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Background: Biologic agents have demonstrated efficacy in treating ulcerative colitis (UC); however, treatment failure to tumor necrosis factor inhibitors (TNFi) is common in the real world. Data on preferential sequencing in clinical practice after failure remain limited. Objectives: This study aimed to evaluate real-world outcomes of patients cycling to TNFis or switching to non-TNFi biologics following first-line failure with TNFis. Design: Retrospective cohort study in Germany. Methods: Adult patients with UC were identified using administrative claims data from 1 May 2014 to 30 June 2022 provided by a statutory sickness fund. Patients newly initiating first-line therapy with TNFis and then switching to another agent were identified. Patients were defined as within-class switched (WCS), if they cycled to another TNFi, or outside-class switchers (OCS), if they switched to a non-TNFi biologic [ustekinumab (UST) or vedolizumab (VDZ)] and followed from index (switch date) to death, insurance end, or study end on 30 June 2022. Inverse probability of treatment weighting (IPTW) was performed to adjust for differences in baseline characteristics between groups, and weighted Cox regression models were used to compare primary (time to discontinuation and second treatment switch) and secondary outcomes (corticosteroid-free drug survival). Results: We identified 166 patients initiating TNFis and switching to a subsequent treatment (mean age: 42.9 years, 49.4% female). Following IPTW, there were 71 and 76 patients in the WCS and OCS groups, respectively. Compared to OCS, WCS were more likely to discontinue the new therapy [hazard ratio (HR), 1.82, 95% confidence interval (CI), 1.14-2.89, p = 0.012], and switch a second time (HR, 3.46, 95% CI, 1.89-6.36, p < 0.001). Moreover, WCS showed an increased likelihood of initiating prolonged corticosteroid therapy (HR, 1.42, 95% CI, 0.77-2.59, p = 0.260); however, the results were not significant. Conclusion: Following first-line TNFi failure, this study suggests that real-world outcomes among patients with UC are less favorable when cycling to another TNFi, compared to switching to a non-TNFi such as UST or VDZ.
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The extracellular environment is sensed by receptors in the plasma membrane. Some of these receptors initiate cytoplasmic signaling cascades involving phosphorylation: the addition of a phosphate group to a specific amino acid, such as tyrosine, in a protein. Receptor Tyrosine Kinases (RTKs) are one large class of membrane receptors that can directly initiate signaling cascades through their intracellular kinase domains, which both catalyze tyrosine phosphorylation and get phosphorylated. In the first step of signaling, the ligands stabilize phosphorylation-competent RTK dimers and oligomers, which leads to the phosphorylation of specific tyrosine residues in the activation loop of the kinases. Here we discuss quantitative measurements of tyrosine phosphorylation efficiencies for RTKs, described by the "transducer function". The transducer function links the phosphorylation (the response) and the binding of the activating ligand to the receptor (the stimulus). We overview a methodology that allows such measurements in direct response to ligand binding. We discuss experiments which demonstrate that EGF is a partial agonist, and that two tyrosines in the intracellular domain of EGFR, Y1068 and Y1173, are differentially phosphorylated in the EGF-bound EGFR dimers.
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The transmembrane helices of receptor tyrosine kinases (RTKs) have been proposed to switch between two different dimeric conformations, one associated with the inactive RTK and the other with the active RTK. Furthermore, recent work has demonstrated that some full-length RTKs are associated into oligomers that are larger than dimers, raising questions about the roles of the TM helices in the assembly and function of these oligomers. Here we probe the roles of the TM helices in the assembly of EphA2 RTK oligomers in the plasma membrane. We employ mutagenesis to evaluate the relevance of a published NMR dimeric structure of the isolated EphA2 TM helix in the context of the full-length EphA2 in the plasma membrane. We use two fluorescence methods, Förster Resonance Energy Transfer and Fluorescence Intensity Fluctuations spectrometry, which yield complementary information about the EphA2 oligomerization process. These studies reveal that the TM helix mutations affect the stability, structure, and size of EphA2 oligomers. However, the effects are multifaceted and point to a more complex role of the TM helix than the one expected from the "TM dimer switch" model.
