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We previously reported that ionizing radiation (IR) mediates cell death through the induction of CUGBP elav-like family member 2 (CELF2), a tumor suppressor. CELF2 is an RNA binding protein that modulates mRNA stability and translation. Since IR induces autophagy, we hypothesized that CELF2 regulates autophagy-mediated colorectal cancer (CRC) cell death. For clinical relevance, we determined CELF2 levels in The Cancer Genome Atlas (TCGA). Role of CELF2 in radiation response was carried out in CRC cell lines by immunoblotting, immunofluorescence, autophagic vacuole analyses, RNA stability assay, quantitative polymerase chain reaction and electron microscopy. In vivo studies were performed in a xenograft tumor model. TCGA analyses demonstrated that compared to normal tissue, CELF2 is expressed at significantly lower levels in CRC, and is associated with better overall 5-year survival in patients receiving radiation. Mechanistically, CELF2 increased levels of critical components of the autophagy cascade including Beclin-1, ATG5, and ATG12 by modulating mRNA stability. CELF2 also increased autophagic flux in CRC. IR significantly induced autophagy in CRC which correlates with increased levels of CELF2 and autophagy associated proteins. Silencing CELF2 with siRNA, mitigated IR induced autophagy. Moreover, knockdown of CELF2 in vivo conferred tumor resistance to IR. These studies elucidate an unrecognized role for CELF2 in inducing autophagy and potentiating the effects of radiotherapy in CRC.
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Autofagia/fisiología , Proteínas CELF/metabolismo , Supervivencia Celular/efectos de la radiación , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/radioterapia , Proteínas del Tejido Nervioso/metabolismo , Animales , Proteína 12 Relacionada con la Autofagia/metabolismo , Proteína 5 Relacionada con la Autofagia/metabolismo , Beclina-1/metabolismo , Proteínas CELF/genética , Línea Celular Tumoral , Supervivencia Celular/genética , Células HCT116 , Humanos , Masculino , Ratones , Trasplante de Neoplasias , Proteínas del Tejido Nervioso/genética , Pronóstico , Interferencia de ARN , ARN Mensajero/genética , ARN Interferente Pequeño/genética , Radiación Ionizante , Trasplante HeterólogoAsunto(s)
Países en Desarrollo , Fiebre Hemorrágica Ebola/prevención & control , Fiebre Hemorrágica Ebola/transmisión , Población Rural , Población Urbana , Estudios Transversales , República Democrática del Congo , Emigración e Inmigración/estadística & datos numéricos , Fiebre Hemorrágica Ebola/epidemiología , Humanos , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/estadística & datos numéricos , Liberia , Turismo Médico/estadística & datos numéricos , Factores de Riesgo , Población Rural/estadística & datos numéricos , Población Urbana/estadística & datos numéricosRESUMEN
ABSTRACT: Few analgesics identified using preclinical models have successfully translated to clinical use. These translational limitations may be due to the unidimensional nature of behavioral response measures used to assess rodent nociception. Advances in high-speed videography for pain behavior allow for objective quantification of nuanced aspects of evoked paw withdrawal responses. However, whether videography-based assessments of mechanical hypersensitivity outperform traditional measurement reproducibility is unknown. First, we determined whether high-speed videography of paw withdrawal was reproducible across experimenters. Second, we examined whether this method distinguishes behavioral responses exhibited by naive mice and mice with complete Freund's adjuvant (CFA)-induced inflammation. Twelve experimenters stimulated naive C57BL/6 mice with varying mechanical stimuli. Paw withdrawal responses were recorded with high-speed videography and scored offline by one individual. Our group was unable to replicate the original findings produced by high-speed videography analysis. Surprisingly, â¼80% of variation was not accounted for by variables previously reported to distinguish between responses to innocuous and noxious stimuli (paw height, paw velocity, and pain score), or by additional variables (experimenter, time-of-day, and animal), but rather by unidentified factors. Similar high-speed videography assessments were performed in CFA- and vehicle-treated animals, and the cumulative data failed to reveal an effect of CFA injection on withdrawal as measured by high-speed videography. This study does not support using paw height, velocity, or pain score measurements from high-speed recordings to delineate behavioral responses to innocuous and noxious stimuli. Our group encourages the continued use of traditional mechanical withdrawal assessments until additional high-speed withdrawal measures are validated in established pain models.
