RESUMEN
Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents2-4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (surfaceome) have been technologically limited until recently and-in the case of PDAC-the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface-where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth-is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.
Asunto(s)
Carcinoma Ductal Pancreático/patología , Neoplasias Pancreáticas/patología , Pinocitosis , Sindecano-1/metabolismo , Factor 6 de Ribosilación del ADP , Factores de Ribosilacion-ADP/metabolismo , Animales , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Proliferación Celular , Progresión de la Enfermedad , Femenino , Factores de Intercambio de Guanina Nucleótido/metabolismo , Humanos , Masculino , Ratones , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Transducción de SeñalRESUMEN
Objective: Anxiety is among the most common psychiatric illnesses, and it commonly co-occurs with epilepsy. This review of the existing literature on anxiety comorbid with epilepsy aims to generate new insights into strategies for assessment and treatment. Methods: The authors conducted a narrative literature review to select key publications that help clarify the phenomenology and management of comorbid anxiety and epilepsy. Results: Anxiety symptoms may be relevant even if the criteria for a diagnosis of an anxiety disorder are not met. Associating specific seizure types or seizure localization with anxiety symptoms remains difficult; however, the amygdala is a brain region commonly associated with seizure foci and panic or fear sensations. The hypothalamic-pituitary-adrenal axis may also be relevant for anxiety symptoms, particularly for the selection of treatments. Nonpharmacological treatment is appropriate for anxiety comorbid with epilepsy, particularly because relaxation techniques may reduce hypersympathetic states, which improve symptoms. Medication options include antidepressants and anticonvulsants that may have efficacy for anxiety symptoms. Benzodiazepines are a good choice to address this comorbid condition, although side effects may limit utility. Conclusions: Ultimately, there are numerous treatment options, and although there is a limited evidence base, quality of life may be improved with appropriate treatment for individuals experiencing comorbid anxiety and epilepsy.
Asunto(s)
Epilepsia , Humanos , Epilepsia/complicaciones , Epilepsia/epidemiología , Epilepsia/terapia , Ansiedad/terapia , Comorbilidad , Trastornos de Ansiedad/complicaciones , Trastornos de Ansiedad/epidemiología , Trastornos de Ansiedad/terapiaRESUMEN
INTRODUCTION: In women with epilepsy, seizure frequency and severity can be affected during pregnancy by factors such as changes in ASD (anti-seizure drug) metabolism, changes in hormone levels, and medication compliance. Some women with epilepsy experience seizure worsening during pregnancy, while others have an improvement. Most epileptic seizures during pregnancy occur in women with pre-existing epilepsy. Rarely, women develop new-onset seizure-like episodes concerning for epileptic seizures during pregnancy, posing a diagnostic and therapeutic challenge for the physician. METHODS: To determine the frequency of new-onset seizures during pregnancy and the clinical course of those with new seizures, we performed a retrospective study of all women with concomitant diagnoses of pregnancy and seizures (excluding eclampsia) at the Johns Hopkins Medical Institutions over a five-year period. We calculated the frequency of events concerning for seizures during pregnancy, including first-lifetime events, and classified these events as epileptic seizures or as seizure mimics. For those with epileptic seizures, we followed up with the patient to determine whether seizures recurred in or after pregnancy, and whether treatment with anti-seizure medication was initiated. RESULTS: Over a five-year period, 41,869 women received care at Johns Hopkins Medical Institutions during pregnancy. 84 women had at least one event concerning for seizure during their pregnancies. Of these, 11 had no prior history of seizures; 5 of these women were found to have first-time unprovoked epileptic seizures supported by epileptiform abnormalities on EEG. All women delivered at term with no major complications. Four of these women continued to have epileptic seizures after delivery. CONCLUSIONS: New onset seizures during pregnancy were rare. Most women with first-time epileptic seizures during pregnancy also had epileptic seizures after pregnancy, indicating a first presentation of epilepsy.