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Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.
Assuntos
Relógios Circadianos , Neoplasias Pancreáticas , Animais , Camundongos , Humanos , Relógios Circadianos/genética , Ritmo Circadiano/genética , Minociclina , Neoplasias Pancreáticas/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Neoplasias PancreáticasRESUMO
BACKGROUND AND OBJECTIVES: Pancreaticoduodenectomy (PD), the only surgical option for right-sided pancreatic ductal adenocarcinoma (PDAC), carries significant morbidity. Not all patients may be deriving a survival benefit from this operation. We sought to identify the rate of futile PD and its associated factors in a large national cohort. METHODS: We performed a retrospective analysis using the National Cancer Database (2004-2020), including all patients who underwent PD for non-metastatic PDAC. The primary outcome was operative futility, which was defined as death within 12 months of diagnosis despite PD. Multivariable regression was used to identify factors associated with futility. We performed a subgroup analysis on patients who received neoadjuvant systemic therapy. RESULTS: Data from 66 326 patients were analyzed, and 16 772 (25.3%) underwent PD that met criteria for futility. Macroscopically positive margins (odds ratio [OR]: 2.87; 95% confidence interval [CI]: 2.36-3.48), poor tumor differentiation (OR: 2.44; 95% CI: 2.25-2.65), and N2 nodal stage (OR: 2.09; 95% CI: 1.98-2.20) were associated with the greatest odds of futility. Meanwhile, receipt of any systemic therapy (OR: 0.33; 95% CI: 0.31-0.34), receipt of any radiation (OR: 0.60; 95% CI: 0.57-0.63), and receipt of neoadjuvant systemic therapy (OR: 0.62; 95% CI: 0.57-0.66) were associated with the lowest odds of futility. In the neoadjuvant subgroup, a longer diagnosis-to-surgery interval was associated with lower odds of futility. CONCLUSION: PD was futile in about one quarter of patients. Futility was associated with higher age and worse tumor biology. Receipt of neoadjuvant therapy resulted in fewer futile operations.
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BACKGROUND: Patients undergoing cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) are frequently admitted to the intensive care unit (ICU) for mitigation of potential complications, although ICU length of stay (LOS) is a significant driver of cost. This study asked whether a fiscal argument could be made for the selective avoidance of ICU admission after CRS/HIPEC. METHODS: Prospective data for select low-risk patients (e.g., lower peritoneal cancer index [PCI]) admitted to the intermediate care unit (IMC) instead of the ICU after CRS/HIPEC were matched with a historic cohort routinely admitted to the ICU. Cohort comparisons and the impact of the intervention on cost were assessed. RESULTS: The study matched 81 CRS/HIPEC procedures to form a cohort of 49 pre- and 15 post-intervention procedures for patients with similar disease burdens (mean PCI, 8 ± 6.7 vs. 7 ± 5.1). The pre-intervention patients stayed a median of 1 day longer in the ICU (1 day [IQR, 1-1 day] vs. 0 days [IQR, 0-0 days]) and had a longer LOS (8 days [IQR, 7-11 days] vs. 6 days [IQR, 5.5-9 days]). Complications and complication severity did not differ statistically. The median total hospital cost was lower after intervention ($30,845 [IQR, $30,181-$37,725] vs. $41,477 [IQR, $33,303-$51,838]), driven by decreased indirect fixed cost ($8984 [IQR, $8643-$11,286] vs. $14,314 [IQR, $12,206-$18,266]). In a weighted multiple variable linear regression analysis, the intervention was associated with a savings of $2208.68 per patient. CONCLUSIONS: Selective admission to the IMC after CRS/HIPEC was associated with $2208.68 in savings per patient without added risk. In this era of cost-conscious practice of medicine, these data highlight an opportunity to decrease cost by more than 5% for patients undergoing CRS/HIPEC.