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Adyuvante de Freund , Inflamación , Ratones Endogámicos C57BL , Dimensión del Dolor , Animales , Ratones , Masculino , Dimensión del Dolor/métodos , Adyuvante de Freund/toxicidad , Modelos Animales de Enfermedad , Hiperalgesia/fisiopatología , Grabación en Video/métodos , Reproducibilidad de los Resultados , Estimulación Física/efectos adversos , Conducta Animal/fisiología , Conducta Animal/efectos de los fármacosRESUMEN
Patients with Fabry disease suffer from chronic debilitating pain and peripheral sensory neuropathy with minimal treatment options, but the cellular drivers of this pain are unknown. Here, we propose a mechanism we believe to be novel in which altered signaling between Schwann cells and sensory neurons underlies the peripheral sensory nerve dysfunction we observed in a genetic rat model of Fabry disease. Using in vivo and in vitro electrophysiological recordings, we demonstrated that Fabry rat sensory neurons exhibited pronounced hyperexcitability. Schwann cells probably contributed to this finding because application of mediators released from cultured Fabry Schwann cells induced spontaneous activity and hyperexcitability in naive sensory neurons. We examined putative algogenic mediators using proteomic analysis and found that Fabry Schwann cells released elevated levels of the protein p11 (S100A10), which induced sensory neuron hyperexcitability. Removal of p11 from Fabry Schwann cell media caused hyperpolarization of neuronal resting membrane potentials, indicating that p11 may contribute to the excessive neuronal excitability caused by Fabry Schwann cells. These findings demonstrate that sensory neurons from rats with Fabry disease exhibit hyperactivity caused in part by Schwann cell release of the protein p11.
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Modelos Animales de Enfermedad , Enfermedad de Fabry , Células de Schwann , Células Receptoras Sensoriales , Animales , Masculino , Ratas , Células Cultivadas , Enfermedad de Fabry/metabolismo , Enfermedad de Fabry/fisiopatología , Proteómica , Células de Schwann/metabolismo , Células Receptoras Sensoriales/metabolismo , Femenino , Ratas Sprague-DawleyRESUMEN
Significance: Diabetic peripheral neuropathy (DPN), a complication of metabolic syndrome, type I and type II diabetes, leads to sensory changes that include slow nerve conduction, nerve degeneration, loss of sensation, pain, and gate disturbances. These complications remain largely untreatable, although tight glycemic control can prevent neuropathy progression. Nonpharmacologic approaches remain the most impactful to date, but additional advances in treatment approaches are needed. Recent Advances: This review highlights several emerging interventions, including a focus on dietary interventions and physical activity, that continue to show promise for treating DPN. We provide an overview of our current understanding of how exercise can improve aspects of DPN. We also highlight new studies in which a ketogenic diet has been used as an intervention to prevent and reverse DPN. Critical Issues: Both exercise and consuming a ketogenic diet induce systemic and cellular changes that collectively improve complications associated with DPN. Both interventions may involve similar signaling pathways and benefits but also impact DPN through unique mechanisms. Future Directions: These lifestyle interventions are critically important as personalized medicine approaches will likely be needed to identify specific subsets of neuropathy symptoms and deficits in patients, and determine the most impactful treatment. Overall, these two interventions have the potential to provide meaningful relief for patients with DPN and provide new avenues to identify new therapeutic targets.
