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Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the anti-tumor activity of the RAS(ON) multi-selective tri-complex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant NSCLC. Broad-spectrum, reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse co-mutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or (OFF) inhibitor resistance. Interrogation of time-resolved single cell transcriptional responses established an in vivo atlas of multi-modal acute and chronic RAS pathway inhibition in the NSCLC ecosystem and uncovered a regenerative mucinous transcriptional program that supports long-term tumor cell persistence. In patients with advanced KRASG12C-mutant NSCLC, the presence of mucinous histological features portended poor response to sotorasib or adagrasib. Our results have potential implications for personalized medicine and the development of rational RAS inhibitor-anchored therapeutic strategies.

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Molecular modifiers of KRASG12C inhibitor (KRASG12Ci) efficacy in advanced KRASG12C-mutant NSCLC are poorly defined. In a large unbiased clinicogenomic analysis of 424 patients with non-small cell lung cancer (NSCLC), we identified and validated coalterations in KEAP1, SMARCA4, and CDKN2A as major independent determinants of inferior clinical outcomes with KRASG12Ci monotherapy. Collectively, comutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ∼50% of those with early disease progression (progression-free survival ≤3 months) with KRASG12Ci. Pathway-level integration of less prevalent coalterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRASG12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRASG12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRASG12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies. SIGNIFICANCE: In this work, we identify co-occurring genomic alterations in KEAP1, SMARCA4, and CDKN2A as independent determinants of poor clinical outcomes with KRASG12Ci monotherapy in advanced NSCLC, and we propose a framework for patient stratification and treatment personalization based on the comutational status of individual tumors. See related commentary by Heng et al., p. 1513. This article is highlighted in the In This Issue feature, p. 1501.

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CONTEXT AND OBJECTIVE: Cerebrovascular disease is one of the most important causes of death and disability worldwide. The patient's inability to identify the warning signs of stroke substantially delays the search for emergency services, which is related directly to a worse outcome. Thus, during the 2011 Stroke Campaign in Brazil, a survey was conducted to identify the lay population's knowledge with regard to the recognition, treatment, and prevention of stroke. DESIGN AND SETTING: This retrospective, cross-sectional, multicenter study was held in cities throughout southeastern Brazil. METHODS: The campaign was conducted by students of several medical schools under the guidance of neurologists (assistants and professors). The students traveled to various public areas in Sao Paulo, Campinas, Sorocaba, Taubaté, and Pouso Alegre, where information about stroke was distributed and a specific questionnaire was administered. RESULTS: A total of 1304 people answered the questionnaire: 43.9% claimed to know what a stroke was, 65% knew someone who has had the disease, 35% knew > 3 risk factors for stroke, and 28.8% knew a preventive measure. Further, 17.9% was able to list at least 3 signs or symptoms of a stroke, 33.6% was aware that they should activate the emergency service, and 3.1% would have checked the time at which the signs and symptoms had developed. CONCLUSION: Despite the severity of stroke, the population that we analyzed has a low level of knowledge. Campaigns should increase the lay population's understanding of this disease, thus improving its prevention and treatment and contributing to public health politics.

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INTRODUCTION: The assessment of cortical excitability (CE) measurements has been increasingly used in neuropsychiatric research. However, there is scant information on the normative values of these measurements, as well as the possible effect of hemisphere laterality, gender and age on these variables. OBJECTIVES: To obtain normative data for CE measurements by transcranial magnetic stimulation, to assess inter-/intra-investigator variability and the influence of sex, age and oral contraception use. METHODS: A sample of 216 healthy volunteers matched according to age and gender was evaluated. Bilateral rest motor thresholds, motor evoked potentials (MEP), intracortical inhibition and facilitation were measured in the first dorsal interosseous muscle area representation of the primary motor cortex with a circular transcranial magnetic stimulation coil delivering biphasic pulses. Normative data were obtained for 200 participants (in a 1:1 male:female ratio) in a balanced proportion between five age groups (18-30; 31-40; 41-50; 51-60; >60 years). Inter/intra-investigator variability was assessed in 20 healthy volunteers in two sessions performed within a 30-minute interval. Measurements were also performed in a subgroup of 16 healthy female volunteers, using oral contraception and during the menstrual phase. RESULTS: Age had a dichotomous effect on CE measurements, providing significantly different normative data for subjects <50 and >50 years old, with smaller MEP's and intracortical inhibition in older individuals. There were no differences between genders or between left and right hemispheres. Also, CE parameters did not significantly differ with use of contraceptive treatment compared to the menstrual phase of the cycle. The inter-/intra-investigator reliability assessment showed some variability that may not be clinically significant. CONCLUSIONS: Age had a non-linear effect on CE. There were non-significant differences between genders, hemispheres or with use of oral contraceptives. There was good inter-/intra-investigator correlation for rest motor thresholds and motor evoked potentials while intracortical inhibition and facilitation had low correlations but acceptable reliability.

