of the poorly soluble drug FF, and the study provided a new idea for a broader role of FF in pet clinics.
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Tecnología , Tianfenicol/análogos & derivados , Animales , Perros , Disponibilidad Biológica , Solubilidad , Liberación de Fármacos , ComprimidosRESUMEN
INTRODUCTION: Gene therapy clinical trials measure steady-state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. AIM: We evaluated the association between FEL and ABR in PwHB. METHODS: This cross-sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis. Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia-treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. RESULTS: The study included 407 PwHB and no inhibitors receiving on-demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p < .001). Predicted number of bleeding events according to FEL showed a significant non-linear relationship between FEL and ABR (p < .05). CONCLUSION: This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US.
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Hemofilia A , Hemofilia B , Masculino , Humanos , Hemofilia B/complicaciones , Hemofilia B/tratamiento farmacológico , Hemofilia A/tratamiento farmacológico , Estudios Transversales , Hemorragia/complicaciones , Factores de Coagulación Sanguínea/uso terapéutico , Factor VIII/uso terapéuticoRESUMEN
Dietary consumption of contaminated vegetables is the main route of human exposure to polycyclic aromatic hydrocarbons (PAHs). However, there is a lack of research on PAHs in vegetables from northwest China. In this study, the concentrations, sources, and risk assessment of PAHs in the soil and vegetables of Urumqi, an urbanized city in Xinjiang, China, were investigated. The total concentrations of 16 PAHs in soil and vegetable samples ranged 10.58-77.20 and 93.7-1071.8 ng/g, with average values of 2.86 and 242.76 ng/g, respectively. Among vegetable samples, the concentrations were in the order: leafy vegetables (299.08 ng/g) > fruits (192.65 ng/g) > vegetable roots (152.05 ng/g). The source apportionment of PAHs was identified using positive matrix factorization. The primary sources of PAHs in soil samples are oil spills, traffic emissions, coal combustion, and coke combustion. The main sources of PAHs in vegetable samples are oil spills and burning of grass, wood, coal, and coke. In soil samples, the ecological risk caused by PAHs is at a safe level, and the incremental lifetime cancer risks (ILCRs) of ingestion exposure exceed 1.0 × 10-6, which will pose potential risks to human body. The ILCRs of vegetable samples revealed that all groups had potential risks from onion and cabbage consumption (ILCRs > 1.0 × 10-6). In particular, adult women had a higher risk of cancer (ILCRs > 1.0 × 10-4). These results emphasize the importance of combating PAHs pollution in vegetable bases.
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Coque , Neoplasias , Hidrocarburos Policíclicos Aromáticos , Contaminantes del Suelo , Adulto , Femenino , Humanos , Hidrocarburos Policíclicos Aromáticos/toxicidad , Hidrocarburos Policíclicos Aromáticos/análisis , Verduras , Monitoreo del Ambiente/métodos , Contaminantes del Suelo/toxicidad , Contaminantes del Suelo/análisis , Medición de Riesgo , Carbón Mineral/análisis , Suelo , ChinaRESUMEN
Vertical nanostructures have been found to induce the deformation of the nuclear envelope during cell adhesion. However, there has been a lack of quantitative analysis of the influence of nanostructures morphology on the degree of nuclear deformation. Here, a theoretical model was proposed to investigate the mechanism of nuclear deformation by analyzing the mechanical force balance. Based on the established model, we analyzed the effects of the morphology of the nanopillar array on nuclear deformation and gave the quantitative relationship of the deformation depth of the nucleus with the pitch and radius of nanopillars. Our theoretical results seem to show broad agreements with experimental observations, which implies that the work can provide useful guidance to the design of nanostructures for biomedical applications.