Assuntos
Hipertermia Induzida , Intervenção Coronária Percutânea , Neoplasias Peritoneais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia do Câncer por Perfusão Regional , Terapia Combinada , Cuidados Críticos , Procedimentos Cirúrgicos de Citorredução/efeitos adversos , Humanos , Hipertermia Induzida/efeitos adversos , Neoplasias Peritoneais/etiologia , Neoplasias Peritoneais/terapia , Estudos Prospectivos , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Cell-autonomous circadian clocks exist in nearly every organ and function to maintain homeostasis through a complex series of transcriptional-translational feedback loops. The response of these peripheral clocks to external perturbations, such as chronic jetlag and shift work, has been extensively investigated. However, an evaluation of the effects of chronic jetlag on the mouse pancreatic transcriptome is still lacking. Herein, we report an evaluation of the diurnal variations encountered in the pancreatic transcriptome following exposure to an established chronic jetlag protocol. We found approximately 5.4% of the pancreatic transcriptome was rhythmic. Following chronic jetlag, we found the number of rhythmic transcripts decreased to approximately 3.6% of the transcriptome. Analysis of the core clock genes, which orchestrate circadian physiology, revealed that nearly all exhibited a shift in the timing of peak gene expression-known as a phase shift. Similarly, over 95% of the rhythmically expressed genes in the pancreatic transcriptome exhibited a phase shift, many of which were found to be important for metabolism. Evaluation of the genes involved in pancreatic exocrine secretion and insulin signaling revealed many pancreas-specific genes were also rhythmically expressed and several displayed a concomitant phase shift with chronic jetlag. Phase differences were found 9 days after normalization, indicating a persistent failure to reentrain to the new light-dark cycle. This study is the first to evaluate the endogenous pancreatic clock and rhythmic gene expression in whole pancreas over 48 h, and how the external perturbation of chronic jetlag affects the rhythmic expression of genes in the pancreatic transcriptome.
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Ritmo Circadiano/genética , Regulação da Expressão Gênica , Síndrome do Jet Lag/genética , Pâncreas/fisiologia , Animais , Comportamento Animal/fisiologia , Escuridão , Feminino , Insulina/genética , Insulina/metabolismo , Luz , Masculino , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Hospital-based care accounts for one third of US health spending or over $1 trillion annually, yet a detailed all-payer assessment of what services contribute to this spending is not available. STUDY DESIGN: Cross-sectional and longitudinal evaluation of hospital financial statements from acute-care general hospitals in California between fiscal years 2007 and 2016. The amounts spent on 41 different revenue centers were included. The primary outcome was state-level and hospital-level spending for each revenue center including decomposing growth trends into changes in volume and prices. RESULTS: The analysis included 2941 annual financial statements from 331 hospitals. Between 2007 and 2016, total spending across all centers increased 66.6% from $43.7B to $72.9B. Five centers-surgery and recovery, drugs sold to patients, acute medical/surgical floor, the clinical laboratory, and emergency services-accounted for over 50% of total spending in 2016. Overall spending growths ranged from 1.1%/y (acute pediatrics) to 17.9%/y (observation). Other revenue centers with large increases in spending included emergency services (164.7%), clinics (on-site 114.5%, satellite 129.7%), anesthesia (119.6%), echocardiography (114.4%), and computed tomography (100.8%). Most services had volume growths within ±2%/y, although there were exceptions (eg, observation hours increased 10.0%/y). Prices grew fastest for echocardiograms (10.5%/y), cardiac catheterization (9.7%/y), therapeutic radiology (8.0%/y), and emergency visits (7.5%/y). In general, median prices for services in 2016 were larger than Medicare allowed amounts. CONCLUSIONS: Overall hospital-based spending increased 66.6% between 2007 and 2016 in California, but there was wide variation in spending growth across revenue centers. Understanding this variation-including the relative contributions of volumes and prices-can guide efforts to curb excessive health care spending and optimize resource dedication to current and future patient care needs.
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Preços Hospitalares/estatística & dados numéricos , Custos Hospitalares/estatística & dados numéricos , Hospitais Gerais/economia , California , Estudos Transversais , Humanos , Estados UnidosRESUMO
BACKGROUND: Malignant gastric outlet obstruction (GOO) is managed with palliative surgical bypass or endoscopic stenting. Limited data exist on differences in cost and outcomes. METHODS: Patients with malignant GOO undergoing palliative gastrojejunostomy (GJ) or endoscopic stent (ES) were identified between 2012 and 2015 using the MarketScan® Database. Median costs (payments) for the index procedure and 90-day readmissions and re-intervention were calculated. Frequency of treatment failure-defined as repeat surgery, stenting, or gastrostomy tube-was measured. RESULTS: A total of 327 patients were included: 193 underwent GJ and 134 underwent ES. Compared to GJ, stenting resulted in lower total median payments for the index hospitalization and procedure-related 90-day readmissions ($18,500 ES vs. $37,200 GJ, p = 0.032). For patients treated with ES, 25 (19%) required a re-intervention for treatment-failure, compared to 18 (9%) patients who underwent GJ (p = 0.010). On multivariable analysis, stenting remained significantly associated with need for secondary re-intervention compared to GJ (HR for ES 2.0 [1.1-3.8], p 0.028). CONCLUSION: In patients with malignant GOO, endoscopic stenting results in significant 90-day cost saving, however was associated with twice the rate of secondary intervention. The decision for surgical bypass versus endoscopic stenting should consider patient prognosis, anticipated cost, and likelihood of needing re-intervention.
