RESUMEN
Proposed is a phenomenological modeling framework that is capable of reproducing the diverse experimental observations of the nonlinear, combustion wave propagation in a rotating detonation engine (RDE), specifically the nucleation and formation of combustion pulses, the soliton-like interactions between these combustion fronts, and the fundamental, underlying Hopf bifurcation to time-periodic modulation of the waves. In this framework, the mode-locked structures are classified as autosolitons or stably propagating nonlinear waves where the local physics of nonlinearity, gain, and dissipation exactly balance. We find that the global dominant balance physics in the RDE combustion chamber are dissipative and multiscale in nature: The fast combustion physics provide the energy input to form the fundamental mode-locked autosoliton state, while the slow physics of exhaust and propellant recovery shape the waveform and dictate the number of autosolitons. In this manner, the global multiscale balance physics give rise to the stable structures-not exclusively the frontal dynamics prescribed by classical detonation theory. Experimental observations and numerical models of the RDE combustion chamber are in strong qualitative agreement. Moreover, numerical continuation (computational bifurcation tracking) of the RDE analog system indicates that a Hopf bifurcation of the steadily propagating pulse train leads to the fundamental instability of the RDE, or time-periodic modulation of the waves. Along branches of Hopf orbits in parameter space exist a continuum of wave-pair interactions that exhibit solitonic interactions of varying strength.
RESUMEN
Activating mutations in HER2 (ERBB2) drive the growth of a subset of breast and other cancers and tend to co-occur with HER3 (ERBB3) missense mutations. The HER2 tyrosine kinase inhibitor neratinib has shown clinical activity against HER2-mutant tumors. To characterize the role of HER3 mutations in HER2-mutant tumors, we integrate computational structural modeling with biochemical and cell biological analyses. Computational modeling predicts that the frequent HER3E928G kinase domain mutation enhances the affinity of HER2/HER3 and reduces binding of HER2 to its inhibitor neratinib. Co-expression of mutant HER2/HER3 enhances HER2/HER3 co-immunoprecipitation and ligand-independent activation of HER2/HER3 and PI3K/AKT, resulting in enhanced growth, invasiveness, and resistance to HER2-targeted therapies, which can be reversed by combined treatment with PI3Kα inhibitors. Our results provide a mechanistic rationale for the evolutionary selection of co-occurring HER2/HER3 mutations and the recent clinical observations that HER3 mutations are associated with a poor response to neratinib in HER2-mutant cancers.
Asunto(s)
Neoplasias de la Mama/genética , Mutación con Ganancia de Función , Quinolinas/farmacología , Receptor ErbB-2/genética , Receptor ErbB-3/genética , Aminopiridinas/administración & dosificación , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Ratones Desnudos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Morfolinas/administración & dosificación , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3/administración & dosificación , Multimerización de Proteína , Quinolinas/administración & dosificación , Quinolinas/química , Quinolinas/metabolismo , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/química , Receptor ErbB-2/metabolismo , Receptor ErbB-3/química , Receptor ErbB-3/metabolismo , Trastuzumab/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Throughout the history of science, physics-based modeling has relied on judiciously approximating observed dynamics as a balance between a few dominant processes. However, this traditional approach is mathematically cumbersome and only applies in asymptotic regimes where there is a strict separation of scales in the physics. Here, we automate and generalize this approach to non-asymptotic regimes by introducing the idea of an equation space, in which different local balances appear as distinct subspace clusters. Unsupervised learning can then automatically identify regions where groups of terms may be neglected. We show that our data-driven balance models successfully delineate dominant balance physics in a much richer class of systems. In particular, this approach uncovers key mechanistic models in turbulence, combustion, nonlinear optics, geophysical fluids, and neuroscience.
RESUMEN
Direct observation of a rotating detonation engine combustion chamber has enabled the extraction of the kinematics of its detonation waves. These records exhibit a rich set of instabilities and bifurcations arising from the interaction of coherent wave fronts and global gain dynamics. We develop a model of the observed dynamics by recasting the Majda detonation analog as an autowave process. The solution fronts become attractors of the engine, i.e., mode-locked rotating detonation waves. We find that denotative energy release competes with dissipation and gain recovery to produce the observed dynamics and a bifurcation structure common to other driven-dissipative systems, such as mode-locked lasers.