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Whole-vessel remodeling critically determines lumen caliber in vascular (patho)physiology, and it is reportedly redox-dependent. We hypothesized that the cell-surface pool of the endoplasmic reticulum redox chaperone protein disulfide isomerase-A1 (peri/epicellular=pecPDI), which is known to support thrombosis, also regulates disease-associated vascular architecture. In human coronary atheromas, PDI expression inversely correlated with constrictive remodeling and plaque stability. In a rabbit iliac artery overdistension model, there was unusually high PDI upregulation (≈25-fold versus basal, 14 days postinjury), involving both intracellular and pecPDI. PecPDI neutralization with distinct anti-PDI antibodies did not enhance endoplasmic reticulum stress or apoptosis. In vivo pecPDI neutralization with PDI antibody-containing perivascular gel from days 12 to 14 post injury promoted 25% decrease in the maximally dilated arteriographic vascular caliber. There was corresponding whole-vessel circumference loss using optical coherence tomography without change in neointima, which indicates constrictive remodeling. This was accompanied by decreased hydrogen peroxide generation. Constrictive remodeling was corroborated by marked changes in collagen organization, that is, switching from circumferential to radial fiber orientation and to a more rigid fiber type. The cytoskeleton architecture was also disrupted; there was a loss of stress fiber coherent organization and a switch from thin to medium thickness actin fibers, all leading to impaired viscoelastic ductility. Total and PDI-associated expressions of ß1-integrin, and levels of reduced cell-surface ß1-integrin, were diminished after PDI antibody treatment, implicating ß1-integrin as a likely pecPDI target during vessel repair. Indeed, focal adhesion kinase phosphorylation, a downstream ß1-integrin effector, was decreased by PDI antibody. Thus, the upregulated pecPDI pool tunes matrix/cytoskeleton reshaping to counteract inward remodeling in vascular pathophysiology.

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AIMS: Superficial erosion of atheromata causes many acute coronary syndromes, but arises from unknown mechanisms. This study tested the hypothesis that Toll-like receptor-2 (TLR2) activation contributes to endothelial apoptosis and denudation and thus contributes to the pathogenesis of superficial erosion. METHODS AND RESULTS: Toll-like receptor-2 and neutrophils localized at sites of superficially eroded human plaques. In vitro, TLR2 ligands (including hyaluronan, a matrix macromolecule abundant in eroded lesions) induced endothelial stress, characterized by reactive oxygen species production, endoplasmic reticulum (ER) stress, and apoptosis. Co-incubation of neutrophils with endothelial cells (ECs) potentiated these effects and induced EC apoptosis and detachment. We then categorized human atherosclerotic plaques (n = 56) based on morphologic features associated with superficial erosion, 'stable' fibrotic, or 'vulnerable' lesions. Morphometric analyses of the human atheromata localized neutrophils and neutrophil extracellular traps (NETs) near clusters of apoptotic ECs in smooth muscle cell (SMC)-rich plaques. The number of luminal apoptotic ECs correlated with neutrophil accumulation, amount of NETs, and TLR2 staining in SMC-rich plaques, but not in 'vulnerable' atheromata. CONCLUSION: These in vitro observations and analyses of human plaques indicate that TLR2 stimulation followed by neutrophil participation may render smooth muscle cell-rich plaques susceptible to superficial erosion and thrombotic complications by inducing ER stress, apoptosis, and favouring detachment of EC.

