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BACKGROUND: Surgery is essential for curative treatment of solid tumors. Evidence from recent retrospective clinical analyses suggests that use of propofol-based total intravenous anesthesia during cancer resection surgery is associated with improved overall survival compared to inhaled volatile anesthesia. Evaluating these findings in prospective clinical studies is required to inform definitive clinical guidelines but will take many years and requires biomarkers to monitor treatment effect. Therefore, we examined the effect of different anesthetic agents on cancer recurrence in mouse models of breast cancer with the overarching goal of evaluating plausible mechanisms that could be used as biomarkers of treatment response. METHODS: To test the hypothesis that volatile anesthesia accelerates breast cancer recurrence after surgical resection of the primary tumor, we used three mouse models of breast cancer. We compared volatile sevoflurane anesthesia with intravenous propofol anesthesia and used serial non-invasive bioluminescent imaging to track primary tumor recurrence and metastatic recurrence. To determine short-term perioperative effects, we evaluated the effect of anesthesia on vascular integrity and immune cell changes after surgery in animal models. RESULTS: Survival analyses found that the kinetics of cancer recurrence and impact on survival were similar regardless of the anesthetic agent used during cancer surgery. Vascular permeability, immune cell infiltration and cytokine profiles showed no statistical difference after resection with inhaled sevoflurane or intravenous propofol anesthesia. CONCLUSIONS: These preclinical studies found no evidence that choice of anesthetic agent used during cancer resection surgery affected either short-term perioperative events or long-term cancer outcomes in mouse models of breast cancer. These findings raise the possibility that mouse models do not recapitulate perioperative events in cancer patients. Nonetheless, the findings suggest that future evaluation of effects of anesthesia on cancer outcomes should focus on cancer types other than breast cancer.
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Anestésicos por Inhalación , Anestésicos , Neoplasias de la Mama , Propofol , Animales , Ratones , Humanos , Femenino , Neoplasias de la Mama/patología , Propofol/farmacología , Sevoflurano/farmacología , Estudios Prospectivos , Estudios Retrospectivos , Recurrencia Local de Neoplasia , Anestesia Intravenosa/métodos , Anestesia General , Biomarcadores , Anestésicos Intravenosos/farmacología , Anestésicos por Inhalación/farmacologíaRESUMEN
Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated ß2-adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or ß2-adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting ß2-adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive ß2-adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.
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Antraciclinas , Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Antraciclinas/farmacología , Antraciclinas/uso terapéutico , Neoplasias de la Mama Triple Negativas/genética , Factor de Crecimiento Nervioso/uso terapéutico , Línea Celular Tumoral , Recurrencia Local de Neoplasia/tratamiento farmacológico , Receptores Adrenérgicos/uso terapéutico , Microambiente TumoralRESUMEN
Disruption of circadian rhythms occurs in rotating shift-work, jetlag, and in individuals with irregular sleep schedules. Circadian disruption is known to alter inflammatory responses and impair immune function. However, there is limited understanding of how circadian disruption modulates cancer-induced inflammation. Inflammation is a hallmark of cancer and is linked to worse prognosis and impaired brain function in cancer patients. Here, we investigated the effect of circadian disruption on cancer-induced inflammation in an orthotopic breast cancer model. Using a validated chronic jetlag protocol that advances the light-cycle by 8 âh every 2 days to disrupt circadian rhythms, we found that circadian disruption alters cancer-induced inflammation in a tissue-specific manner, increasing inflammation in the body and brain while decreasing inflammation within the tumor tissue. Circadian disruption did not affect inflammation in mice without tumors, suggesting that the impact of circadian disruption may be particularly detrimental in the context of underlying inflammatory conditions, such as cancer. Importantly, circadian disruption did not affect tumor burden, suggesting that increased inflammation was not a result of increased cancer progression. Overall, these findings identify the importance of healthy circadian rhythms for limiting cancer-induced inflammation.