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We developed neratinib-resistant HER2-mutant cancer cells by gradual dose escalation. RNA sequencing identified TORC1 signaling as an actionable mechanism of drug resistance. Primary and acquired neratinib resistance in HER2-mutant breast cancer patient-derived xenografts (PDXs) was also associated with TORC1 hyperactivity. Genetic suppression of RAPTOR or RHEB ablated P-S6 and restored sensitivity to the tyrosine kinase inhibitor. The combination of the TORC1 inhibitor everolimus and neratinib potently arrested the growth of neratinib-resistant xenografts and organoids established from neratinib-resistant PDXs. RNA and whole-exome sequencing revealed RAS-mediated TORC1 activation in a subset of neratinib-resistant models. DNA sequencing of HER2-mutant tumors clinically refractory to neratinib, as well as circulating tumor DNA profiling of patients who progressed on neratinib, showed enrichment of genomic alterations that converge to activate the mTOR pathway.
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Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/efectos de los fármacos , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Quinolinas/farmacología , Neoplasias de la Mama/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos/genética , Humanos , Diana Mecanicista del Complejo 1 de la Rapamicina/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Receptor ErbB-2/efectos de los fármacos , Receptor ErbB-2/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Alzheimer's disease is characterized by cognitive alterations, cerebral atrophy and neuropathological lesions including neuronal loss, accumulation of misfolded and aggregated ß-amyloid peptides (Aß) and tau proteins. Iatrogenic induction of Aß is suspected in patients exposed to pituitary-derived hormones, dural grafts, or surgical instruments, presumably contaminated with Aß. Induction of Aß and tau lesions has been demonstrated in transgenic mice after contamination with Alzheimer's disease brain homogenates, with very limited functional consequences. Unlike rodents, primates naturally express Aß or tau under normal conditions and attempts to transmit Alzheimer pathology to primates have been made for decades. However, none of earlier studies performed any detailed functional assessments. For the first time we demonstrate long term memory and learning impairments in a non-human primate (Microcebus murinus) following intracerebral injections with Alzheimer human brain extracts. Animals inoculated with Alzheimer brain homogenates displayed progressive cognitive impairments (clinical tests assessing cognitive and motor functions), modifications of neuronal activity (detected by electroencephalography), widespread and progressive cerebral atrophy (in vivo MRI assessing cerebral volume loss using automated voxel-based analysis), neuronal loss in the hippocampus and entorhinal cortex (post mortem stereology). They displayed parenchymal and vascular Aß depositions and tau lesions for some of them, in regions close to the inoculation sites. Although these lesions were sparse, they were never detected in control animals. Tau-positive animals had the lowest performances in a memory task and displayed the greatest neuronal loss. Our study is timely and important as it is the first one to highlight neuronal and clinical dysfunction following inoculation of Alzheimer's disease brain homogenates in a primate. Clinical signs in a chronic disease such as Alzheimer take a long time to be detectable. Documentation of clinical deterioration and/or dysfunction following intracerebral inoculations with Alzheimer human brain extracts could lead to important new insights about Alzheimer initiation processes.