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Multimerización de Proteína , Receptor EphA2 , Receptor EphA2/metabolismo , Receptor EphA2/química , Receptor EphA2/genética , Humanos , Transferencia Resonante de Energía de Fluorescencia , Membrana Celular/metabolismo , Conformación Proteica en Hélice alfa , MutaciónRESUMEN
Introduction: Reducing brain levels of both soluble and insoluble forms of amyloid beta (Aß) remains the primary goal of most therapies that target Alzheimer's disease (AD). However, no treatment has so far resulted in patient benefit, and clinical trials of the most promising drug candidates have generally failed due to significant adverse effects. This highlights the need for safer and more selective ways to target and modulate Aß biogenesis. Methods: Peptide technology has advanced to allow reliable synthesis, purification, and delivery of once-challenging hydrophobic sequences. This is opening up new routes to target membrane processes associated with disease. Here we deploy a combination of atomic detail molecular dynamics (MD) simulations, living-cell Förster resonance energy transfer (FRET), and in vitro assays to elucidate the atomic-detail dynamics, molecular mechanisms, and cellular activity and selectivity of a membrane-active peptide that targets the Aß precursor protein (APP). Results: We demonstrate that Aß biogenesis can be downregulated selectively using an APP occlusion peptide (APPOP). APPOP inhibits Aß production in a dose-dependent manner, with a mean inhibitory concentration (IC50) of 450 nM toward exogenous APP and 50 nM toward endogenous APP in primary rat cortical neuronal cultures. APPOP does not impact the γ-secretase cleavage of Notch-1, or exhibit toxicity toward cultured primary rat neurons, suggesting that it selectively shields APP from proteolysis. Discussion: Drugs targeting AD need to be given early and for very long periods to prevent the onset of clinical symptoms. This necessitates being able to target Aß production precisely and without affecting the activity of key cellular enzymes such as γ-secretase for other substrates. Peptides offer a powerful way for targeting key pathways precisely, thereby reducing the risk of adverse effects. Here we show that protecting APP from proteolytic processing offers a promising route to safely and specifically lower Aß burden. In particular, we show that the amyloid pathway can be targeted directly and specificically. This reduces the risk of off-target effects and paves the way for a safe prophylactic treatment.
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Signaling bias is the ability of a receptor to differentially activate downstream signaling pathways in response to different ligands. Bias investigations have been hindered by inconsistent results in different cellular contexts. Here we introduce a methodology to identify and quantify bias in signal transduction across the plasma membrane without contributions from feedback loops and system bias. We apply the methodology to quantify phosphorylation efficiencies and determine absolute bias coefficients. We show that the signaling of epidermal growth factor receptor (EGFR) to EGF and TGFα is biased towards Y1068 and against Y1173 phosphorylation, but has no bias for epiregulin. We further show that the L834R mutation found in non-small-cell lung cancer induces signaling bias as it switches the preferences to Y1173 phosphorylation. The knowledge gained here challenges the current understanding of EGFR signaling in health and disease and opens avenues for the exploration of biased inhibitors as anti-cancer therapies.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Fosforilación , Factor de Crecimiento Epidérmico/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Ligandos , Neoplasias Pulmonares/genética , Receptores ErbB/metabolismo , MutaciónRESUMEN
The activity of many membrane receptors is controlled through their lateral association into dimers or higher-order oligomers. Although Förster resonance energy transfer (FRET) measurements have been used extensively to characterize the stability of receptor dimers, the utility of FRET in studies of larger oligomers has been limited. Here we introduce an effective equilibrium dissociation constant that can be extracted from FRET measurements for EphA2, a receptor tyrosine kinase (RTK) known to form active oligomers of heterogeneous distributions in response to its ligand ephrinA1-Fc. The newly introduced effective equilibrium dissociation constant has a well-defined physical meaning and biological significance. It denotes the receptor concentration for which half of the receptors are monomeric and inactive, and the other half are associated into oligomers and are active, irrespective of the exact oligomer size. This work introduces a new dimension to the utility of FRET in studies of membrane receptor association and signaling in the plasma membrane.