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OBJECTIVE: To review the literature on the analgesic effects of repetitive transcranial magnetic stimulation (rTMS) in chronic pain according to different pain syndromes and stimulation parameters. DATA SOURCES: Publications on rTMS and chronic pain were searched in PubMed and Google Scholar using the following key words: chronic pain, analgesia, transcranial magnetic stimulation, neuropathic pain, fibromyalgia, and complex regional pain syndrome. STUDY SELECTION: This review only included double-blind, controlled studies with >10 participants in each arm that were published from 1996 to 2014 and written in English. Studies with relevant information for the understanding of the effects of rTMS were also cited. DATA EXTRACTION: The following data were retained: type of pain syndrome, type of study, coil type, target, stimulation intensity, frequency, number of pulses, orientation of induced current, number of session, and a brief summary of intervention outcomes. DATA SYNTHESIS: A total of 33 randomized trials were found. Many studies reported significant pain relief by rTMS, especially high-frequency stimulation over the primary motor cortex performed in consecutive treatment sessions. Pain relief was frequently >30% compared with control treatment. Neuropathic pain, fibromyalgia, and complex regional pain syndrome were the pain syndromes more frequently studied. However, among all published studies, only a few performed repetitive sessions of rTMS. CONCLUSIONS: rTMS has potential utility in the management of chronic pain; however, studies using maintenance sessions of rTMS and assessing the effects of rTMS on the different aspects of chronic pain are needed to provide a more solid basis for its clinical application for pain relief.

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OBJECTIVE: Substantial evidence implicates interstitial collagenases of the matrix metalloproteinase (MMP) family in plaque rupture and fatal thrombosis. Understanding the compensatory mechanisms that may influence the expression of these enzymes and their functions, therefore, has important clinical implications. This study assessed in mice the relative effect of the 2 principal mouse collagenases on collagen content and other plaque characteristics. APPROACH AND RESULTS: Apolipoprotein E-deficient (apoE(-/-)) mice, MMP-13(-/-) apoE(-/-), MMP-8(-/-) apoE(-/-) double knockout mice, and MMP-13(-/-) MMP-8(-/-) apoE(-/-) triple knockout mice consumed a high-cholesterol diet for 10 and 24 weeks. Both double knockout and triple knockout mice showed comparable atherosclerotic lesion formation compared with apoE(-/-) controls. Analysis of aortic root sections indicated that lesions of MMP-8/MMP-13-deficient and MMP-13-deficient mice accumulate more fibrillar collagen than apoE(-/-) controls and MMP-8(-/-) apoE(-/-) double knockout. We further tested the relative effect of MMPs on plaque collagenolysis using in situ zymography. MMP-13 deletion alone abrogated collagenolytic activity in lesions, indicating a predominant role for MMP-13 in this process. MMP-13 and MMP-13/MMP-8 deficiency did not alter macrophage content but associated with reduced accumulation of smooth muscle cells. CONCLUSIONS: These results show that among MMP interstitial collagenases in mice, MMP-13 prevails over MMP-8 in collagen degradation in atheromata. These findings provide a rationale for the identification and selective targeting a predominant collagenase for modulating key aspects of plaque structure considered critical in clinical complications, although they do not translate directly to human lesions, which also contain MMP-1.

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Estimulação magnética transcraniana (EMT) é uma técnica conhecida desde o começo dos anos 90 e que atualmentetem ganhado destaque devido a sua segurança e possível aplicabilidade para tratar diversas patologias neuropsiquiátricas refratárias. A fim de clarificar os possíveis usos da EMT e suas variações no campo da clínica como forma de tratamento, procedemos à revisão da literatura selecionando os artigos nas áreas em que a técnica de EMT já tem sido largamente utilizada,a saber: AVC, Dor, Doença de Parkinson e Depressão. Essas doenças possuem elevada morbidade, possuindo grandesimplicações na qualidade de vida devido ao elevado grau de incapacidade associado e ao fato de ainda carecerem de métodos terapêuticos totalmente eficientes. Nesse contexto, a EMT emerge como ferramenta promissora, apresentando bons resultados, os quais fornecem margem para aplicações diretas na prática clínica. É necessário, todavia, o desenvolvimento de mais estudos randomizados, para se padronizar e aperfeiçoar as abordagensdessa técnica no tratamento de tais patologias...

Transcranial Magnetic Stimulation (TMS) is a technique that emerged in the 90s and has currently become recognized for its safety and potential applicability in the treatment of neuropsychiatry diseases. To clarify the possible uses of TMS and its variations in the clinical scope as a treatment, weproceeded a literature review selecting articles in the areas where the technique of TMS has already been widely used: Stroke, Pain, Parkinson’s Disease and Depression. These diseases have high morbidity, with large implications for the quality of life due to the high degree of disability and the fact that we still lack of fully efficient therapeutic methods. In this context, EMT emerges as a promising tool with amazing results, which provide scope for direct applications in clinical practice. However, the developmentof more randomized studies is necessary, in order to standardizeand improve the approaches of this technique in the treatment of such pathologies...

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