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Diabetes Mellitus Tipo 2 , Neuropatías Diabéticas , Síndrome Metabólico , Humanos , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/terapia , Neuropatías Diabéticas/terapia , Neuropatías Diabéticas/complicaciones , Transducción de Señal , DolorRESUMEN
Background: Intraepidermal nerve fiber density (IENFD) has become an important biomarker for neuropathy diagnosis and research. The consequences of reduced IENFD can include sensory dysfunction, pain, and a significant decrease in quality of life. We examined the extent to which IENFD is being used as a tool in human and mouse models and compared the degree of fiber loss between diseases to gain a broader understanding of the existing data collected using this common technique. Methods: We conducted a scoping review of publications that used IENFD as a biomarker in human and non-human research. PubMed was used to identify 1,004 initial articles that were then screened to select articles that met the criteria for inclusion. Criteria were chosen to standardize publications so they could be compared rigorously and included having a control group, measuring IENFD in a distal limb, and using protein gene product 9.5 (PGP9.5). Results: We analyzed 397 articles and collected information related to publication year, the condition studied, and the percent IENFD loss. The analysis revealed that the use of IENFD as a tool has been increasing in both human and non-human research. We found that IENFD loss is prevalent in many diseases, and metabolic or diabetes-related diseases were the most studied conditions in humans and rodents. Our analysis identified 73 human diseases in which IENFD was affected, with 71 reporting IENFD loss and an overall average IENFD change of -47%. We identified 28 mouse and 21 rat conditions, with average IENFD changes of -31.6% and -34.7%, respectively. Additionally, we present data describing sub-analyses of IENFD loss according to disease characteristics in diabetes and chemotherapy treatments in humans and rodents. Interpretation: Reduced IENFD occurs in a surprising number of human disease conditions. Abnormal IENFD contributes to important complications, including poor cutaneous vascularization, sensory dysfunction, and pain. Our analysis informs future rodent studies so they may better mirror human diseases impacted by reduced IENFD, highlights the breadth of diseases impacted by IENFD loss, and urges exploration of common mechanisms that lead to substantial IENFD loss as a complication in disease.
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Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a KATP channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of KATP channels with the KATP channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK+ cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of KATP channels to provide ketogenic diet-related analgesia. This study also identifies KATP channels as a new target to mimic the antinociceptive effects of a ketogenic diet.
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Chronic pain is a substantial health burden and options for treating chronic pain remain minimally effective. Ketogenic diets are emerging as well-tolerated, effective therapeutic strategies in preclinical models of chronic pain, especially diabetic neuropathy. We tested whether a ketogenic diet is antinociceptive through ketone oxidation and related activation of ATP-gated potassium (KATP) channels in mice. We demonstrate that consumption of a ketogenic diet for one week reduced evoked nocifensive behaviors (licking, biting, lifting) following intraplantar injection of different noxious stimuli (methylglyoxal, cinnamaldehyde, capsaicin, or Yoda1) in mice. A ketogenic diet also decreased the expression of p-ERK, an indicator of neuronal activation in the spinal cord, following peripheral administration of these stimuli. Using a genetic mouse model with deficient ketone oxidation in peripheral sensory neurons, we demonstrate that protection against methylglyoxal-induced nociception by a ketogenic diet partially depends on ketone oxidation by peripheral neurons. Injection of tolbutamide, a KATP channel antagonist, prevented ketogenic diet-mediated antinociception following intraplantar capsaicin injection. Tolbutamide also restored the expression of spinal activation markers in ketogenic diet-fed, capsaicin-injected mice. Moreover, activation of KATP channels with the KATP channel agonist diazoxide reduced pain-like behaviors in capsaicin-injected, chow-fed mice, similar to the effects observed with a ketogenic diet. Diazoxide also reduced the number of p-ERK+ cells in capsaicin-injected mice. These data support a mechanism that includes neuronal ketone oxidation and activation of KATP channels to provide ketogenic diet-related analgesia. This study also identifies KATP channels as a new target to mimic the antinociceptive effects of a ketogenic diet.