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Derivação Gástrica/economia , Obstrução da Saída Gástrica/cirurgia , Gastroscopia/economia , Custos de Cuidados de Saúde , Cuidados Paliativos/economia , Stents/economia , Adulto , Idoso , Custos e Análise de Custo , Feminino , Obstrução da Saída Gástrica/economia , Obstrução da Saída Gástrica/etiologia , Humanos , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente/economia , Reoperação/economia , Estudos Retrospectivos , Neoplasias Gástricas/economia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: The use of radiation therapy in the treatment of retroperitoneal sarcomas has increased in recent years. Its impact on survival and recurrence is unclear. METHODS: A retrospective propensity score matched (PSM) analysis of patients with primary retroperitoneal soft tissue sarcomas, who underwent resection from 2000 to 2016 at eight institutions of the US Sarcoma Collaborative, was performed. Patients with metastatic disease, desmoid tumors, and palliative resections were excluded. RESULTS: Total 425 patients were included, 56 in the neoadjuvant radiation group (neo-RT), 75 in the adjuvant radiation group (adj-RT), and 294 in the no radiotherapy group (no-RT). Median age was 59.5 years, 186 (43.8%) were male with a median follow up of 31.4 months. R0 and R1 resection was achieved in 253 (61.1%) and 143 (34.5%), respectively. Overall 1:1 match of 46 adj-RT and 59 neo-RT patients was performed using histology, sex, age, race, functional status, tumor size, grade, resection status, and chemotherapy. Unadjusted recurrence-free survival (RFS) was 35.9 months (no-RT) vs 33.5 months (neo-RT) and 27.2 months (adj-RT), P = .43 and P = .84, respectively. In the PSM, RFS was 17.6 months (no-RT) vs 33.9 months (neo-RT), P = .28 and 19 months (no-RT) vs 27.2 months (adj-RT), P = .1. CONCLUSIONS: Use of radiotherapy, both in adjuvent or neoadjuvent setting, was not associated with improved survival or reduced recurrence rate.
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Terapia Neoadjuvante/mortalidade , Radioterapia Adjuvante/mortalidade , Neoplasias Retroperitoneais/radioterapia , Sarcoma/radioterapia , Idoso , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Pontuação de Propensão , Estudos Prospectivos , Neoplasias Retroperitoneais/patologia , Estudos Retrospectivos , Sarcoma/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Minimally invasive distal pancreatectomy (MIDP) is associated with improved peri-operative outcomes compared to the open approach, though cost-effectiveness of MIDP remains unclear. METHODS: Patients with pancreatic tumors undergoing open (ODP), robotic (RDP), or laparoscopic distal pancreatectomy (LDP) between 2012-2014 were identified through the Truven Health MarketScan® Database. Median costs (payments) for the index operation and 90-day readmissions were calculated. Multivariable regression was used to predict associations with log 90-day payments. RESULTS: 693 patients underwent ODP, 146 underwent LDP, and 53 RDP. Compared to ODP, LDP and RDP resulted in shorter median length of stay (6 d. ODP vs. 5 d. RDP vs. 4 d. LDP, p<0.01) and lower median payments ($38,350 ODP vs. $34,870 RDP vs. $32,148 LDP, p<0.01) during the index hospitalization. Total median 90-day payments remained significantly lower for both minimally invasive approaches ($40,549 ODP vs. $35,160 RDP vs. $32,797 LDP, p<0.01). On multivariable analysis, LDP and RDP resulted in 90-day cost savings of 21% and 25% relative to ODP, equating to an amount of $8,500-$10,000. CONCLUSION: MIDP is associated with >$8,500 in lower cost compared to the open approach. Quality improvement initiatives in DP should ensure that lack of training and technical skill are not barriers to MIDP.