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Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Encefalopatías/diagnóstico por imagen , Encefalopatías/genética , Encéfalo/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Animales , Encéfalo/patología , Encefalopatías/patología , Cheirogaleidae , Electroencefalografía/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Ratones , Ratones Transgénicos , Primates , Especificidad de la EspecieRESUMEN
Identifying methods to improve assay sensitivity in randomized clinical trials (RCTs) may facilitate the discovery of efficacious pain treatments. RCTs evaluating pain treatments typically use average pain intensity (API) or worst pain intensity (WPI) as the primary efficacy outcome. However, little evidence is available comparing the assay sensitivity of these 2 measures. In this systematic review and meta-analysis, we comprehensively reviewed all low back pain, osteoarthritis pain, fibromyalgia, diabetic peripheral neuropathy pain, and postherpetic neuralgia RCTs that used a parallel group design. Eligibility required: 1) primary RCT report published between 1980 and 2016, 2) comparing 1 or more active, efficacious pharmacologic pain treatment(s) with placebo, and 3) providing data on the standardized effect size (SES) for API as well as WPI for all treatment arms. Twenty-seven active versus placebo comparisons were identified in 23 eligible articles. Using a random-effects meta-analysis, API SES and WPI SES did not differ significantly (difference = -.021, 95% confidence interval = -.047 to .004, P = .12). The findings indicate that, depending on the objectives of the study, either API or WPI could be used as a primary outcome measure in clinical trials for the chronic pain conditions included in this analysis. PERSPECTIVE: Understanding the comparative assay sensitivity of API and WPI may advance pain treatment research. A meta-analysis of trials of efficacious pharmacologic treatments in 5 pain conditions did not show a statistically significant difference between the assay sensitivity of API and WPI.
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Dimensión del Dolor/normas , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
An important element of highway design is ensuring that the available sight distance (ASD) on a highway meets driver needs. For instance, if the ASD at any point on a highway is less than the distance required to come to a complete stop after seeing a hazard (i.e. Stopping Sight Distance (SSD)), the driver will not be able to stop in time to avoid a collision. SSD is function of a number of variables which vary depending on the driver, the vehicle driven and surface conditions; examples of such variables include a driver's perception reaction time or PRT (i.e. the time required by the driver to perceive and react to a hazard) and the deceleration rate of the vehicle. Most design guides recommend deterministic values for PRT and deceleration rates. Although these values may serve the needs of the average driver, they may not satisfy the needs of drivers with limited abilities. In other words, even if the ASD exceeds required SSD defined in the design guide, it might not always satisfy the needs of all drivers. While it is impossible to design roads that satisfy the needs of all drivers, the fact that most developed countries suffer from an aging population, means that the number of old drivers on our roads is expected to increase. Since a large proportion of old drivers often have limited abilities, it is expected that the general population of drivers with limited abilities on our roads will increase with time. Accordingly, more efforts are required to ensure that existing road infrastructure is prepared to handle such a change. This paper aims to explore the extent to which ASD on highways satisfies the needs of drivers with limited abilities. The paper first develops MATLAB and Python codes to automatically estimate the ASD on highway point cloud data collected using Light Detection and Ranging (LiDAR) remote sensing technology. The developed algorithms are then used to estimate ASD on seven different crash prone segments in the Province of Alberta, Canada and the ASD is compared to the required SSD on each highway. Three different levels of SSD are defined (SSD for drivers with limited ability, AASHTOs SSD requirements and SSD for drivers with high skill). The results show that, when compared to SSD requirements which integrate limitations in cognitive abilities, a substantial portion of the analyzed segments do not meet the requirements (up to 20%). Similarly, when compared to AASHTO's SSD requirements, up to 6% of the analyzed segments do not meet the requirements. In an attempt to explore the effects of such design limitations on safety, the paper also explores crash rates in noncompliant regions (i.e. regions that do not provide sufficient SSD) and compares them to crash rates in compliant regions. On average, it was found that noncompliant regions experience crash rates that are 2.15 and 1.25 times higher than compliant regions for AASHTO's SSD requirements and those integrating driver limitations, respectively. Furthermore, the study found that a significantly higher proportion of drivers involved in collisions in the noncompliant regions were old drivers.