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Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated sensory neuron-specific, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and skin and spinal dorsal horn innervation. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. Adv-KO-SCOT mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet Adv-KO-SCOT mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.
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Ataxia de Friedreich , Animales , Ratones , Ataxia de Friedreich/patología , Ratones Noqueados , Cetonas , Oxidación-Reducción , Células Receptoras Sensoriales/patologíaRESUMEN
Ketogenic diets are emerging as protective interventions in preclinical and clinical models of somatosensory nervous system disorders. Additionally, dysregulation of succinyl-CoA 3-oxoacid CoA-transferase 1 (SCOT, encoded by Oxct1 ), the fate-committing enzyme in mitochondrial ketolysis, has recently been described in Friedreich's ataxia and amyotrophic lateral sclerosis. However, the contribution of ketone metabolism in the normal development and function of the somatosensory nervous system remains poorly characterized. We generated sensory neuron-specific, Advillin-Cre knockout of SCOT (Adv-KO-SCOT) mice and characterized the structure and function of their somatosensory system. We used histological techniques to assess sensory neuronal populations, myelination, and skin and spinal dorsal horn innervation. We also examined cutaneous and proprioceptive sensory behaviors with the von Frey test, radiant heat assay, rotarod, and grid-walk tests. Adv-KO-SCOT mice exhibited myelination deficits, altered morphology of putative Aδ soma from the dorsal root ganglion, reduced cutaneous innervation, and abnormal innervation of the spinal dorsal horn compared to wildtype mice. Synapsin 1-Cre-driven knockout of Oxct1 confirmed deficits in epidermal innervation following a loss of ketone oxidation. Loss of peripheral axonal ketolysis was further associated with proprioceptive deficits, yet Adv-KO-SCOT mice did not exhibit drastically altered cutaneous mechanical and thermal thresholds. Knockout of Oxct1 in peripheral sensory neurons resulted in histological abnormalities and severe proprioceptive deficits in mice. We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.
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ABSTRACT: Dietary interventions are promising approaches to treat pain associated with metabolic changes because they impact both metabolic and neural components contributing to painful neuropathy. Here, we tested whether consumption of a ketogenic diet could affect sensation, pain, and epidermal innervation loss in type 1 diabetic mice. C57Bl/6 mice were rendered diabetic using streptozotocin and administered a ketogenic diet at either 3 weeks (prevention) or 9 weeks (reversal) of uncontrolled diabetes. We quantified changes in metabolic biomarkers, sensory thresholds, and epidermal innervation to assess impact on neuropathy parameters. Diabetic mice consuming a ketogenic diet had normalized weight gain, reduced blood glucose, elevated blood ketones, and reduced hemoglobin-A1C levels. These metabolic biomarkers were also improved after 9 weeks of diabetes followed by 4 weeks of a ketogenic diet. Diabetic mice fed a control chow diet developed rapid mechanical allodynia of the hind paw that was reversed within a week of consumption of a ketogenic diet in both prevention and reversal studies. Loss of thermal sensation was also improved by consumption of a ketogenic diet through normalized thermal thresholds. Finally, diabetic mice consuming a ketogenic diet had normalized epidermal innervation, including after 9 weeks of uncontrolled diabetes and 4 weeks of consumption of the ketogenic diet. These results suggest that, in mice, a ketogenic diet can prevent and reverse changes in key metabolic biomarkers, altered sensation, pain, and axon innervation of the skin. These results identify a ketogenic diet as a potential therapeutic intervention for patients with painful diabetic neuropathy and/or epidermal axon loss.