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Custos Hospitalares , Laparoscopia/economia , Pancreatectomia/economia , Procedimentos Cirúrgicos Robóticos/economia , Adulto , Idoso , Redução de Custos , Análise Custo-Benefício , Bases de Dados Factuais , Feminino , Humanos , Laparoscopia/efeitos adversos , Tempo de Internação/economia , Masculino , Pessoa de Meia-Idade , Modelos Econômicos , Pancreatectomia/efeitos adversos , Pancreatectomia/métodos , Readmissão do Paciente/economia , Procedimentos Cirúrgicos Robóticos/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Many surgeons advocate the use of neoadjuvant treatment for resectable pancreatic cancer, however little is known about variation in the utilization of neoadjuvant therapy (NAT) at the hospital level. METHODS: The National Cancer Data Base was used to identify patients undergoing resection for pancreatic cancer between 2006 and 2014 at high-volume centers. Hospitals were grouped by NAT utilization using standard deviations (SD) from the mean as follows: high neoadjuvant utilizers (> 2 SDs above the mean, > 40% of patients receiving NAT); medium-high (1-2 SDs, 27-40%), medium (0-1 SD, 14-26%); or low (- 1.1 to 0 SDs, < 14%). Overall survival (OS) was compared across NAT utilization groups. RESULTS: Among 107 high-volume centers, 20,119 patients underwent resection. The proportion of patients receiving NAT varied widely among hospitals, ranging from 0 to 74%, with only five centers using NAT in > 40% of patients. These five hospitals had the longest median OS at 28.9 months, compared with 21.1 months for low neoadjuvant utilizers (p < 0.001). On multivariable analysis, high and medium-high NAT utilization predicted improved OS, with a hazard ratio (HR) of 0.68 (95% confidence interval [CI] 0.56-0.83, p < 0.001) and 0.80 (95% CI 0.68-0.95, p = 0.010), respectively, compared with low utilizers. After excluding patients who underwent NAT, there remained an association of improved OS with high NAT utilization (HR 0.74, 95% CI 0.60-0.93, p = 0.009). CONCLUSION: High-volume hospitals that more commonly utilize NAT demonstrated longer survival for all patients treated at those centers. In addition to altering patient selection for surgery, high neoadjuvant utilization may be a marker of institutional factors that contribute to improved outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hospitais com Alto Volume de Atendimentos/estatística & dados numéricos , Terapia Neoadjuvante/mortalidade , Pancreatectomia/mortalidade , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/mortalidade , Idoso , Terapia Combinada , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Masculino , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Prognóstico , Taxa de SobrevidaRESUMO
OBJECTIVE: Regret is a powerful motivating factor in medical decision making among patients and surgeons. Regret can be particularly important for surgical decisions, which often carry significant risk and may have uncertain outcomes. We performed a systematic review of the literature focused on patient and physician regret in the surgical setting. METHODS: A search of the English literature between 1986 and 2016 that examined patient and physician self-reported decisional regret was carried out using the MEDLINE/PubMed and Web of Science databases. Clinical studies performed in patients and physicians participating in elective surgical treatment were included. RESULTS: Of 889 studies identified, 73 patient studies and 6 physician studies met inclusion criteria. Among the 73 patient studies, 57.5% examined patients with a cancer diagnosis, with breast (26.0%) and prostate (28.8%) cancers being most common. Interestingly, self-reported patient regret was relatively uncommon with an average prevalence across studies of 14.4%. Factors most often associated with regret included type of surgery, disease-specific quality of life, and shared decision making. Only 6 studies were identified that focused on physician regret; 2 pertained to surgical decision making. These studies primarily measured regret of omission and commission using hypothetical case scenarios and used the results to develop decision curve analysis tools. CONCLUSION: Self-reported decisional regret was present in about 1 in 7 surgical patients. Factors associated with regret were both patient- and procedure related. While most studies focused on patient regret, little data exist on how physician regret affects shared decision making.
