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Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of "cancer neuroscience" and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.
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Neoplasias/metabolismo , Sistema Nervioso/metabolismo , Humanos , NeurocienciasRESUMEN
BACKGROUND/OBJECTIVES: Current treatments for chronic pancreatitis focus on symptom management and therapeutics targeting disease reversal are lacking. Given the role of the cyclooxygenase-2 (COX-2) enzyme in producing prostaglandin E2 (PGE2), a key component in the inflammatory pathway of chronic pancreatitis, this study evaluates the physiologic effect of oral indomethacin, a COX-2 inhibitor, on PGE2 levels in pancreatic fluid. METHODS: This pilot two-center randomized controlled trial seeks to examine 32 subjects with chronic pancreatitis who have no contraindications to indomethacin. Subjects will be randomized to either oral indomethacin 50 mg twice a day or placebo twice a day for a total of 28 days. Baseline (pre-treatment) assessment of pain and quality of life will be performed using the Brief Pain Inventory and the PROMIS-10 questionnaires, respectively. Biological specimens including blood, urine, and saliva will be collected at pre-treatment and post-treatment(day 28). Endoscopic pancreatic function testing with concomitant pancreatic fluid collection will also be performed pre- and post-treatment to assess the change in pancreatic fluid PGE2 levels. The relationship between pancreatic fluid PGE2 levels with blood and saliva PGE2 levels will be examined. CONCLUSIONS: This study will elucidate the effect of oral indomethacin on PGE2 levels in the pancreas to assess its role in the inflammatory pathway of chronic pancreatitis. Should indomethacin significantly reduce PGE2 levels, this may represent a potential disease-altering treatment for chronic pancreatitis.
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Indometacina , Pancreatitis Crónica , Humanos , Indometacina/uso terapéutico , Calidad de Vida , Pancreatitis Crónica/diagnóstico , Antiinflamatorios no Esteroideos/uso terapéutico , Páncreas/metabolismo , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Multicéntricos como Asunto , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como AsuntoRESUMEN
PDL1 is a protein that induces immunosuppression by binding to PD1 expressed on immune cells. In line with historical studies, we found that membrane-bound PD1 expression was largely restricted to immune cells; PD1 was not detectable at either the mRNA or protein level in peripheral neurons using single neuron qPCR, immunolabeling and flow cytometry. However, we observed widespread expression of PDL1 in both sensory and sympathetic neurons that could have important implications for patients receiving immunotherapies targeting this pathway that include unexpected autonomic and sensory related effects. While signaling pathways downstream of PD1 are well established, little to no information is available regarding the intracellular signaling downstream of membrane-bound PDL1 (also known as reverse signaling). Here, we administered soluble PD1 to engage neuronally expressed PDL1 and found that PD1 significantly reduced nocifensive behaviors evoked by algogenic capsaicin. We used calcium imaging to examine the underlying neural mechanism of this reduction and found that exogenous PD1 diminished TRPV1-dependent calcium transients in dissociated sensory neurons. Furthermore, we observed a reduction in membrane expression of TRPV1 following administration of PD1. Exogenous PD1 had no effect on pain-related behaviors in sensory neuron specific PDL1 knockout mice. These data indicate that neuronal PDL1 activation is sufficient to modulate sensitivity to noxious stimuli and as such, may be an important homeostatic mechanism for regulating acute nociception.
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Antígeno B7-H1 , Nocicepción , Animales , Antígeno B7-H1/metabolismo , Calcio , Capsaicina , Ratones , ARN MensajeroRESUMEN
The neuronal cell death-promoting loss of cytoplasmic K+ following injury is mediated by an increase in Kv2.1 potassium channels in the plasma membrane. This phenomenon relies on Kv2.1 binding to syntaxin 1A via 9 amino acids within the channel intrinsically disordered C terminus. Preventing this interaction with a cell and blood-brain barrier-permeant peptide is neuroprotective in an in vivo stroke model. Here a rational approach was applied to define the key molecular interactions between syntaxin and Kv2.1, some of which are shared with mammalian uncoordinated-18 (munc18). Armed with this information, we found a small molecule Kv2.1-syntaxin-binding inhibitor (cpd5) that improves cortical neuron survival by suppressing SNARE-dependent enhancement of Kv2.1-mediated currents following excitotoxic injury. We validated that cpd5 selectively displaces Kv2.1-syntaxin-binding peptides from syntaxin and, at higher concentrations, munc18, but without affecting either synaptic or neuronal intrinsic properties in brain tissue slices at neuroprotective concentrations. Collectively, our findings provide insight into the role of syntaxin in neuronal cell death and validate an important target for neuroprotection.