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Transferencia Resonante de Energía de Fluorescencia , Transducción de Señal , Transferencia Resonante de Energía de Fluorescencia/métodos , Membrana Celular/metabolismo , Membranas , Proteínas de la Membrana/metabolismoRESUMEN
PURPOSE: The aim of this study was to investigate the burden of disease among a real-world cohort of patients with prevalent Crohn's disease (CD) in Germany. METHODS: We conducted a retrospective cohort analysis using administrative claims data from the German AOK PLUS health insurance fund. Continuously insured patients with a CD diagnosis between 01 October 2014 and 31 December 2018 were selected and followed for at least 12 months or longer until death or end of data availability on 31 December 2019. Medication use (biologics, immunosuppressants (IMS), steroids, 5-aminosalicylic acid) was assessed sequentially in the follow-up period. Among patients with no IMS or biologics (advanced therapy), we investigated indicators of active disease and corticosteroid use. RESULTS: Overall, 9284 prevalent CD patients were identified. Within the study period, 14.7% of CD patients were treated with biologics and 11.6% received IMS. Approximately 47% of all prevalent CD patients had mild disease, defined as no advanced therapy and signs of disease activity. Of 6836 (73.6%) patients who did not receive advanced therapy in the follow-up period, 36.3% showed signs of active disease; 40.1% used corticosteroids (including oral budesonide), with 9.9% exhibiting steroid dependency (≥ 1 prescription every 3 months for at least 12 months) in the available follow-up. CONCLUSIONS: This study suggests that there remains a large burden of disease among patients who do not receive IMS or biologics in the real world in Germany. A revision of treatment algorithms of patients in this setting according to the latest guidelines may improve patient outcomes.
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Productos Biológicos , Enfermedad de Crohn , Administración Financiera , Humanos , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/epidemiología , Estudios Retrospectivos , Inmunosupresores/uso terapéutico , Costo de Enfermedad , Productos Biológicos/efectos adversosRESUMEN
Lipid rafts are ordered lipid domains that are enriched in saturated lipids, such as the ganglioside GM1. While lipid rafts are believed to exist in cells and to serve as signaling platforms through their enrichment in signaling components, they have not been directly observed in the plasma membrane without treatments that artificially cluster GM1 into large lattices. Here, we report that microscopic GM1-enriched domains can form, in the plasma membrane of live mammalian cells expressing the EphA2 receptor tyrosine kinase in response to its ligand ephrinA1-Fc. The GM1-enriched microdomains form concomitantly with EphA2-enriched microdomains. To gain insight into how plasma membrane heterogeneity controls signaling, we quantify the degree of EphA2 segregation and study initial EphA2 signaling steps in both EphA2-enriched and EphA2-depleted domains. By measuring dissociation constants, we demonstrate that the propensity of EphA2 to oligomerize is similar in EphA2-enriched and -depleted domains. However, surprisingly, EphA2 interacts preferentially with its downstream effector SRC in EphA2-depleted domains. The ability to induce microscopic GM1-enriched domains in live cells using a ligand for a transmembrane receptor will give us unprecedented opportunities to study the biophysical chemistry of lipid rafts.
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BACKGROUND: The fully human monoclonal antibody guselkumab is an effective treatment option for patients with moderate to severe psoriasis. OBJECTIVE: The objective of this study was to examine the cost per responder of guselkumab compared with other targeted therapies for the treatment of moderate to severe plaque psoriasis in Germany. METHODS: A one-year cost per responder model was developed based on efficacy and safety data from a published network meta-analysis. Drug, treatment administration, resource use, and adverse event costs were included in the analysis. The primary analysis assessed the cost per Psoriasis Area and Severity Index (PASI) 90 responder at week 16. Additional analyses were conducted at year 1. In the year 1 analyses, treatment response was assessed at the end of the induction period (week 16) to determine which patients continued onto maintenance therapy (responders) and which patients moved onto a subsequent adalimumab or secukinumab therapy (non-responders). RESULTS: At week 16, the cost per PASI 90 responder was lower for guselkumab than all comparators except adalimumab and brodalumab. Similarly, in the year 1 analyses, guselkumab had a lower cost per PASI 90 responder than all comparators except brodalumab. CONCLUSIONS: Guselkumab is a cost-effective therapy option in Germany.