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PURPOSE: The sympathetic nervous system drives breast cancer progression through ß-adrenergic receptor signalling. This discovery has led to the consideration of cardiac ß-blocker drugs as novel strategies for anticancer therapies. Carvedilol is a ß-blocker used in the management of cardiovascular disorders, anxiety, migraine and chemotherapy-induced cardiotoxicity. However, little is known about how carvedilol affects cancer-related outcomes. METHODS: To address this, we investigated the effects of carvedilol on breast cancer cell lines, in mouse models of breast cancer and in a large cohort of patients with breast cancer (n = 4014). RESULTS: Treatment with carvedilol blocked the effects of sympathetic nervous system activation, reducing primary tumour growth and metastasis in a mouse model of breast cancer and preventing invasion by breast cancer cell lines. A retrospective analysis found that women using carvedilol at breast cancer diagnosis (n = 136) had reduced breast cancer-specific mortality compared with women who did not (n = 3878) (5-year cumulative incidence of breast cancer deaths: 3.1% versus 5.7%; p = 0.024 and 0.076 from univariate and multivariable analyses, respectively) after a median follow-up of 5.5 years. CONCLUSIONS: These findings provide a rationale to further explore the use of the ß-blocker carvedilol as a novel strategy to slow cancer progression.
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Antagonistas Adrenérgicos beta/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Carvedilol/uso terapéutico , Antagonistas Adrenérgicos beta/efectos adversos , Animales , Antineoplásicos/efectos adversos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Carvedilol/efectos adversos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Femenino , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Invasividad Neoplásica , Metástasis de la Neoplasia , Estudios Retrospectivos , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Inflammation has been proposed to play a causal role in chemobrain which-if true-would represent an opportunity to repurpose existing anti-inflammatory drugs for the prevention and treatment of chemobrain. Here, we show that the chemoagent paclitaxel induces memory impairment and anhedonia in mice within 24 h of treatment cessation, but inflammation is not present until 2 weeks after treatment. We find no evidence of brain inflammation as measured by cytokine analysis at any time point. Furthermore, treating with aspirin to block inflammation did not affect paclitaxel-induced memory impairment. These findings suggest that inflammation may not be responsible for memory impairment induced by paclitaxel. These results contrast with recent findings of a causal role for inflammation in cancer-induced memory deficits in mice that were prevented by treatment with oral aspirin, suggesting that cognitive impairment in cancer patients undergoing treatment may arise from multiple convergent mechanisms.
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BACKGROUND: Computed radiography (CR), digital radiography (DR) and biplanar radiography (EOS™ imaging system) are common imaging tools for radiographic evaluation of adolescent idiopathic scoliosis (AIS). The effect of imaging methods in relation to later-on Cobb angle measurements on radiographs is not yet quantified. The study aimed to examine the compatibility between CR, DR and EOS for scoliotic quantification by evaluating the reliability, agreement of different imaging methods, and assessing the prediction performance for EOS measurement from that of CR and DR. METHOD: A flexible spine phantom was used to simulate 32 different scoliotic curves ranging from 10° to 60°. Each curvature was imaged using DR, CR and EOS systems accordingly. Each of the six observers independently measured Cobb angle twice on each image at a two-week interval. Intraclass correlation coefficient (model 2 and 3), Bland-Altman plot and linear regression analysis were completed to evaluate the reliability, agreement, and the prediction of Cobb angle measurement, respectively. RESULTS: Reliability analysis showed excellent intra-observer reliability (Intraclass correlation coefficient >0.9) for each observer and good inter-observer reliability (Intraclass correlation coefficient = 0.84 for EOS; 0.739 for CR; 0.877 for DR) for each method. Bland-Altman plots demonstrated good agreement between imaging methods without fixed or proportional bias. Excellent coefficient of determination was achieved, with 0.980 for CR versus EOS measurements, and 0.973 for DR versus EOS measurements. CONCLUSIONS: Radiographs produced by all of the three methods can provide reliable and accurate Cobb angle measurements for scoliosis assessments. None of the methods systemically underestimates or overestimates the Cobb angle measurement. Additionally, all of the evaluated methods are satisfactory in obtaining images for Cobb angle measurement in AIS. However, the 3D post-processing techniques offered by EOS should also be taken into consideration as it takes a vital role in treatment and monitoring of 3D deformity in the case of scoliosis. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: In view of the limited availability of biplanar radiography (EOS™ imaging system), computed radiography and digital radiography are demonstrated to be reliable alternatives in scoliosis monitoring as evident in the reliability, agreement and prediction of Cobb angle measurement.