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Encéfalo/metabolismo , Fármacos Neuroprotectores , Canales de Potasio Shab/metabolismo , Sintaxina 1/metabolismo , Animales , Proteínas Munc18/metabolismo , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Ratas , Proteínas SNARE/metabolismoRESUMEN
Chronic pancreatitis (CP) is a complex inflammatory disorder with numerous associated genetic and environmental risk factors. The most distressing characteristic of CP is recalcitrant pain, often requiring surgical resection including total pancreatectomy with islet autotransplantation (TPIAT). We studied five consented subjects undergoing pancreatic resection and processed isolated cells for single-cell RNA sequencing (scRNA-Seq). Using high-dimensional transcriptomic cluster analysis, we identified 11 unique cell clusters in the pancreas tissue. These cell clusters include a cluster of undifferentiated/dedifferentiated cells and two unique clusters of acinar cells, one of which appears to be in a transitional stage. To determine the cellular response to protease inhibitor and stimulation, we treated aliquots of cells from one subject with a protease inhibitor cocktail with and without bethanechol (a muscarinic receptor agonist) at 100 and 400 µM and compared gene expression profiles. The protease inhibitors appeared to reduce cell stress. Pancreatic digestive enzymes and islet hormones were upregulated in both doses of bethanechol-treated cells compared with naïve cells. High-dose bethanechol appeared to be toxic and consistent with hyperstimulation. These studies demonstrate the feasibility of investigating human acinar cell physiology at the single-cell level and initial evidence that these cells retain responsiveness to agonist stimulation with predicted second messenger and transcriptomic responses.NEW & NOTEWORTHY We conducted single cell RNA sequencing on pancreas tissue from five individuals. We identified eleven unique cell clusters including a large population of dedifferentiated cells as well as two unique clusters of acinar cells, one of which appears to exist in a transitional state. We also examined the cellular response of pancreas tissue to stimulation and identified affected genes and pathways, including pancreatic digestive enzymes.
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Células Acinares/metabolismo , Perfilación de la Expresión Génica , Páncreas/metabolismo , Pancreatitis Crónica/genética , RNA-Seq , Análisis de la Célula Individual , Transcriptoma , Células Acinares/efectos de los fármacos , Células Acinares/patología , Desdiferenciación Celular , Análisis por Conglomerados , Estudios de Factibilidad , Humanos , Agonistas Muscarínicos/farmacología , Páncreas/efectos de los fármacos , Páncreas/patología , Páncreas/cirugía , Pancreatectomía , Pancreaticoduodenectomía , Pancreatitis Crónica/metabolismo , Pancreatitis Crónica/patología , Pancreatitis Crónica/cirugía , Inhibidores de Proteasas/farmacologíaRESUMEN
Evolutionarily, the nervous system and immune cells have evolved to communicate with each other to control inflammation and host responses against injury. Recent findings in neuroimmune communication demonstrate that these mechanisms extend to cancer initiation and progression. Lymphoid structures and tumors, which are often associated with inflammatory infiltrate, are highly innervated by multiple nerve types (e.g. sympathetic, parasympathetic, sensory). Recent preclinical and clinical studies demonstrate that targeting the nervous system could be a therapeutic strategy to promote antitumor immunity while simultaneously reducing cancer-associated neurological symptoms, such as chronic pain, fatigue and cognitive impairment. Sympathetic nerve activity is associated with physiological or psychological stress, which can be induced by tumor development and cancer diagnosis. Targeting the stress response through suppression of sympathetic activity or activation of parasympathetic activity has been shown to drive activation of effector T cells and inhibition of myeloid-derived suppressor cells within the tumor. In addition, there is emerging evidence that sensory nerves may regulate tumor growth and metastasis by promoting or inhibiting immunosuppression in a tumor-type specific manner. Because neural effects are often tumor-type specific, further study is required to optimize clinical therapeutic strategies. This review examines the emerging evidence that neuroimmune communication can regulate antitumor immunity as well as contribute to development of cancer-related neurological symptoms.