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Accidentes de Tránsito/prevención & control , Conducción de Automóvil/psicología , Planificación Ambiental/normas , Accidentes de Tránsito/estadística & datos numéricos , Factores de Edad , Anciano , Alberta , Conducción de Automóvil/estadística & datos numéricos , Desaceleración , Femenino , Humanos , Masculino , Tiempo de Reacción/fisiologíaRESUMEN
OBJECTIVES: Interpretation of CIs in randomised clinical trials (RCTs) with treatment effects that are not statistically significant can distinguish between results that are 'negative' (the data are not consistent with a clinically meaningful treatment effect) or 'inconclusive' (the data remain consistent with the possibility of a clinically meaningful treatment effect). This interpretation is important to ensure that potentially beneficial treatments are not prematurely abandoned in future research or clinical practice based on invalid conclusions. DESIGN: Systematic review of RCT reports published in 2014 in Annals of Internal Medicine, New England Journal of Medicine, JAMA, JAMA Internal Medicine and The Lancet (n=247). RESULTS: 85 of 99 articles with statistically non-significant results reported CIs for the treatment effect. Only 17 of those 99 articles interpreted the CI. Of the 22 articles in which CIs indicated an inconclusive result, only four acknowledged that the study could not rule out a clinically meaningful treatment effect. CONCLUSIONS: Interpretation of CIs is important but occurs infrequently in study reports of trials with treatment effects that are not statistically significant. Increased author interpretation of CIs could improve application of RCT results. Reporting recommendations are provided.
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Interpretación Estadística de Datos , Ensayos Clínicos Controlados Aleatorios como Asunto/normas , HumanosRESUMEN
PIK3CA mutations are associated with resistance to HER2-targeted therapies. We previously showed that HER2+/PIK3CAH1047R transgenic mammary tumors are resistant to the HER2 antibodies trastuzumab and pertuzumab but respond to PI3K inhibitor buparlisib (TPB). In this study, we identified mechanisms of resistance to combined inhibition of HER2 and PI3K. TPB-resistant tumors were generated by treating HER2+/PIK3CAH1047R tumor-bearing mice long term with the drug combination. RNA sequencing of TPB-resistant tumors revealed that extracellular matrix and cell adhesion genes, including collagen II (Col2a1), were markedly upregulated, accompanied by activation of integrin ß1/Src. Cells derived from drug-resistant tumors were sensitive to TBP when grown in vitro, but exhibited resistance when plated on collagen or when reintroduced into mice. Drug resistance was partially reversed by the collagen synthesis inhibitor ethyl-3,4-dihydroxybenzoate. Inhibition of integrin ß1/Src blocked collagen-induced resistance to TPB and inhibited growth of drug-resistant tumors. High collagen II expression was associated with significantly lower clinical response to neoadjuvant anti-HER2 therapy in HER2+ breast cancer patients. Overall, these data suggest that upregulation of collagen/integrin/Src signaling contributes to resistance to combinatorial HER2 and PI3K inhibition. Cancer Res; 77(12); 3280-92. ©2017 AACR.
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Neoplasias de la Mama/patología , Colágeno Tipo II/metabolismo , Resistencia a Antineoplásicos/fisiología , Integrina beta1/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Receptor ErbB-2/antagonistas & inhibidores , Animales , Neoplasias de la Mama/metabolismo , Modelos Animales de Enfermedad , Matriz Extracelular/metabolismo , Femenino , Humanos , Immunoblotting , Inmunohistoquímica , Ratones , Ratones Transgénicos , Reacción en Cadena de la Polimerasa , Transducción de Señal/fisiologíaRESUMEN
Purpose: Dual blockade of HER2 with trastuzumab and lapatinib or pertuzumab has been shown to be superior to single-agent trastuzumab. However, a significant fraction of HER2-overexpressing (HER2+) breast cancers escape from these drug combinations. In this study, we sought to discover the mechanisms of acquired resistance to the combination of lapatinib + trastuzumab.Experimental Design: HER2+ BT474 xenografts were treated with lapatinib + trastuzumab long-term until resistance developed. Potential mechanisms of acquired resistance were evaluated in lapatinib + trastuzumab-resistant (LTR) tumors by targeted capture next-generation sequencing. In vitro experiments were performed to corroborate these findings, and a novel drug combination was tested against LTR xenografts. Gene expression and copy-number analyses were performed to corroborate our findings in clinical samples.Results: LTR tumors exhibited an increase in FGF3/4/19 copy number, together with an increase in FGFR phosphorylation, marked stromal changes in the tumor microenvironment, and reduced tumor uptake of lapatinib. Stimulation of BT474 cells with FGF4 promoted resistance to lapatinib + trastuzumab in vitro Treatment with FGFR tyrosine kinase inhibitors reversed these changes and overcame resistance to lapatinib + trastuzumab. High expression of FGFR1 correlated with a statistically shorter progression-free survival in patients with HER2+ early breast cancer treated with adjuvant trastuzumab. Finally, FGFR1 and/or FGF3 gene amplification correlated with a lower pathologic complete response in patients with HER2+ early breast cancer treated with neoadjuvant anti-HER2 therapy.Conclusions: Amplification of FGFR signaling promotes resistance to HER2 inhibition, which can be diminished by the combination of HER2 and FGFR inhibitors. Clin Cancer Res; 23(15); 4323-34. ©2017 AACR.