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Nanoestructuras , Adhesión Celular , Núcleo Celular , Nanoestructuras/químicaRESUMEN
AIM: Mucin-degrading bacteria are known to be beneficial for gut health. We aimed to isolate human-derived mucin-degrading bacteria and identify potential probiotic characteristics and their effects on the bacterial community and short-chain fatty acid (SCFA) production according to three different enterotypes of the host. METHODS AND RESULTS: Bacteria with mucin decomposition ability from human faeces were isolated and identified by 16S rRNA sequencing and MALDI-TOF. Heat resistance, acid resistance, antibiotic resistance, and antibacterial activity were analysed in the selected bacteria. Their adhesion capability to the Caco-2 cell was determined by scanning electron microscopy. Their ability to alter the bacterial community and SCFA production of the isolated bacteria was investigated in three enterotypes. The three isolated strains were Bifidobacterium(Bif.) animalis SPM01 (CP001606.1, 99%), Bif. longum SPM02 (NR_043437.1, 99%), and Limosilactobacillus(L.) reuteri SPM03 (CP000705.1, 99%) deposited in Korean Collection for Type Culture (KCTC-18958P). Among them, Bif. animalis exhibited the highest mucin degrading ability. They exhibited strong resistance to acidic conditions, moderate resistance to heat, and the ability to adhere tightly to Caco-2 cells. Three isolated mucin-degrading bacteria incubation increased Lactobacillus in the faecal bacteria from Bacteroides and Prevotella enterotypes. However, only L. reuteri elevated Lactobacillus in the faecal bacteria from the Ruminococcus enterotype. B. longum and B. animalis increased the α-diversity in the Ruminococcus enterotype, while their incubation with other intestinal types decreased the α-diversity. Bifidobacterium animalis and L. reuteri increased the butyric acid level in faecal bacteria from the Prevotella enterotype, and L. reuteri elevated the acetic acid level in those from the Ruminococcus enterotype. However, the overall SCFA changes were minimal. CONCLUSIONS: The isolated mucin-degrading bacteria act as probiotics and modulate gut microbiota and SCFA production differently according to the host's enterotypes. SIGNIFICANCE AND IMPACT OF STUDY: Probiotics need to be personalized according to the enterotypes in clinical application.
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Microbioma Gastrointestinal , Probióticos , Bacterias , Bifidobacterium , Células CACO-2 , Ácidos Grasos Volátiles/metabolismo , Heces/microbiología , Humanos , Lactobacillus/genética , Mucinas/metabolismo , ARN Ribosómico 16S/genética , ARN Ribosómico 16S/metabolismo , RuminococcusRESUMEN
INTRODUCTION: People with inherited and long-term conditions such as haemophilia have been shown to adapt to their levels of disability, often reporting better quality of life (QoL) than expected from the general population (the disability paradox). AIM: To investigate the disability paradox in people with haemophilia in the United States by examining preference differences in health state valuations versus the general population. METHODS: We conducted a discrete choice experiment including duration to capture valuations of health states based on patient-reported preferences. Participants indicated their preferences for hypothetical health states using the EQ-5D-5L, where each participant completed 15 of the 120 choice tasks. Response inconsistencies were evaluated with dominated and repeated scenarios. Conditional-logit regressions with random sampling of the general population responses were used to match the sample of patients with haemophilia. We compared model estimates and derived preferences associated with EQ-5D-5L health states. RESULTS: After removing respondents with response inconsistencies, 1327/2138 (62%) participants remained (177/283 haemophilia; 1150/1900 general population). Patients with haemophilia indicated higher preference value for 99% of EQ-5D-5L health states compared to the general population (when matched on age and gender). The mean health state valuation difference of 0.17 indicated a meaningful difference compared to a minimal clinically important difference threshold of 0.07. Results were consistent by haemophilia type and severity. CONCLUSION: Our findings indicated the presence of a disability paradox among patients with haemophilia, who reported higher health states than the general population, suggesting the impact of haemophilia may be underestimated if general population value sets are used.
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Hemofilia A , Calidad de Vida , Estado de Salud , Humanos , Medición de Resultados Informados por el Paciente , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments. AIM: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes. METHODS: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post-treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity. RESULTS: A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%). CONCLUSION: People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia.
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Hemofilia A , Adulto , Conducta de Elección , Terapia Genética , Hemofilia A/genética , Hemofilia A/terapia , Hemorragia/terapia , Humanos , Masculino , Prioridad del Paciente , Encuestas y CuestionariosRESUMEN
Gene therapy for hemophilia is designed to produce health gains for patients over many years. Rewarding that value creation on the basis of a one-time treatment implies a large upfront cost. This cost can only be justified by long-term health benefits and being cost-effective compared with conventional treatments. Yet, uncertainties about the long-term benefits make it challenging to assess clinical and economic value of gene therapies at launch. We identify and discuss key methodological challenges in assessing the value of gene therapy for hemophilia, including the immaturity of evidence on the durability of benefits, lack of definition and valuation of cure for chronic diseases, absence of randomized controlled trials, limitations of traditional quality of life measures in hemophilia, approach for qualifying cost-savings compared with current treatments, and choice of perspective. The Institute for Clinical and Economic Review has developed a framework for assessing single or short-term therapies (ICER-SST) and has applied it in hemophilia. After reviewing this framework and its application, we recommend the following when assessing the value of hemophilia gene therapies: (1) leveraging expert clinical opinion to justify assumptions on the durability of benefits; (2) using external synthetic controls and lead-in, self-controlled trials to assess comparative effectiveness; (3) addressing limitations of traditional quality of life measures through the use of modified utility collection approaches; (4) adjusting cost offsets from gene therapies with caution; (5) considering outcome-based contracting to address uncertainties about prices and long-term outcomes; and (6) presenting societal and healthcare system perspectives in parallel.