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Neoplasias , Neuroinmunomodulación , Humanos , Inflamación , Sistema Nervioso Simpático , Linfocitos TRESUMEN
OBJECTIVES: Chronic pancreatitis (CP) is associated with debilitating refractory pain. Distinct subtypes of CP pain have been previously characterized based on severity (none, mild-moderate, severe) and temporal (none, intermittent, constant) nature of pain, but no mechanism-based tools are available to guide pain management. This exploratory study was designed to determine if potential pain biomarkers could be detected in patient serum and whether they associate with specific pain patterns. METHODS: Cytokines, chemokines, and peptides associated with nociception and pain were measured in legacy serum samples from CP patients (N = 99) enrolled in the North American Pancreatitis Studies. The unsupervised hierarchical cluster analysis was applied to cluster CP patients based on their biomarker profile. Classification and regression tree was used to assess whether these biomarkers can predict pain outcomes. RESULTS: The hierarchical cluster analysis revealed a subset of patients with predominantly constant, mild-moderate pain exhibited elevated interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), and monocyte chemoattractant protein-1 (MCP1) whereas patients with higher interleukin-4 (IL-4), interleukin-8 (IL-8) and calcitonin gene related peptide (CGRP) were more likely to have severe pain. Interestingly, analyses of each individual biomarker revealed that patients with constant pain had reduced circulating TNFα and fractalkine. Patients with severe pain exhibited a significant reduction in TNFα as well as trends towards lower levels of IL-6 and substance P. DISCUSSION: The observations from this study indicate that unique pain experiences within the chronic pancreatitis population can be associated with distinct biochemical signatures. These data indicate that further hypothesis-driven analyses combining biochemical measurements and detailed pain phenotyping could be used to develop precision approaches for pain management in patients with chronic pancreatitis.
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Interleucina-6 , Pancreatitis Crónica , Biomarcadores/sangre , Humanos , Dolor , Pancreatitis Crónica/complicaciones , Factor de Necrosis Tumoral alfaRESUMEN
Epithelial cells of the colon provide a vital interface between the internal environment (lumen of the colon) and colon parenchyma. To examine epithelial-neuronal signaling at this interface, we analyzed mice in which channelrhodopsin (ChR2) was targeted to either TRPV1-positive afferents or to villin-expressing colon epithelial cells. Expression of a ChR2-EYFP fusion protein was directed to either primary sensory neurons or to colon epithelial cells by crossing Ai32 mice with TRPV1-Cre or villin-Cre mice, respectively. An ex vivo preparation of the colon was used for single-fiber analysis of colon sensory afferents of the pelvic nerve. Afferents were characterized using previously described criteria as mucosal, muscular, muscular-mucosal, or serosal and then tested for blue light-induced activation. Light activation of colon epithelial cells produced robust firing of action potentials, similar to that elicited by physiologic stimulation (e.g., circumferential stretch), in 50.5% of colon afferents of mice homozygous for ChR2 expression. Light-induced activity could be reduced or abolished in most fibers using a cocktail of purinergic receptor blockers suggesting ATP release by the epithelium contributed to generation of sensory neuron action potentials. Using electromyographic recording of visceromotor responses we found that light stimulation of the colon epithelium evoked behavioral responses in Vil-ChR2 mice that was similar to that seen with balloon distension of the colon. These ex vivo and in vivo data indicate that light stimulation of colon epithelial cells alone, without added mechanical or chemical stimuli, can directly activate colon afferents and elicit behavioral responses.SIGNIFICANCE STATEMENT Abdominal pain that accompanies inflammatory diseases of the bowel is particularly vexing because it can occur without obvious changes in the structure or inflammatory condition of the colon. Pain reflects abnormal sensory neuron activity that may be controlled in part by release of substances from lining epithelial cells. In support of this mechanism we determined that blue-light stimulation of channelrhodopsin-expressing colon epithelial cells could evoke action potential firing in sensory neurons and produce changes in measures of behavioral sensitivity. Thus, activity of colon epithelial cells alone, without added mechanical or chemical stimuli, is sufficient to activate pain-sensing neurons.