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Psoriasis , Adalimumab/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Humanos , Psoriasis/inducido químicamente , Psoriasis/tratamiento farmacológico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVES: Medical emergencies in psychiatric inpatients are challenging due to the model of care and limited medical resources. The study aims were to determine the triggers and outcomes of a medical emergency team (MET) call in psychiatric wards, and the risk factors for MET activation and mortality. DESIGN: Retrospective multisite cohort study. SETTING: Psychiatry units colocated with acute medical services at three major metropolitan hospitals in Melbourne, Australia. PARTICIPANTS: We studied 487 adult inpatients who experienced a total of 721 MET calls between January 2015 and January 2020. Patients were relatively young (mean age, 45 years) and had few medical comorbidities, but a high prevalence of smoking, excessive alcohol intake and illicit drug use. OUTCOME MEASURES: We performed a descriptive analysis of the triggers and outcomes (transfer rates, investigations, final diagnosis) of MET calls. We used logistic regression to determine the factors associated with the primary outcome of inpatient mortality, and the secondary outcome of the need for specific medical treatment compared with simple observation. RESULTS: The most common MET triggers were a reduced Glasgow Coma Scale, tachycardia and hypotension, and 49% of patients required transfer. The most frequent diagnosis was a drug adverse effect or toxidrome, followed by infection and dehydration. There was a strong association between a leave of absence and MET calls, tachycardia and the final diagnosis of drug adverse effects. Mortality occurred in 3% after MET calls. Several baseline and MET clinical variables were associated with mortality but a model with age (per 10 years, OR 1.61, 95% CI 1.29 to 2.01) and hypoxia (OR 3.59, 95% CI 1.43 to 9.04) independently predicted mortality. CONCLUSION: Vigilance is required in patients returning from day leave, and drug adverse effects remain a challenging problem in psychiatric units. Hypoxic older patients with cardiovascular comorbidity have a higher risk of death.
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Servicios Médicos de Urgencia , Psiquiatría , Niño , Estudios de Cohortes , Urgencias Médicas , Humanos , Pacientes Internos , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
The spatial distribution of proteins in cell membranes is crucial for signal transduction, cell communication and membrane trafficking. Members of the Tetraspanin family organize functional protein clusters within the plasma membrane into so-called Tetraspanin-enriched microdomains (TEMs). Direct interactions between Tetraspanins are believed to be important for this organization. However, studies thus far have utilized mainly co-immunoprecipitation methods that cannot distinguish between direct and indirect, through common partners, interactions. Here we study Tetraspanin 8 homointeractions in living cells via quantitative fluorescence microscopy. We demonstrate that Tetraspanin 8 exists in a monomer-dimer equilibrium in the plasma membrane. Tetraspanin 8 dimerization is described by a high dissociation constant (Kd = 14 700 ± 1100â Tspan8/µm2), one of the highest dissociation constants measured for membrane proteins in live cells. We propose that this high dissociation constant, and thus the short lifetime of the Tetraspanin 8 dimer, is critical for Tetraspanin 8 functioning as a master regulator of cell signaling.