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Up to 70% of survivors of adult-onset, non-central nervous system (CNS) solid tumors report cognitive symptoms, and approximately 30% have impairment on formal neuropsychological testing. The etiology of the impairment is unknown. There is a lack of robust evidence on how to prevent or treat cancer-related cognitive impairment (CRCI). Here, we review the evidence for the putative mechanisms of CRCI by examining clinical and preclinical models, primarily those associated with chemotherapy. Pharmacologic and nonpharmacologic options for treating CRCI are discussed based on the best evidence available. Practical clinical advice for health professionals managing patients with CRCI is also provided.
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Antineoplásicos/efectos adversos , Disfunción Cognitiva/etiología , Disfunción Cognitiva/terapia , Neoplasias/complicaciones , Humanos , Neoplasias/psicología , SobrevivientesRESUMEN
Bone and bone marrow serve as an imperative ecosystem to various types of cells participating in critical body functions. The chemokine Cxcl12, also known as stromal cell-derived factor 1 (Sdf1), is one of the communication factors in the marrow microenvironment that regulates hematopoietic stem/progenitor cell homeostasis. However, the function of Cxcl12 in other bone marrow cells in vivo is yet to be discovered. Here we report a novel function of Cxcl12 in postnatal bone development and homeostasis. Targeted deletion of Cxcl12 in Paired related homeobox 1 (Prx1)-expressing or osterix (Osx)-expressing mesenchymal stem/progenitor cells (MSPCs), but not in mature osteoblasts, resulted in marrow adiposity and reduced trabecular bone content. In vivo lineage tracing analysis revealed biased differentiation of MSPCs toward adipocytes. In contrast, adult-stage deletion of Cxcl12 in Osx-expressing cells led to reduced bone content but not adiposity. Targeting the receptor Cxcr4 in the Prx1-expressing cells also resulted in reduced trabecular bone content but not adiposity. Our study reveals a previously unidentified role of the MSPC-secreting Cxcl12 that regulates its osteogenesis and adipogenesis through the cell-autonomous and non-autonomous mechanism, respectively; which could further influence the homeostatic control of the hematopoietic system. © 2017 American Society for Bone and Mineral Research.
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Adipogénesis , Células de la Médula Ósea/metabolismo , Quimiocina CXCL12/deficiencia , Células Madre Mesenquimatosas/metabolismo , Osteoblastos/metabolismo , Osteogénesis , Animales , Células de la Médula Ósea/patología , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Células Madre Mesenquimatosas/patología , Ratones , Ratones Transgénicos , Osteoblastos/patología , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Factor de Transcripción Sp7/genética , Factor de Transcripción Sp7/metabolismoRESUMEN
Homozygous Cav3.2 knockout mice, which are defective in the pore-forming subunit of a low voltage activated T-type calcium channel, have been documented to show impaired maintenance of late-phase long-term potentiation (L-LTP) and defective retrieval of context-associated fear memory. To investigate the role of Cav3.2 in global gene expression, we performed a microarray transcriptome study on the hippocampi of the Cav3.2-/- mice and their wild-type littermates, either naïve (untrained) or trace fear conditioned. We found a significant left-right asymmetric effect on the hippocampal transcriptome caused by the Cav3.2 knockout. Between the naive Cav3.2-/- and the naive wild-type mice, 3522 differentially expressed genes (DEGs) were found in the left hippocampus, but only 4 DEGs were found in the right hippocampus. Remarkably, the effect of Cav3.2 knockout was partially reversed by trace fear conditioning. The number of DEGs in the left hippocampus was reduced to 6 in the Cav3.2 knockout mice after trace fear conditioning, compared with the wild-type naïve mice. To our knowledge, these results demonstrate for the first time the asymmetric effects of the Cav3.2 and its partial reversal by behavior training on the hippocampal transcriptome.