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Colon/fisiología , Mucosa Intestinal/fisiología , Mucosa Intestinal/efectos de la radiación , Células Receptoras Sensoriales/fisiología , Células Receptoras Sensoriales/efectos de la radiación , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de la radiación , Animales , Colon/inervación , Colon/efectos de la radiación , Femenino , Rayos Láser , Luz , Masculino , Ratones , OptogenéticaRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is characterized by an exuberant inflammatory desmoplastic response. The PDAC microenvironment is complex, containing both pro- and antitumorigenic elements, and remains to be fully characterized. Here, we show that sensory neurons, an under-studied cohort of the pancreas tumor stroma, play a significant role in the initiation and progression of the early stages of PDAC. Using a well-established autochthonous model of PDAC (PKC), we show that inflammation and neuronal damage in the peripheral and central nervous system (CNS) occurs as early as the pancreatic intraepithelial neoplasia (PanIN) 2 stage. Also at the PanIN2 stage, pancreas acinar-derived cells frequently invade along sensory neurons into the spinal cord and migrate caudally to the lower thoracic and upper lumbar regions. Sensory neuron ablation by neonatal capsaicin injection prevented perineural invasion (PNI), astrocyte activation, and neuronal damage, suggesting that sensory neurons convey inflammatory signals from Kras-induced pancreatic neoplasia to the CNS. Neuron ablation in PKC mice also significantly delayed PanIN formation and ultimately prolonged survival compared with vehicle-treated controls (median survival, 7.8 vs. 4.5 mo; P = 0.001). These data establish a reciprocal signaling loop between the pancreas and nervous system, including the CNS, that supports inflammation associated with oncogenic Kras-induced neoplasia. Thus, pancreatic sensory neurons comprise an important stromal cell population that supports the initiation and progression of PDAC and may represent a potential target for prevention in high-risk populations.
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Capsaicina/uso terapéutico , Carcinoma Ductal Pancreático/prevención & control , Desnervación , Páncreas/inervación , Neoplasias Pancreáticas/prevención & control , Células Receptoras Sensoriales/fisiología , Adenocarcinoma in Situ/patología , Adenocarcinoma in Situ/fisiopatología , Vías Aferentes , Animales , Animales Recién Nacidos , Capsaicina/administración & dosificación , Capsaicina/farmacología , Carcinoma Ductal Pancreático/etiología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/fisiopatología , Carcinoma Ductal Pancreático/terapia , Ceruletida/toxicidad , Progresión de la Enfermedad , Femenino , Ganglios Simpáticos/fisiopatología , Genes ras , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mielitis/complicaciones , Mielitis/genética , Mielitis/fisiopatología , Invasividad Neoplásica , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/fisiopatología , Neoplasias Pancreáticas/terapia , Pancreatitis/inducido químicamente , Pancreatitis/complicaciones , Pancreatitis/fisiopatología , Lesiones Precancerosas/inducido químicamente , Lesiones Precancerosas/complicaciones , Lesiones Precancerosas/fisiopatología , Células Receptoras Sensoriales/efectos de los fármacos , Médula Espinal/fisiopatología , Tractos Espinotalámicos/fisiopatología , Vértebras TorácicasRESUMEN
The voltage-gated K+ channel Kv2.1 has been intimately linked with neuronal apoptosis. After ischemic, oxidative, or inflammatory insults, Kv2.1 mediates a pronounced, delayed enhancement of K+ efflux, generating an optimal intracellular environment for caspase and nuclease activity, key components of programmed cell death. This apoptosis-enabling mechanism is initiated via Zn2+-dependent dual phosphorylation of Kv2.1, increasing the interaction between the channel's intracellular C-terminus domain and the SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein syntaxin 1A. Subsequently, an upregulation of de novo channel insertion into the plasma membrane leads to the critical enhancement of K+ efflux in damaged neurons. Here, we investigated whether a strategy designed to interfere with the cell death-facilitating properties of Kv2.1, specifically its interaction with syntaxin 1A, could lead to neuroprotection following ischemic injury in vivo The minimal syntaxin 1A-binding sequence of Kv2.1 C terminus (C1aB) was first identified via a far-Western peptide screen and used to create a protherapeutic product by conjugating C1aB to a cell-penetrating domain. The resulting peptide (TAT-C1aB) suppressed enhanced whole-cell K+ currents produced by a mutated form of Kv2.1 mimicking apoptosis in a mammalian expression system, and protected cortical neurons from slow excitotoxic injury in vitro, without influencing NMDA-induced intracellular calcium responses. Importantly, intraperitoneal administration of TAT-C1aB in mice following transient middle cerebral artery occlusion significantly reduced ischemic stroke damage and improved neurological outcome. These results provide strong evidence that targeting the proapoptotic function of Kv2.1 is an effective and highly promising neuroprotective strategy.SIGNIFICANCE STATEMENT Kv2.1 is a critical regulator of apoptosis in central neurons. It has not been determined, however, whether the cell death-enabling function of this K+ channel can be selectively targeted to improve neuronal survival following injury in vivo The experiments presented here demonstrate that the cell death-specific role of Kv2.1 can be uniquely modulated to provide neuroprotection in an animal model of acute ischemic stroke. We thus reveal a novel therapeutic strategy for neurological disorders that are accompanied by Kv2.1-facilitated forms of cell death.