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Diabetes Mellitus Experimental , Neuropatías Diabéticas , Dieta Cetogénica , Animales , Biomarcadores , Neuropatías Diabéticas/tratamiento farmacológico , Humanos , Hiperalgesia/etiología , Ratones , Ratones Endogámicos C57BL , DolorRESUMEN
ABSTRACT: Methylglyoxal (MGO) is a reactive dicarbonyl byproduct of glycolysis implicated in a growing number of neuropathic pain conditions, including chemotherapy-induced peripheral neuropathy, diabetic peripheral neuropathy, and radiculopathy with lumbar disk herniation. Recent studies show success in preclinical models treating these disorders with an interventional ketogenic diet. Here, we tested the hypothesis that a ketogenic diet modifies pathological MGO signaling as a mechanism underlying neuropathy improvement. We found that mice injected with MGO displayed nocifensive behaviors, whereas mice prefed a ketogenic diet were resistant to mechanical allodynia elicited by MGO. In addition, levels of circulating MGO were reduced in ketogenic diet-fed mice and negatively correlated with levels of the ketone body ß-hydroxybutyrate (ß-HB). Methylglyoxal is normally scavenged by the glyoxalase system, and ketogenic diet-fed mice displayed increased glyoxalase 1 activity compared with chow-fed control mice. Recent studies also suggest that ketone bodies contribute to MGO detoxification, consistent with a negative correlation between ß-HB and MGO. To assess whether ketone bodies modified MGO-evoked nociception through direct MGO detoxification, we coincubated either acetoacetate or ß-HB with MGO before injection. Mice receiving intraplantar MGO injection exhibit increased nociceptive behavior (lifting, licking, biting, and scratching), which was significantly reduced by coincubation with either acetoacetate or ß-HB. Methylglyoxal increased phospho-extracellular signal-regulated kinase-positive cells in the spinal dorsal horn, and this evoked spinal activation was ameliorated by preincubation with acetoacetate or ß-HB. These results suggest that a ketogenic diet and ketone bodies ameliorate MGO-evoked nociception, partially through detoxification of MGO, and provide rationale for therapeutic intervention with a ketogenic diet in MGO-driven pathologies.
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Dieta Cetogénica , Piruvaldehído , Ratones , Animales , Piruvaldehído/toxicidad , Acetoacetatos , Nocicepción , Óxido de Magnesio , Cuerpos Cetónicos , Ácido 3-HidroxibutíricoRESUMEN
OBJECTIVES/HYPOTHESIS: Human papillomavirus (HPV) is a DNA virus that causes cancer in multiple sites. Although sexual activity is the primary means of oropharyngeal HPV acquisition, studies suggest HPV transmission through occupational exposure from medical instruments and surgical fumes. We assess if aerosolization of HPV16 DNA via electrocautery places otolaryngologists at risk for exposure. STUDY DESIGN: Animal and human laboratory model. METHODS: Plasmid (pLXSN16E6E7) expressing HPV p16 E6/E7 genes was transformed into DH5α Escherichia coli cells using the heat shock method. Miniprep and maxiprep purification of transformed DNA with subsequent restriction enzyme double digestion confirmed presence of E6E7 fragment. We injected 2 µg plasmid DNA in 20 µL TE (Tris and ethylenediaminetetraacetic acid) buffer intradermally into freshly severed mouse tail then cauterized for 5 to 10 seconds. Generated fumes were collected through a suction tube fitted with Whatman filter paper. Filter paper was placed in 100 µL TE buffer. Additionally, six patients undergoing transoral robotic surgery for resection of oropharyngeal cancer were identified, three with p16-negative tumors and three with p16-positive tumors. Intraoperatively, Whatman filter paper was exposed to electrocautery fumes, then placed in 100 uL TE buffer. Additional samples were collected from the suction tubing and filter, the surgical mask of the surgeon at head of the bed, and the robot arm. RESULTS: Samples were analyzed via polymerase chain reaction with an assay sensitivity of 1.5 ng E6E7 DNA. None of the patient or mouse tail samples yielded detectable HPV16 DNA in the electrocautery fumes. We did not detect HPV16 DNA on the surgical masks, suction apparatus, or robot arm intraoperatively. CONCLUSIONS: There is likely minimal risk of occupational exposure to HPV16 via electrocautery fumes. LEVEL OF EVIDENCE: NA Laryngoscope, 130:2366-2371, 2020.