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Microdominios de Membrana/química , Microdominios de Membrana/metabolismo , Transducción de Señal/genética , Tetraspaninas/química , Tetraspaninas/metabolismo , Transferencia Resonante de Energía de Fluorescencia/métodos , Células HEK293 , Humanos , Lipoilación , Microdominios de Membrana/genética , Microscopía Fluorescente/métodos , Multimerización de Proteína , Tetraspaninas/genética , Termodinámica , TransfecciónRESUMEN
In recent years, there has been an explosion of fluorescence microscopy studies of live cells in the literature. The analysis of the images obtained in these studies often requires labor-intensive manual annotation to extract meaningful information. In this study, we explore the utility of a neural network approach to recognize, classify, and select plasma membranes in high-resolution images, thus greatly speeding up data analysis and reducing the need for personnel training for highly repetitive tasks. Two different strategies are tested: 1) a semantic segmentation strategy, and 2) a sequential application of an object detector followed by a semantic segmentation network. Multiple network architectures are evaluated for each strategy, and the best performing solutions are combined and implemented in the Recognition Of Cellular Membranes software. We show that images annotated manually and with the Recognition Of Cellular Membranes software yield identical results by comparing Förster resonance energy transfer binding curves for the membrane protein fibroblast growth factor receptor 3. The approach that we describe in this work can be applied to other image selection tasks in cell biology.
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Procesamiento de Imagen Asistido por Computador , Redes Neurales de la Computación , Membrana Celular , Microscopía Fluorescente , Programas InformáticosRESUMEN
The use of antipsychotic medications is associated with side effects, but the occurrence of severe tachycardia (heart rate ≥ 130 per minute) is not well described. The aim of this study was to determine the frequency and strength of the association between antipsychotic use and severe tachycardia in an inpatient population of patients with mental illness, while considering factors which may contribute to tachycardia. We retrospectively analyzed data from 636 Medical Emergency Team (MET) calls occurring in 449 psychiatry inpatients in three metropolitan hospitals co-located with acute medical services, and used mixed-effects logistic regression to model the association between severe tachycardia and antipsychotic use. The median age of patients was 42 years and 39% had a diagnosis of schizophrenia or psychotic disorder. Among patients who experienced MET calls, the use of second-generation (atypical) antipsychotics was commonly encountered (70%), but the use of first-generation (conventional) antipsychotics was less prevalent (10%). Severe tachycardia was noted in 22% of all MET calls, and sinus tachycardia was the commonest cardiac rhythm. After adjusting for age, anticholinergic medication use, temperature >38 °C and hypoglycemia, and excluding patients with infection and venous thromboembolism, the odds ratio for severe tachycardia with antipsychotic medication use was 4.09 (95% CI: 1.64 to 10.2).
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AIMS: Obstructive sleep apnoea (OSA) associates with atrial fibrillation (AF), but the relationship of OSA severity and AF phenotype with the atrial substrate remains poorly defined. We sought to define the atrial substrate across the spectrum of OSA severity utilizing high-density mapping. METHODS AND RESULTS: Sixty-six consecutive patients (male 71%, age 61 ± 9) having AF ablation (paroxysmal AF 36, persistent AF 30) were recruited. All patents underwent formal overnight polysomnography and high-density left atrial (LA) mapping (mean 2351 ± 1244 points) in paced rhythm. Apnoea-hypopnoea index (AHI) (mean 21 ± 18) associated with lower voltage (-0.34, P = 0.005), increased complex points (r = 0.43, P < 0.001), more low-voltage areas (r = 0.42, P < 0.001), and greater voltage heterogeneity (r = 0.39, P = 0.001), and persisted after multivariable adjustment. Atrial conduction heterogeneity (r = 0.24, P = 0.025) but not conduction velocity (r = -0.09, P = 0.50) associated with AHI. Patchy regions of low voltage that co-localized with slowed conduction defined the atrial substrate in paroxysmal AF, while a diffuse atrial substrate predominated in persistent AF. The association of AHI with remodelling was most apparent among paroxysmal AF [LA voltage: paroxysmal AF -0.015 (-0.025, -0.005), P = 0.004 vs. persistent AF -0.006 (-0.017, 0.005), P = 0.30]. Furthermore, in paroxysmal AF an AHI ≥ 30 defined a threshold at which atrial remodelling became most evident (nil-mild vs. moderate vs. severe: 1.92 ± 0.42 mV vs. 1.84 ± 0.28 mV vs. 1.34 ± 0.41 mV, P = 0.006). In contrast, significant remodelling was observed across all OSA categories in persistent AF (1.67 ± 0.55 mV vs. 1.50 ± 0.66 mV vs. 1.55 ± 0.67 mV, P = 0.82). CONCLUSION: High-density mapping observed that OSA associates with marked atrial remodelling, predominantly among paroxysmal AF cohorts with severe OSA. This may facilitate the identification of AF patients that stand to derive the greatest benefit from OSA management.