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Apoptosis/efectos de los fármacos , Canal de Potasio Kv.1.2/antagonistas & inhibidores , Canal de Potasio Kv.1.2/metabolismo , Fármacos Neuroprotectores/administración & dosificación , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/fisiopatología , Animales , Células Cultivadas , Sistemas de Liberación de Medicamentos/métodos , Femenino , Masculino , Bloqueadores de los Canales de Potasio/administración & dosificación , Proteínas Qa-SNARE/antagonistas & inhibidores , Proteínas Qa-SNARE/metabolismo , Ratas , Accidente Cerebrovascular/patología , Resultado del TratamientoRESUMEN
Designer receptors exclusively activated by designer drugs (DREADDs) are an advanced experimental tool that could potentially provide a novel approach to pain management. In particular, expression of an inhibitory (Gi-coupled) DREADD in nociceptors might enable ligand-dependent analgesia. To test this possibility, TRPV1-cre mice were used to restrict expression of Gi-DREADDs to predominantly C-fibers. Whereas baseline heat thresholds in both male and female mice expressing Gi-DREADD were normal, 1 mg/kg clozapine-N-oxide (CNO) produced a significant 3 h increase in heat threshold that returned to baseline by 5 h after injection. Consistent with these behavioral results, CNO decreased action potential firing in isolated sensory neurons from Gi-DREADD mice. Unexpectedly, however, the expression of Gi-DREADD in sensory neurons caused significant changes in voltage-gated Ca2+ and Na+ currents in the absence of CNO, as well as an increase in Na+ channel (NaV1.7) expression. Furthermore, CNO-independent excitatory and inhibitory second-messenger signaling was also altered in these mice, which was associated with a decrease in the analgesic effect of endogenous inhibitory G-protein-coupled receptor activation. These results highlight the potential of this exciting technology, but also its limitations, and that it is essential to identify the underlying mechanisms for any observed behavioral phenotypes. SIGNIFICANCE STATEMENT: DREADD technology is a powerful tool enabling manipulation of activity and/or transmitter release from targeted cell populations. The purpose of this study was to determine whether inhibitory DREADDs in nociceptive afferents could be used to produce analgesia, and if so, how. DREADD activation produced a ligand-dependent analgesia to heat in vivo and a decrease in neuronal firing at the single-cell level. However, we observed that expression of Gi-DREADD also causes ligand-independent changes in ion channel activity and second-messenger signaling. These findings highlight both the potential and the limitations of this exciting technology as well as the necessity to identify the mechanisms underlying any observed phenotype.
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Analgesia , Drogas de Diseño/farmacología , Nervios Periféricos/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Canales de Calcio/efectos de los fármacos , Clozapina/farmacología , Femenino , Masculino , Ratones , Nociceptores/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Técnicas de Placa-Clamp , Canales de Potasio con Entrada de Voltaje/efectos de los fármacos , Receptores Acoplados a Proteínas G/efectos de los fármacos , Sistemas de Mensajero Secundario/efectos de los fármacos , Canales Catiónicos TRPV/efectos de los fármacosRESUMEN
Abdominal pain is the most common symptom of chronic pancreatitis (CP) and is often debilitating for patients and very difficult to treat. To date, there exists no cure for the disease. Treatment strategies focus on symptom management and on mitigation of disease progression by reducing toxin exposure and avoiding recurrent inflammatory events. Traditional treatment protocols start with medical management followed by consideration of procedural or surgical intervention on selected patients with severe and persistent pain. The incorporation of adjuvant therapies to treat comorbidities including psychiatric disorders, exocrine pancreatic insufficiency, mineral bone disease, frailty, and malnutrition, are in its early stages. Recent clinical studies and animal models have been designed to improve investigation into the pathophysiology of CP pain, as well as to improve pain management. Despite the array of tools available, many therapeutic options for the management of CP pain provide incomplete relief. There still remains much to discover about the neural regulation of pancreas-related pain. In this review, we will discuss research from the last 5 years that has provided new insights into novel methods of pain phenotyping and the pathophysiology of CP pain. These discoveries have led to improvements in patient selection for optimization of outcomes for both medical and procedural management, and identification of potential future therapies.