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Atitude do Pessoal de Saúde , Atitude Frente a Saúde , Tomada de Decisões , Cirurgiões , Procedimentos Cirúrgicos Operatórios , Adulto , Idoso , Procedimentos Cirúrgicos Eletivos , Emoções , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Cirurgiões/psicologiaRESUMO
OBJECTIVE: To determine the role of the aryl hydrocarbon receptor (AHR) in colitis-associated colorectal tumorigenesis. BACKGROUND: Colorectal cancer (CRC) is the third most commonly diagnosed cancer in United States. Chronic intestinal inflammation increases the risk for the development of CRC. We investigated the involvement of AHR, a ligand-activated transcriptional regulator, in colitis-associated colorectal tumorigenesis. METHODS: We used a mouse model of colitis-associated colorectal tumorigenesis that employs treatment with azoxymethane and dextran sodium sulfate. We examined the role of AHR using both an Ahr-deletion mouse model (Ahr) and treatment with the AHR pro-agonist indole-3-carbinol (I3C). Incidence, multiplicity, and location of tumors were visually counted. Tumors were defined as neoplasms. Intestinal inflammation was assessed by quantitative PCR for proinflammatory markers and colon length. Data were evaluated and compared using GraphPad Prism software (version 6, La Jolla, CA). RESULTS: Tumor incidence was increased 32% in Ahr null mice and tumor multiplicity was approximately increased 3-fold compared with wild-type mice (2.4 vs 7; P < 0.05). Furthermore, tumor multiplicity was reduced 92% by treatment of I3C in wild-type mice, whereas the suppressor effect of I3C was not observed in Ahr null mice (P < 0.05). CONCLUSIONS: We found that AHR plays a protective role in colitis-associated colorectal tumorigenesis. This conclusion is based on the observations that Ahr null mice showed increased number of colorectal tumors, and mice treated with I3C exhibited fewer tumors. This study supports the use of AHR agonists such as I3C as a chemopreventive therapy for IBD-associated CRC in human patients.
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Colite/complicações , Neoplasias Colorretais/prevenção & controle , Receptores de Hidrocarboneto Arílico/fisiologia , Animais , Azoximetano/farmacologia , Dano ao DNA , Sulfato de Dextrana , Expressão Gênica , Indóis/farmacologia , Indóis/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , RNA/análise , Receptores de Hidrocarboneto Arílico/agonistasRESUMO
PURPOSE OF REVIEW: Historically, surgical treatment of choledochal cyst consisted of cyst enterostomy. However, incomplete cyst excision can result in recurrent symptoms and malignant transformation within the cyst remnant. Accordingly, management of choledochal cyst now includes complete cyst excision whenever possible. We provide a review detailing the up to date management of choledochal cysts. We describe choledochal cyst-type specific surgical approaches, the impact of minimally invasive surgery in choledochal cyst therapy, and long-term sequelae of choledochal cyst management. RECENT FINDINGS: Treatment of choledochal cyst aims to avoid the numerous hepatic, pancreatic, or biliary complications that may occur. More recently, minimally invasive approaches are being used for the treatment of choledochal cyst with acceptable morbidity and mortality. Moreover, long-term follow up of choledochal cyst patients after resection has demonstrated that although the risk of biliary malignancy is significantly decreased after choledochal cyst resection, these patients may remain at a slightly increased risk of biliary malignancy even after excision. SUMMARY: Management of choledochal cyst and the operative conduct will depend upon the patient comorbidities and choledochal cyst subtype. However, given the complex nature of choledochal cyst and limited experience of most centers, these patients should be evaluated and treated at high-volume hepatopancreaticobiliary centers familiar with management of choledochal cyst.
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Cisto do Colédoco/cirurgia , Cisto do Colédoco/diagnóstico , HumanosRESUMO
A growing body of research has identified circadian-rhythm disruption as a risk factor for metabolic health. However, the underlying biological basis remains complex, and complete molecular mechanisms are unknown. There is emerging evidence from animal and human research to suggest that the expression of core circadian genes, such as circadian locomotor output cycles kaput gene (CLOCK), brain and muscle ARNT-Like 1 gene (BMAL1), period (PER), and cyptochrome (CRY), and the consequent expression of hundreds of circadian output genes are integral to the regulation of cellular metabolism. These circadian mechanisms represent potential pathophysiological pathways linking circadian disruption to adverse metabolic health outcomes, including obesity, metabolic syndrome, and type 2 diabetes. Here, we aim to summarize select evidence from in vivo animal models and compare these results with epidemiologic research findings to advance understanding of existing foundational evidence and potential mechanistic links between circadian disruption and altered clock gene expression contributions to metabolic health-related pathologies. Findings have important implications for the treatment, prevention, and control of metabolic pathologies underlying leading causes of death and disability, including diabetes, cardiovascular disease, and cancer.