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Carcinoma de Células Escamosas/virología , Electrocoagulación/instrumentación , Exposición Profesional , Neoplasias Orofaríngeas/virología , Otorrinolaringólogos , Infecciones por Papillomavirus/transmisión , Aerosoles , Microbiología del Aire , Animales , Carcinoma de Células Escamosas/genética , Contaminación de Equipos , Papillomavirus Humano 16/genética , Humanos , Ratones , Quirófanos , Neoplasias Orofaríngeas/genética , Infecciones por Papillomavirus/genética , Factores de Riesgo , Procedimientos Quirúrgicos RobotizadosRESUMEN
Arginine vasopressin (AVP) and its type-2 receptor (V2R) play an essential role in the regulation of salt and water homeostasis by the kidneys. V2R activation also stimulates proliferation of renal cell carcinoma (RCC) cell lines in vitro. The current studies investigated V2R expression and activity in human RCC tumors, and its role in RCC tumor growth. Examination of the cancer genome atlas (TCGA) database, and analysis of human RCC tumor tissue microarrays, cDNA arrays and tumor biopsy samples demonstrated V2R expression and activity in clear cell RCC (ccRCC). In vitro, V2R antagonists OPC31260 and Tolvaptan, or V2R gene silencing reduced wound closure and cell viability of 786-O and Caki-1 human ccRCC cell lines. Similarly in mouse xenograft models, Tolvaptan and OPC31260 decreased RCC tumor growth by reducing cell proliferation and angiogenesis, while increasing apoptosis. In contrast, the V2R agonist dDAVP significantly increased tumor growth. High intracellular cAMP levels and ERK1/2 activation were observed in human ccRCC tumors. In mouse tumors and Caki-1 cells, V2R agonists reduced cAMP and ERK1/2 activation, while dDAVP treatment had the reverse effect. V2R gene silencing in Caki-1 cells also reduced cAMP and ERK1/2 activation. These results provide novel evidence for a pathogenic role of V2R signaling in ccRCC, and suggest that inhibitors of the AVP-V2R pathway, including the FDA-approved drug Tolvaptan, could be utilized as novel ccRCC therapeutics.
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Carcinoma de Células Renales/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias Renales/tratamiento farmacológico , Receptores de Vasopresinas/química , Tolvaptán/farmacología , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas/farmacología , Apoptosis , Biomarcadores de Tumor , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Estudios de Casos y Controles , Ciclo Celular , Proliferación Celular , Femenino , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Ratones , Ratones Desnudos , Pronóstico , Receptores de Vasopresinas/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Despite aggressive therapies, head and neck squamous cell carcinoma (HNSCC) is associated with a less than 50% 5-year survival rate. Late-stage HNSCC frequently consists of up to 80% cancer-associated fibroblasts (CAF). We previously reported that CAF-secreted HGF facilitates HNSCC progression; however, very little is known about the role of CAFs in HNSCC metabolism. Here, we demonstrate that CAF-secreted HGF increases extracellular lactate levels in HNSCC via upregulation of glycolysis. CAF-secreted HGF induced basic FGF (bFGF) secretion from HNSCC. CAFs were more efficient than HNSCC in using lactate as a carbon source. HNSCC-secreted bFGF increased mitochondrial oxidative phosphorylation and HGF secretion from CAFs. Combined inhibition of c-Met and FGFR significantly inhibited CAF-induced HNSCC growth in vitro and in vivo (P < 0.001). Our cumulative findings underscore reciprocal signaling between CAF and HNSCC involving bFGF and HGF. This contributes to metabolic symbiosis and a targetable therapeutic axis involving c-Met and FGFR.Significance: HNSCC cancer cells and CAFs have a metabolic relationship where CAFs secrete HGF to induce a glycolytic switch in HNSCC cells and HNSCC cells secrete bFGF to promote lactate consumption by CAFs. Cancer Res; 78(14); 3769-82. ©2018 AACR.