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Pancreatic and duodenal homeobox 1 (PDX1) is a transcription factor required for the development and differentiation of the pancreas. Previous studies indicated that PDX1 expression was restricted to the gastrointestinal tract. Using a cre-dependent reporter, we observed PDX1-dependent expression of tdtomato (PDX1-tom) in a subpopulation of sensory nerves. Many of these PDX1-tom afferents expressed the neurofilament 200 protein and projected to the skin. Tdtomato-labeled terminals were associated with hair follicles in the form of longitudinal and circumferential lanceolate endings suggesting a role in tactile and proprioceptive perception. To begin to examine the functional significance of PDX1 in afferents, we used Fura-2 imaging to examine calcium (Ca2+) handling under naïve and nerve injury conditions. Neuropathic injury is associated with increased intracellular Ca2+ signaling that in part results from dysregulation of the sarco/endoplasmic reticulum calcium transport ATPase (SERCA). Here we demonstrate that under naïve conditions, PDX1 regulates expression of the SERCA2B isoform in sensory neurons. In response to infraorbital nerve injury, a significant reduction of PDX1 and SERCA2B expression and dysregulation of Ca2+ handling occurs in PDX1-tom trigeminal ganglia neurons. The identification of PDX1 expression in the somatosensory system and its regulation of SERCA2B and Ca2+ handling provide a new mechanism to explain pathological changes in primary afferents that may contribute to pain associated with nerve injury.
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Calcio , Proteínas de Homeodominio , Homeostasis , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico , Células Receptoras Sensoriales , Transactivadores , Animales , Células Receptoras Sensoriales/metabolismo , Calcio/metabolismo , Proteínas de Homeodominio/metabolismo , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Transactivadores/metabolismo , Ratones , Señalización del Calcio , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: Treatment for abdominal pain in patients with chronic pancreatitis (CP) remains challenging in the setting of central nervous system sensitisation, a phenomenon of remodelling and neuronal hyperexcitability resulting from persistent pain stimuli. This is suspected to render affected individuals less likely to respond to conventional therapies. Endotherapy or surgical decompression is offered to patients with pancreatic duct obstruction. However, the response to treatment is unpredictable. Pancreatic quantitative sensory testing (P-QST), an investigative technique of standardised stimulations to test the pain system in CP, has been used for phenotyping patients into three mutually exclusive groups: no central sensitisation, segmental sensitisation (pancreatic viscerotome) and widespread hyperalgesia suggestive of supraspinal central sensitisation. We will test the predictive capability of the pretreatment P-QST phenotype to predict the likelihood of pain improvement following invasive treatment for painful CP. METHODS AND ANALYSIS: This observational clinical trial will enrol 150 patients from the University of Pittsburgh, Johns Hopkins and Indiana University. Participants will undergo pretreatment phenotyping with P-QST. Treatment will be pancreatic endotherapy or surgery for clearance of painful pancreatic duct obstruction. PRIMARY OUTCOME: average pain score over the preceding 7 days measured by Numeric Rating Scale at 6 months postintervention. Secondary outcomes will include changes in opioid use during follow-up, and patient-reported outcomes in pain and quality of life at 3, 6 and 12 months after the intervention. Exploratory outcomes will include creation of a model for individualised prediction of response to invasive treatment. ETHICS AND DISSEMINATION: The trial will evaluate the ability of P-QST to predict response to invasive treatment for painful CP and develop a predictive model for individualised prediction of treatment response for widespread use. This trial was approved by the University of Pittsburgh Institutional Review Board. Data and results will be reported and disseminated in conjunction with National Institutes of Health policies. TRIAL REGISTRATION NUMBER: NCT04996628.