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Proteínas CLOCK , Ritmo Circadiano , Diabetes Mellitus Tipo 2 , Humanos , Animais , Ritmo Circadiano/genética , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/genética , Obesidade/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Relógios Circadianos/genéticaRESUMO
OBJECTIVES: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the development of several cancers and can be targeted for therapeutic effect. However, its involvement in the pathogenesis of PDAC remains unclear. To address this gap, we evaluated the role of AHR in the development of PDAC precancerous lesions in vivo . MATERIALS AND METHODS: We created a global AHR-null, mutant Kras -driven PDAC mouse model (A -/- KC) and evaluated the changes in PDAC precursor lesion formation (PanIN-1, 2, and 3) and associated fibro-inflammation between KC and A -/- KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes. RESULTS: We identified a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A -/- KC versus KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation. CONCLUSIONS: These findings show the loss of AHR results in heightened Kras -induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.
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Modelos Animais de Doenças , Camundongos Knockout , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas p21(ras) , Receptores de Hidrocarboneto Arílico , Microambiente Tumoral , Animais , Camundongos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Inflamação/genética , Camundongos Endogâmicos C57BL , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) cancer cells specifically produce abnormal oncogenic collagen to bind with integrin α3ß1 receptor and activate the downstream focal adhesion kinase (FAK), protein kinase B (AKT), and mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, this promotes immunosuppression and tumor proliferation and restricts the response rate of clinical cancer immunotherapies. METHODS: Here, by leveraging the hypoxia tropism and excellent motility of the probiotic Escherichia coli strain Nissle 1917 (ECN), we developed nanodrug-bacteria conjugates to penetrate the extracellular matrix (ECM) and shuttle the surface-conjugated protein cages composed of collagenases and anti-programmed death-ligand 1 (PD-L1) antibodies to PDAC tumor parenchyma. FINDINGS: We found the oncogenic collagen expression in human pancreatic cancer patients and demonstrated its interaction with integrin α3ß1. We proved that reactive oxygen species (ROS) in the microenvironment of PDAC triggered collagenase release to degrade oncogenic collagen and block integrin α3ß1-FAK signaling pathway, thus overcoming the immunosuppression and synergizing with anti-PD-L1 immunotherapy. CONCLUSIONS: Collectively, our study highlights the significance of oncogenic collagen in PDAC immunotherapy, and consequently, we developed a therapeutic strategy that can deplete oncogenic collagen to synergize with immune checkpoint blockade for enhanced PDAC treatment efficacy. FUNDING: This work was supported by the University of Wisconsin Carbone Cancer Center Research Collaborative and Pancreas Cancer Research Task Force, UWCCC Transdisciplinary Cancer Immunology-Immunotherapy Pilot Project, and the start-up package from the University of Wisconsin-Madison (to Q.H.).
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Carcinoma Ductal Pancreático , Nanopartículas , Neoplasias Pancreáticas , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Integrina alfa3beta1 , Projetos Piloto , Neoplasias Pancreáticas/tratamento farmacológico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Colágeno , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Microambiente TumoralRESUMO
Objectives: The pathogenesis of pancreas cancer (PDAC) remains poorly understood, hindering efforts to develop a more effective therapy for PDAC. Recent discoveries show the aryl hydrocarbon receptor (AHR) plays a crucial role in the pathogenesis of several cancers, and can be targeted for therapeutic effect. However, its involvement in PDAC remains unclear. Therefore, we evaluated the role of AHR in the development of PDAC in vivo. Methods: We created a global AHR-null, mutant Kras-driven PDAC mouse model (A-/-KC) and evaluated the changes in PDAC precursor lesion formation (Pan-IN 1, 2, and 3) and associated fibro-inflammation between KC and A-/-KC at 5 months of age. We then examined the changes in the immune microenvironment followed by single-cell RNA-sequencing analysis to evaluate concomitant transcriptomic changes. Results: We found a significant increase in PanIN-1 lesion formation and PanIN-1 associated fibro-inflammatory infiltrate in A-/-KC vs KC mice. This was associated with significant changes in the adaptive immune system, particularly a decrease in the CD4+/CD8+ T-cell ratio, as well as a decrease in the T-regulatory/Th17 T-cell ratio suggesting unregulated inflammation. Conclusion: These findings show the loss of AHR results in heightened Kras-induced PanIN formation, through modulation of immune cells within the pancreatic tumor microenvironment.