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Conducta Animal , Canales de Calcio Tipo T/deficiencia , Canales de Calcio Tipo T/genética , Condicionamiento Psicológico , Hipocampo/metabolismo , Transcriptoma , Animales , Miedo/psicología , Técnicas de Inactivación de Genes , Hipocampo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Among all voltage-gated calcium channels, the T-type Ca²âº channels encoded by the Ca(v)3.2 genes are highly expressed in the hippocampus, which is associated with contextual, temporal and spatial learning and memory. However, the specific involvement of the Ca(v)3.2 T-type Ca²âº channel in these hippocampus-dependent types of learning and memory remains unclear. To investigate the functional role of this channel in learning and memory, we subjected Ca(v)3.2 homozygous and heterozygous knockout mice and their wild-type littermates to hippocampus-dependent behavioral tasks, including trace fear conditioning, the Morris water-maze and passive avoidance. The Ca(v)3.2 â»/â» mice performed normally in the Morris water-maze and auditory trace fear conditioning tasks but were impaired in the context-cued trace fear conditioning, step-down and step-through passive avoidance tasks. Furthermore, long-term potentiation (LTP) could be induced for 180 minutes in hippocampal slices of WTs and Ca(v)3.2 âº/â» mice, whereas LTP persisted for only 120 minutes in Ca(v)3.2 â»/â» mice. To determine whether the hippocampal formation is responsible for the impaired behavioral phenotypes, we next performed experiments to knock down local function of the Ca(v)3.2 T-type Ca²âº channel in the hippocampus. Wild-type mice infused with mibefradil, a T-type channel blocker, exhibited similar behaviors as homozygous knockouts. Taken together, our results demonstrate that retrieval of context-associated memory is dependent on the Ca(v)3.2 T-type Ca²âº channel.
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Canales de Calcio Tipo T/metabolismo , Memoria/fisiología , Animales , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Región CA1 Hipocampal/citología , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/fisiología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/deficiencia , Canales de Calcio Tipo T/genética , Condicionamiento Psicológico/efectos de los fármacos , Condicionamiento Psicológico/fisiología , Señales (Psicología) , Miedo/efectos de los fármacos , Miedo/fisiología , Técnicas de Inactivación de Genes , Audición/fisiología , Potenciación a Largo Plazo/efectos de los fármacos , Potenciación a Largo Plazo/fisiología , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria/efectos de los fármacos , Mibefradil/farmacología , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Percepción/efectos de los fármacos , Percepción/fisiología , Sinapsis/efectos de los fármacosRESUMEN
We report an outbreak of ciguatoxin poisoning after barracuda fish ingestion in southern Taiwan. Three members of a family developed nausea, vomiting, watery diarrhea, and myalgias about 1 hour after eating three to ten eggs of a barracuda fish. Numbness of the lips and extremities followed the gastrointestinal symptoms about 2 hours after ingestion. Other manifestations included hyperthermia, hypotension, bradycardia, and hyperreflexia. Bradycardia persisted for several days, and one patient required a continuous infusion of intravenous atropine totaling 40 mg over 2 days. Further follow-up of the patients disclosed improvement of neurologic sequelae and bradycardia, but sensory abnormalities resolved several months later. In conclusion, ciguatoxin poisoning causes mainly gastrointestinal and neurologic effects of variable severity. In two patients with ciguatoxin poisoning after barracuda fish egg ingestion, persistent bradycardia required prolonged atropine infusion.