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Enfermedades Pancreáticas , Pancreatitis Crónica , Humanos , Calidad de Vida , Pancreatitis Crónica/complicaciones , Pancreatitis Crónica/cirugía , Páncreas/cirugía , Dolor Abdominal/etiología , Conductos Pancreáticos/cirugía , Estudios Observacionales como AsuntoRESUMEN
INTRODUCTION: Chronic Pancreatitis Prognosis Score (COPPS) was developed to discriminate disease severity and predict risk for future hospitalizations. In this cohort study, we evaluated if COPPS predicts the likelihood of hospitalization(s) in an American cohort. METHODS: The Chronic Pancreatitis, Diabetes, and Pancreatic Cancer consortium provided data and serum from subjects with chronic pancreatitis (N = 279). COPPS was calculated with baseline data and stratified by severity (low, moderate, and high). Primary endpoints included number and duration of hospitalizations during 12-month follow-up. RESULTS: The mean ± SD COPPS was 8.4 ± 1.6. COPPS correlated with all primary outcomes: hospitalizations for any reason (number: r = 0.15, P = 0.01; duration: r = 0.16, P = 0.01) and pancreas-related hospitalizations (number: r = 0.15, P = 0.02; duration: r = 0.13, P = 0.04). The severity distribution was 13.3% low, 66.0% moderate, and 20.8% high. 37.6% of subjects had ≥1 hospitalization(s) for any reason; 32.2% had ≥1 pancreas-related hospitalizations. All primary outcomes were significantly different between severity groups: hospitalizations for any reason (number, P = 0.004; duration, P = 0.007) and pancreas-related hospitalizations (number, P = 0.02; duration, P = 0.04). The prevalence of continued drinking at follow-up ( P = 0.04) was higher in the low and moderate groups. The prevalence of anxiety at enrollment ( P = 0.02) and follow-up ( P < 0.05) was higher in the moderate and high groups. DISCUSSION: Statistically, COPPS significantly correlated with hospitalization outcomes, but the correlations were weaker than in previous studies, which may be related to the outpatient nature of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies cohort and lower prevalence of high severity disease. Studies in other prospective cohorts are needed to understand the full utility of COPPS as a potential tool for clinical risk assessment and intervention.
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ABSTRACT: Pain is common in chronic pancreatitis (CP) and profoundly reduces quality of life (QoL). Multiple underlying mechanisms contribute to a heterogenous pain experience and reduce efficacy of pain management. This study was designed to characterize the distribution of mechanism-based pain phenotypes in painful CP. The data analyzed were collected as part of the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, an NCI/NIDDK-funded longitudinal study of the natural history of CP. The PROspective Evaluation of Chronic pancreatitis for EpidEmiologic and translational stuDies includes patient-reported outcome (PRO) measures of pain, medication use, global health, and QoL. Of subjects (N = 681) with CP, 80% experienced abdominal pain within the year before enrollment. Subjects who experienced pain in the week before enrollment (N = 391) completed PROMIS Neuropathic and Nociceptive Pain Quality instruments which were then used to classify them by pain type: 40% had nociceptive, 5% had neuropathic-like, and 32% had both types of pain. The prevalence of having both types of pain was higher among women and subjects with diabetes mellitus, whereas nociceptive-only pain was more prevalent among men and those with pancreatic duct stricture. Other factors, including pain medication use and healthcare utilization, did not differ between groups based on pain type. Subjects in the Both group had significantly worse health and QoL scores relative to those with nociceptive-only pain, suggesting that using psychosocial pain surveys may be useful for understanding pain subtypes in patients with CP. Additional research is needed to identify biochemical and biophysical signatures that may associate with and predict responses to mechanism-specific interventions.
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Pancreatitis Crónica , Calidad de Vida , Femenino , Humanos , Estudios Transversales , Estudios Longitudinales , Pancreatitis Crónica/complicaciones , Pancreatitis Crónica/epidemiología , Pancreatitis Crónica/psicología , Dolor Abdominal/epidemiología , FenotipoRESUMEN
Chronic pancreatitis is a debilitating disease affecting millions worldwide. These patients suffer from bouts of severe pain that are minimally relieved by pain medications and may necessitate major surgeries with high morbidity and mortality. Previously, we demonstrated that "chemical pancreatectomy," a pancreatic intraductal infusion of dilute acetic acid solution, ablated the exocrine pancreas while preserving the endocrine pancreas. Notably, chemical pancreatectomy resolved chronic inflammation, alleviated allodynia in the cerulein pancreatitis model, and improved glucose homeostasis. Herein, we extensively tested the feasibility of a chemical pancreatectomy in NHPs and validated our previously published pilot study. We did serial computed tomography (CT) scans of the abdomen and pelvis, analyzed dorsal root ganglia, measured serum enzymes, and performed histological and ultrastructural assessments and pancreatic endocrine function assays. â¯Based on serial CT scans, chemical pancreatectomy led to the loss of pancreatic volume. Immunohistochemistry and transmission electron microscopy demonstrated exocrine pancreatic ablation with endocrine islet preservation. Importantly, chemical pancreatectomy did not increase pro-nociceptive markers in harvested dorsal root ganglia. Also, chemical pancreatectomy improved insulin secretion to supranormal levels in vivo and in vitro. Thus, this study may provide a foundation for translating this procedure to patients with chronic pancreatitis or other conditions requiring a pancreatectomy.