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Análisis Costo-Beneficio , Terapia Genética/economía , Hemofilia A/terapia , Análisis Costo-Beneficio/métodos , Humanos , Calidad de Vida , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Long-acting products are changing the haemophilia A treatment landscape by giving patients and caregivers treatment options with varying product attributes. AIM: A discrete choice experiment (DCE) was used to elicit treatment attribute preferences among patients with haemophilia A and caregivers of children with haemophilia A. MATERIALS & METHODS: A survey of sociodemographics and preferences was completed by an online panel of adult patients with haemophilia A and caregivers of children (<18 years) with haemophilia A. The DCE included a series of questions in which respondents chose their preferred option from pairs of hypothetical treatment profiles with systematic variation in the levels of six attributes (safety concerns with too much clotting, bleed protection, dosing frequency, length of time the product has been approved for use, product type and joint health studies). Preference weights and relative attribute importance scores were estimated using random parameters logit models. RESULTS: One hundred and thirteen patients (mean age: 35.5 years) and 96 caregivers (mean age of child: 10.3 years) were included. For patients with haemophilia A, the top three attributes ranked from the most to least important were: (a) dosing frequency; (b) bleed protection; and (c) safety concerns with too much clotting. For caregivers of children with haemophilia A, the ranking was as follows: (a) safety concerns; (b) bleed protection; and (c) dosing. CONCLUSIONS: Patients with haemophilia A viewed dosing as the most important driver of treatment decision-making whereas caregivers of children with haemophilia A valued safety the most.
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Hemofilia A/terapia , Adolescente , Adulto , Anciano , Cuidadores , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prioridad del Paciente , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Chinese medicine is the traditional treasure of China nation. As the basis of Chinese medicine, traditional Chinese medicine(TCM) plays an important part for the development of Chinese medicine. Genuine medicinal materials with special characteristics of TCM growing in special ecological environment, is recognized as the high quality medicine. Research on genuineness evaluation of TCM is the key to ensure its clinical applications, efficacy and the process of modernization and internationalization for Chinese medicine. Lingnan region of China is situated in the tropical and subtropical zones, where there are rich geothermal and hydrothermal resources. The superior natural and geographic environment of Lingnan has given birth to a variety of native herbal drugs. And treating and preventing diseases with Lingnan herbal drugs has a long story. This study mainly evaluated the genuineness of Lingnan herbal drugs from the aspects of ecological factor, thegenetic information, the history, the culture, the clinical efficacy and the processing, and proposed a new idea to investigate the genuineness of TCM, aiming to provide a scientific basis for genuineness evaluation.
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Medicamentos Herbarios Chinos/normas , China , Ambiente , Medicina Tradicional ChinaRESUMEN
The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
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Bases de Datos Factuales , Ensayos de Selección de Medicamentos Antitumorales/métodos , Enciclopedias como Asunto , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Antineoplásicos/farmacología , Línea Celular Tumoral , Linaje de la Célula , Cromosomas Humanos/genética , Ensayos Clínicos como Asunto/métodos , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Genes ras/genética , Genoma Humano/genética , Genómica , Humanos , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Farmacogenética , Células Plasmáticas/citología , Células Plasmáticas/efectos de los fármacos , Células Plasmáticas/metabolismo , Medicina de Precisión/métodos , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Análisis de Secuencia de ADN , Inhibidores de Topoisomerasa/farmacologíaRESUMEN
This study aimed to develop a prediction model to identify patients with candidemia who were at high risk of failing fluconazole treatment. Adult patients in the United States with candidemia who received fluconazole during hospitalization were selected from the Cerner Health Facts Hospital Database (04/2004 to 03/2013). Fluconazole failure was defined as switching/adding another antifungal, positive Candida culture ≥10 days after fluconazole initiation, or death during hospitalization. Patients were randomized into modeling and validation samples. Using the modeling sample, a regression analysis of least absolute shrinkage and selection operator was used to select risk predictors of fluconazole failure (demographics, Candida species, initiation of fluconazole before positive culture and after admission, and comorbidities, procedures, and treatments during the 6 months before admission and fluconazole initiation). The prediction model was evaluated using the validation sample. We found that of 987 identified patients (average age of 61 years, 51% male, 72% Caucasian), 49% failed and 51% did not fail fluconazole treatment. Of those who failed, 70% switched or added another antifungal, 21% had a second positive Candida test, and 42% died during hospitalization. Nine risk factors were included in the prediction model: days to start fluconazole after admission, Candida glabrata or Candida krusei infection, hematological malignancy, venous thromboembolism (VTE), enteral nutrition, use of nonoperative intubation/irrigation, and other antifungal use. All but VTE were associated with a higher risk of failure. The model's c-statistic was 0.65, with a Hosmer-Lemeshow test P value of 0.23. In summary, this prediction model identified patients with a high risk of fluconazole failure, illustrating the potential value and feasibility of personalizing candidemia treatment.