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Neoplasias de la Mama/tratamiento farmacológico , Factor 3 de Crecimiento de Fibroblastos/genética , Receptor ErbB-2/genética , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Animales , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Femenino , Factor 3 de Crecimiento de Fibroblastos/antagonistas & inhibidores , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Lapatinib , Ratones , Terapia Neoadyuvante/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/antagonistas & inhibidores , Trastuzumab/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib.Significance: We found an acquired HER2 gatekeeper mutation in a patient with HER2-mutant breast cancer upon clinical progression on neratinib. We speculate that HER2T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2-activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib. Cancer Discov; 7(6); 575-85. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinolinas/uso terapéutico , Receptor ErbB-2/genética , Afatinib , Línea Celular Tumoral , Femenino , Humanos , Persona de Mediana Edad , Mutación , Fenotipo , Quinazolinas/farmacología , Receptor ErbB-2/antagonistas & inhibidoresRESUMEN
Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition of this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 inhibition is driven by cancer stem cell (CSC)-like populations that could be targeted to enhance the antitumor action of these drugs. Therefore, we investigated the molecular mechanisms by which PI3K/mTOR inhibitors affect the stem-like properties of TNBC cells. Treatment of established TNBC cell lines with a PI3K/mTOR inhibitor or a TORC1/2 inhibitor increased the expression of CSC markers and mammosphere formation. A CSC-specific PCR array revealed that inhibition of TORC1/2 increased FGF1 and Notch1 expression. Notch1 activity was also induced in TNBC cells treated with TORC1/2 inhibitors and associated with increased mitochondrial metabolism and FGFR1 signaling. Notably, genetic and pharmacologic blockade of Notch1 abrogated the increase in CSC markers, mammosphere formation, and in vivo tumor-initiating capacity induced by TORC1/2 inhibition. These results suggest that targeting the FGFR-mitochondrial metabolism-Notch1 axis prevents resistance to TORC1/2 inhibitors by eradicating drug-resistant CSCs in TNBC, and may thus represent an attractive therapeutic strategy to improve drug responsiveness and efficacy.
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Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Células Madre Neoplásicas/metabolismo , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias de la Mama Triple Negativas/genética , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Diana Mecanicista del Complejo 2 de la Rapamicina , Transducción de Señal , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
INTRODUCTION: Ipilimumab, a monoclonal anti-CTLA-4 antibody, is used to treat melanoma. Neuromuscular side effects, possibly autoimmune, may occur. METHODS: In this investigation we undertook a retrospective review of patient records. RESULTS: After 3 doses of ipilimumab, a 31-year-old man developed asymmetric, severe weakness involving all limbs, respiration, and cranial nerves, which was progressive over 2 weeks. EMG/NCS showed an axonal polyradiculoneuropathy with multifocal motor conduction blocks. CSF protein was 749 mg/dl. Nerve pathology showed inflammation around the endoneurial microvessels and subperineurial edema and inflammation. Spine MRI showed leptomeningeal and anterior and posterior root enhancement. Strength improved slowly over months after ipilimumab discontinuation and immunomodulating treatment. CONCLUSIONS: Ipilimumab toxicity presented as a monophasic, multifocal, asymmetric polyradiculoneuropathy involving roots and peripheral and cranial nerves. Ipilimumab may produce a polyradiculoneuropathy with disruption of the blood-nerve barrier due to a microvasculopathy.