RESUMO
Misalignment of the circadian clock compared to environmental cues causes circadian desynchrony, which is pervasive in humans. Clock misalignment can lead to various pathologies including obesity and diabetes, both of which are associated with pancreatic ductal adenocarcinoma - a devastating cancer with an 80% five-year mortality rate. Although circadian desynchrony is associated with an increased risk of several solid-organ cancers, the correlation between clock misalignment and pancreas cancer is unclear. Using a chronic jetlag model, we investigated the impact of clock misalignment on pancreas cancer initiation in mice harboring a pancreas-specific activated Kras mutation. We found that chronic jetlag accelerated the development of pancreatic cancer precursor lesions, with a concomitant increase in precursor lesion grade. Cell-autonomous knock-out of the clock in pancreatic epithelial cells of Kras-mutant mice demonstrated no acceleration of precursor lesion formation, indicating non-cell-autonomous clock dysfunction was responsible for the expedited tumor development. Therefore, we applied single-cell RNA sequencing over time and identified fibroblasts as the cell population manifesting the greatest clock-dependent changes, with enrichment of specific cancer-associated fibroblast pathways due to circadian misalignment.
Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Humanos , Camundongos , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Ritmo Circadiano/genética , Obesidade , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismoRESUMO
Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1 +/CD274+ (PD-L1) + dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.
RESUMO
OBJECTIVES: The innate biologic clock plays a significant role in lipid metabolism, including the peripheral clock in the pancreas. However, an evaluation of the downstream lipids in the pancreatic lipidome is lacking. We sought to understand the diurnal variations of lipids within the pancreatic lipidome. METHODS: At 4 weeks of age, C57Bl/6J mice were subjected to either normal lighting conditions or a chronic jetlag (CJ) condition known to mimic chronic shiftwork in humans. At 9 months, mice were serially killed at 4-hour intervals for 24 hours. The pancreas was removed and subjected to untargeted liquid chromatography-mass spectrometry to examine the pancreatic lipidome. RESULTS: A total of 4.7% of the pancreatic lipidome was rhythmically expressed, which increased to 12.9% after CJ. After CJ, there was a 4.58-hour shift in the timing of peak 24-hour lipid expression. Chronic jetlag also led to the enrichment of diacylglycerols and triglycerides, while promoting a decrease in lysophosphatidylcholines and 44-carbon acyl chain lipids. CONCLUSIONS: The pancreatic lipidome exhibits diurnal rhythmicity across a broad number of lipid classes. Chronic jetlag led to alterations in lipid composition that mirrored other metabolically active organs. Several of the reported changes may link altered sleep-wake cycles with known circadian disruption-induced pancreatic diseases.
Assuntos
Lipidômica , Hormônios Pancreáticos/metabolismo , Privação do Sono/metabolismo , Animais , Ritmo Circadiano , Humanos , Camundongos Endogâmicos C57BLRESUMO
Anal squamous cell carcinoma (SCC) will be diagnosed in an estimated 9,080 adults in the United States this year, and rates have been rising over the last several decades. Most people that develop anal SCC have associated human papillomavirus (HPV) infection (~85-95%), with approximately 5-15% of anal SCC cases occurring in HPV-negative patients from unknown etiology. This study identified and characterized the Kras-driven, female sex hormone-dependent development of anal squamous cell carcinoma (SCC) in the LSL-KrasG12D; Pdx1-Cre (KC) mouse model that is not dependent on papillomavirus infection. One hundred percent of female KC mice develop anal SCC, while no male KC mice develop tumors. Both male and female KC anal tissue express Pdx1 and Cre-recombinase mRNA, and the activated mutant KrasG12D gene. Although the driver gene mutation KrasG12D is present in anus of both sexes, only female KC mice develop Kras-mutant induced anal SCC. To understand the sex-dependent differences, KC male mice were castrated and KC female mice were ovariectomized. Castrated KC males displayed an unchanged phenotype with no anal tumor formation. In contrast, ovariectomized KC females demonstrated a marked reduction in anal SCC development, with only 15% developing anal SCC. Finally, exogenous administration of estrogen rescued the tumor development in ovariectomized KC female mice and induced tumor development in castrated KC males. These results confirm that the anal SCC is estrogen mediated. The delineation of the role of female sex hormones in mediating mutant Kras to drive anal SCC pathogenesis highlights a subtype of anal SCC that is independent of papillomavirus infection. These findings may have clinical applicability for the papillomavirus-negative subset of anal SCC patients that typically respond poorly to standard of care chemoradiation.