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Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidemia/tratamiento farmacológico , Candidemia/mortalidad , Fluconazol/uso terapéutico , Farmacorresistencia Fúngica , Femenino , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Modelos Teóricos , Factores de Riesgo , Insuficiencia del TratamientoRESUMEN
OBJECTIVES: To assess real-world treatment patterns of targeted therapies after failure of first-line tyrosine kinase inhibitors in patients with advanced renal cell carcinoma. METHODS: A large, retrospective review of medical charts of patients with advanced renal cell carcinoma in the USA was carried out. Descriptive statistics were used to summarize physicians' and patients' characteristics, treatment sequences, and reasons for treatment choices. P-values were calculated using χ2 -tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. A descriptive comparison was carried out between current results and those of a previous treatment pattern study conducted in 2012 to identify changes in treatment patterns over time. RESULTS: Sunitinib and everolimus remained the most commonly-used first and second targeted therapies, respectively. Among patients who continued to a third targeted therapy, everolimus and axitinib were the most commonly-used treatments after second targeted therapy with a tyrosine kinase inhibitor and a mammalian target of rapamycin inhibitor, respectively. The use of pazopanib as first targeted therapy, and of axitinib and sorafenib as second targeted therapies, increased over time. Efficacy, treatment guidelines and a different mechanism of action were the main reasons given by physicians for choosing among second targeted therapies after failure of a first tyrosine kinase inhibitor. CONCLUSIONS: The results of the present study document patterns of care during a period of rapid and ongoing therapeutic advancement in advanced renal cell carcinoma. Sequencing of therapies warrants ongoing analysis in light of new agents entering the advanced renal cell carcinoma treatment landscape.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/terapia , Neoplasias Renales/terapia , Pautas de la Práctica en Medicina/estadística & datos numéricos , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano , Antineoplásicos/farmacología , Axitinib/farmacología , Axitinib/uso terapéutico , Carcinoma de Células Renales/patología , Progresión de la Enfermedad , Resistencia a Antineoplásicos , Everolimus/farmacología , Everolimus/uso terapéutico , Femenino , Humanos , Indazoles , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/normas , Terapia Molecular Dirigida/estadística & datos numéricos , Nefrectomía , Guías de Práctica Clínica como Asunto , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Estudios Retrospectivos , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Sunitinib/farmacología , Sunitinib/uso terapéutico , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described.
Asunto(s)
Antineoplásicos/síntesis química , Diseño de Fármacos , Inhibidores de Proteínas Quinasas/síntesis química , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , 4-Aminopiridina/análogos & derivados , 4-Aminopiridina/química , Quinasa de Linfoma Anaplásico , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Semivida , Humanos , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Ratones , Ratones SCID , Microsomas Hepáticos/metabolismo , Simulación de Dinámica Molecular , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Estructura Terciaria de Proteína , Ratas , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Trasplante HeterólogoRESUMEN
Decreased neuronal dendrite branching and plasticity of the hippocampus, a limbic structure implicated in mood disorders, is thought to contribute to the symptoms of depression. However, the mechanisms underlying this effect, as well as the actions of antidepressant treatment, remain poorly characterized. Here, we show that hippocampal expression of neuritin, an activity-dependent gene that regulates neuronal plasticity, is decreased by chronic unpredictable stress (CUS) and that antidepressant treatment reverses this effect. We also show that viral-mediated expression of neuritin in the hippocampus produces antidepressant actions and prevents the atrophy of dendrites and spines, as well as depressive and anxiety behaviors caused by CUS. Conversely, neuritin knockdown produces depressive-like behaviors, similar to CUS exposure. The ability of neuritin to increase neuroplasticity is confirmed in models of learning and memory. Our results reveal a unique action of neuritin in models of stress and depression, and demonstrate a role for neuroplasticity in antidepressant treatment response and related behaviors.