RESUMEN
Chronic pancreatitis is a debilitating disease affecting millions worldwide. These patients suffer from bouts of severe pain that are minimally relieved by pain medications and may necessitate major surgeries with high morbidity and mortality. Previously, we demonstrated that "chemical pancreatectomy," a pancreatic intraductal infusion of dilute acetic acid solution, ablated the exocrine pancreas while preserving the endocrine pancreas. Notably, chemical pancreatectomy resolved chronic inflammation, alleviated allodynia in the cerulein pancreatitis model, and improved glucose homeostasis. Herein, we extensively tested the feasibility of a chemical pancreatectomy in NHPs and validated our previously published pilot study. We did serial computed tomography (CT) scans of the abdomen and pelvis, analyzed dorsal root ganglia, measured serum enzymes, and performed histological and ultrastructural assessments and pancreatic endocrine function assays. Based on serial CT scans, chemical pancreatectomy led to the loss of pancreatic volume. Immunohistochemistry and transmission electron microscopy demonstrated exocrine pancreatic ablation with endocrine islet preservation. Importantly, chemical pancreatectomy did not increase pro-nociceptive markers in harvested dorsal root ganglia. Also, chemical pancreatectomy improved insulin secretion to supranormal levels in vivo and in vitro. Thus, this study may provide a foundation for translating this procedure to patients with chronic pancreatitis or other conditions requiring a pancreatectomy.
Asunto(s)
Pancreatectomía , Pancreatitis Crónica , Animales , Pancreatectomía/métodos , Proyectos Piloto , Pancreatitis Crónica/cirugía , Primates , Dolor , Enfermedad CrónicaRESUMEN
Debilitating abdominal pain is a common symptom affecting most patients with chronic pancreatitis (CP). There are multiple underlying mechanisms that contribute to CP-related pain, which makes successful treatment difficult. The identification of biomarkers for subtypes of pain could provide viable targets for nonopioid interventions and the development of mechanistic approaches to pain management in CP. Nineteen inflammation- and nociception-associated proteins were measured in serum collected from 358 subjects with definite CP enrolled in PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translational StuDies, a prospective observational study of pancreatitis in US adult subjects. First, serum levels of putative biomarkers were compared between CP subjects with and without pain. Only platelet-derived growth factor B (PDGF-B) stood out, with levels significantly higher in the CP pain group as compared to subjects with no pain. Subjects with pain were then stratified into 4 pain subtypes (Neuropathic, Nociceptive, Mixed, and Unclassified). A comparison of putative biomarker concentration among 5 groups (no pain and 4 pain subtypes) identified unique proteins that were correlated with pain subtypes. Serum transforming growth factor beta 1 (TGFß1) level was significantly higher in the Nociceptive pain group compared to the No pain group, suggesting that TGFß1 may be a biomarker for nociceptive pain. The Neuropathic pain only group was too small to detect statistical differences. However, glycoprotein 130 (GP130), a coreceptor for interleukin 6, was significantly higher in the Mixed pain group compared to the groups lacking a neuropathic pain component. These data suggest that GP130 may be a biomarker for neuropathic pain in CP. PERSPECTIVE: Serum TGFß1 and GP130 may be biomarkers for nociceptive and neuropathic CP pain, respectively. Preclinical data suggest inhibiting TGFß1 or GP130 reduces CP pain in rodent models, indicating that additional translational and clinical studies may be warranted to develop a precision medicine approach to the management of pain in CP.
Asunto(s)
Dolor Crónico , Neuralgia , Dolor Nociceptivo , Pancreatitis Crónica , Adulto , Humanos , Biomarcadores , Receptor gp130 de Citocinas , Neuralgia/diagnóstico , Neuralgia/etiología , Neuralgia/tratamiento farmacológico , Nocicepción , Pancreatitis Crónica/complicaciones , Pancreatitis Crónica/diagnósticoRESUMEN
ABSTRACT: Differences in methods for biospecimen collection, processing, and storage can yield considerable variability and error. Therefore, best practices for standard operating procedures are critical for successful discovery, development, and validation of disease biomarkers. Here, we describe standard operating procedures developed for biospecimen collection during the DREAM (Diabetes RElated to Acute pancreatitis and its Mechanisms) Study within the Type 1 Diabetes in Acute Pancreatitis Consortium. Notably, these protocols were developed using an integrative process based on prior consortium experience and with input from working groups with expertise in immunology, pancreatitis, and diabetes. Publication and adoption consistent biospecimen protocols will inform future studies and allow for better comparisons across different metabolic research efforts.