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Fibrilación Atrial , Remodelación Atrial , Ablación por Catéter , Apnea Obstructiva del Sueño , Anciano , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/cirugía , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/cirugía , Humanos , Masculino , Persona de Mediana Edad , Apnea Obstructiva del Sueño/diagnósticoRESUMEN
Since the introduction of the Medicines Market Reorganization Act (AMNOG) in 2011, there have been some structural changes for pharmaceutical manufacturers, due to the early assessment of benefits in the market launch of innovative drugs. This means that the manufacturer is constantly faced with challenges in determining the target population by using prevalence and incidence. Even given the same indication, there are often different approaches and models used for estimating the target population. In bladder carcinoma, the fourth most common tumor in men, there have been many advances in the field of immunotherapy for the treatment of locally advanced or metastatic carcinomas. These can be used to compare existing dossiers. The aim of this study was to evaluate the quality of the prevalence and incidence calculations of the dossiers in the indication urothelial carcinoma and to identify the recommendations for action that can be derived for their future determination. This problem was examined based on the methods paper of the Institute for Quality and Efficiency in Health Care and the benefit assessments of the decisions on additional benefits. Our comparison showed similarities in the use of epidemiological measures, but identified mainly differences in the calculation steps of the target population. As a result, the target population was mostly underestimated or overestimated. The quality of the dossiers differed mostly in the traceability of the calculations and the origin of data. With regard to external validity and generalizability to the German health care system, there is still room for improvement.
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Carcinoma , Necesidades y Demandas de Servicios de Salud , Alemania/epidemiología , Humanos , Incidencia , PrevalenciaRESUMEN
Intermediate filament (IF) proteins are a class of proteins that constitute different filamentous structures in mammalian cells. As such, IF proteins are part of the load-bearing cytoskeleton and support the nuclear envelope. Molecular dynamics simulations show that IF proteins undergo secondary structural changes to compensate mechanical loads, which is confirmed by experimental in vitro studies on IF hydrogels. However, the structural response of intracellular IF to mechanical load is yet to be elucidated in cellulo. Here, in situ nonlinear Raman imaging combined with multivariate data analysis is used to quantify the intracellular secondary structure of the IF cytoskeletal protein vimentin under different states of cellular tension. It is found that cells under native cellular tension contain more unfolded vimentin than chemically or physically relaxed specimens. This indicates that the unfolding of IF proteins occurs intracellularly when sufficient forces are applied, suggesting that IF structures act as local force sensors in the cell to mark locations under large mechanical tension.
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Desplegamiento Proteico , Vimentina , Células HeLa , Humanos , Filamentos Intermedios/química , Filamentos Intermedios/metabolismo , Mecanotransducción Celular/fisiología , Microscopía , Estructura Secundaria de Proteína , Espectrometría Raman , Vimentina/química , Vimentina/metabolismoRESUMEN
BACKGROUND: The economic burden of ulcerative colitis (UC), specifically related to indirect costs, is not extensively documented. Understanding and quantifying it is required by health care decision makers. AIM: To assess the impact of indirect costs of UC in observation studies. METHOD: A systematic literature search was conducted in MEDLINE®, Embase® and Cochrane Library to capture all relevant publications reporting outcomes on absenteeism, presenteeism and productivity losses in moderate to severe UC. Eligibility criteria for inclusion into the review were established using a predefined PICOS scheme. All costs were adjusted to 2017 currency values (USD dollars, $). RESULTS: In total, 18 studies reporting data on indirect costs were included in the analysis. Absenteeism costs were classified into three categories: sick leave, short-term and long-term disability. Most of the studies captured absenteeism costs related specifically to sick leave, which was experienced on average by 10 to 24% patients with UC. Only three studies captured presenteeism costs, as these are difficult to measure, however costs ranged from 1602 $ to 2947 $ per patient year. The proportion of indirect costs accounted for 35% of total UC costs (Total UC costs were defined as the sum of healthcare costs, productivity costs and out-of-pocket costs). DISCUSSION: A limited number of studies were identified describing the indirect costs in patients with moderate to severe UC. Insufficient data on different components of costs allowed a limited analysis on the impact of indirect costs in patients with UC. Further studies are needed to gain an understanding of the influence of UC on patients' functional abilities.