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Fibroblastos Asociados al Cáncer/patología , Glucólisis/fisiología , Neoplasias de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Animales , Fibroblastos Asociados al Cáncer/metabolismo , Línea Celular Tumoral , Movimiento Celular/fisiología , Progresión de la Enfermedad , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Ratones , Ratones Desnudos , Fosforilación Oxidativa , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal/fisiología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Regulación hacia Arriba/fisiologíaRESUMEN
Head and neck squamous cell carcinoma (HNSCC) is a highly morbid disease. Recent developments including Food and Drug Administration (FDA) approved molecular targeted agent's pembrolizumab and cetuximab show promise but did not improve the five-year survival which is currently less than 40%. The hepatocyte growth factor receptor; also known as mesenchymal-epithelial transition factor (c-Met) and its ligand hepatocyte growth factor (HGF) are overexpressed in head and neck squamous cell carcinoma (HNSCC); and regulates tumor progression and response to therapy. The c-Met pathway has been shown to regulate many cellular processes such as cell proliferation, invasion, and angiogenesis. The c-Met pathway is involved in cross-talk, activation, and perpetuation of other signaling pathways, curbing the cogency of a blockade molecule on a single pathway. The receptor and its ligand act on several downstream effectors including phospholipase C gamma (PLCγ), cellular Src kinase (c-Src), phosphotidylinsitol-3-OH kinase (PI3K) alpha serine/threonine-protein kinase (Akt), mitogen activate protein kinase (MAPK), and wingless-related integration site (Wnt) pathways. They are also known to cross-talk with other receptors; namely epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) and specifically contribute to treatment resistance. Clinical trials targeting the c-Met axis in HNSCC have been undertaken because of significant preclinical work demonstrating a relationship between HGF/c-Met signaling and cancer cell survival. Here we focus on HGF/c-Met impact on cellular signaling in HNSCC to potentiate tumor growth and disrupt therapeutic efficacy. Herein we summarize the current understanding of HGF/c-Met signaling and its effects on HNSCC. The intertwining of c-Met signaling with other signaling pathways provides opportunities for more robust and specific therapies, leading to better clinical outcomes.
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BACKGROUND: Contact tracing is one of the key response activities necessary for halting Ebola Virus Disease (EVD) transmission. Key elements of contact tracing include identification of persons who have been in contact with confirmed EVD cases and careful monitoring for EVD symptoms, but the details of implementation likely influence their effectiveness. In November 2015, several months after a major Ebola outbreak was controlled in Liberia, three members of a family were confirmed positive for EVD in the Duport Road area of Monrovia. The cluster provided an opportunity to implement and evaluate modified approaches to contact tracing. METHODS: The approaches employed for improved contact tracing included classification and risk-based management of identified contacts (including facility based isolation of some high risk contacts, provision of support to persons being monitored, and school-based surveillance for some persons with potential exposure but not listed as contacts), use of phone records to help locate missing contacts, and modifications to data management tools. We recorded details about the implementation of these approaches, report the overall outcomes of the contact tracing efforts and the challenges encountered, and provide recommendations for management of future outbreaks. RESULTS: 165 contacts were identified (with over 150 identified within 48 hours of confirmation of the EVD cases) and all initially missing contacts were located. Contacts were closely monitored and promptly tested if symptomatic; no contacts developed disease. Encountered challenges related to knowledge gaps among contact tracing staff, data management, and coordination of contact tracing activities with efforts to offer Ebola vaccine. CONCLUSIONS: The Duport Road EVD cluster was promptly controlled. Missing contacts were effectively identified, and identified contacts were effectively monitored and rapidly tested. There is a persistent risk of EVD reemergence in Liberia; the experience controlling each cluster can help inform future Ebola control efforts in Liberia and elsewhere.