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Colitis Ulcerosa/economía , Costo de Enfermedad , Gastos en Salud/estadística & datos numéricos , Humanos , Estudios Observacionales como AsuntoRESUMEN
Background: Biologics used to treat ulcerative colitis (UC) may lose their effect over time, requiring patients to undergo dose escalation or treatment switching, and systematic literature reviews of real-world evidence on these topics are lacking. Aim: To summarize the occurrence and outcomes of dose escalation and treatment switching in UC patients in real-world evidence. Methods: Studies were searched through MEDLINE, MEDLINE IN PROCESS, Embase and Cochrane (2006-2017) as well as proceedings from three major scientific meetings. Results: In total, 41 studies were included in the review among which 35 covered dose escalation and 12 covered treatment switching of biologics. Tumor necrosis factor antagonist (anti-TNF) escalation for all patients included at induction ranged from 5% (6 months) to 50% (median 0.67 years) and 15.2% to 70.8% (8 weeks) for anti-TNF induction responders. Mean/median time to dose escalation on anti-TNF ranged from 1.84 to 11 months. The most common switching pattern, infliximab â adalimumab, occurred in 3.8% (median 5.6 years) to 25.5% (mean 3.3 years) of patients. Conclusions: Dose escalation and treatment switching of biologics may be considered as indicators of suboptimal therapy suggesting a lack of long-term remission and response under current therapies.
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Adalimumab/administración & dosificación , Colitis Ulcerosa/tratamiento farmacológico , Infliximab/administración & dosificación , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , HumanosRESUMEN
Here we use a quantitative FRET approach, specifically developed to probe membrane protein interactions, to study the homo-association of neuropilin 1 (NRP1) in the plasma membrane, as well as its hetero-interactions with vascular endothelial growth factor receptor 2 (VEGFR2). Experiments are performed both in the absence and presence of the soluble ligand vascular endothelial growth factor A (VEGFA), which binds to both VEGFR2 and NRP1. We demonstrate the presence of homo-interactions between NRP1 molecules, as well as hetero-interactions between NRP1 and VEGFR2 molecules, in the plasma membrane. Our results underscore the complex nature of the interactions between self-associating receptors, co-receptors, and their ligands in the plasma membrane. They also highlight the need for new methodologies that capture this complexity, and the need for precise physiological measurements of local receptor surface densities in the membrane of cells. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo.
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Membrana Celular/metabolismo , Neuropilina-1/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Membrana Celular/química , Endotelio Vascular/metabolismo , Transferencia Resonante de Energía de Fluorescencia/métodos , Células HEK293 , Humanos , Ligandos , Neuropilina-1/química , Transducción de Señal , Factor A de Crecimiento Endotelial Vascular/química , Factor A de Crecimiento Endotelial Vascular/metabolismo , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
BACKGROUND: Prior studies have suggested that the interactions occurring between VEGFR2 extracellular domains in the absence of ligand are complex. Here we seek novel insights into these interactions, and into the role of the different Ig-like domains (D1 through D7) in VEGFR2 dimerization. METHODS: We study the dimerization of a single amino acid mutant and of three deletion mutants in the plasma membrane using two photon microscopy and fully quantified spectral imaging. RESULTS: We demonstrate that a set of cooperative interactions between the different Ig-like domains ensure that VEGFR2 dimerizes with a specific affinity instead of forming oligomers. CONCLUSIONS: The contributions of subunits D7 and D4 seem to be the most critical, as they appear essential for strong lateral interactions and for the formation of dimers, respectively. GENERAL SIGNIFICANCE: This study provides new insights into the mechanism of VEGFR2 dimerization and activation.