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1.
Can J Gastroenterol Hepatol ; 2021: 5212953, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34888264

RESUMO

Introduction: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver malignancies and is currently the fourth most common cause of cancer-related death worldwide. Due to varying underlying etiologies, the prognosis of HCC differs greatly among patients. It is important to develop ways to help stratify patients upon initial diagnosis to provide optimal treatment modalities and follow-up plans. The current study uses Artificial Neural Network (ANN) and Classification Tree Analysis (CTA) to create a gene signature score that can help predict survival in patients with HCC. Methods: The Cancer Genome Atlas (TCGA-LIHC) was analyzed for differentially expressed genes. Clinicopathological data were obtained from cBioPortal. ANN analysis of the 75 most significant genes predicting disease-free survival (DFS) was performed. Next, CTA results were used for creation of the scoring system. Cox regression was performed to identify the prognostic value of the scoring system. Results: 363 patients diagnosed with HCC were analyzed in this study. ANN provided 15 genes with normalized importance >50%. CTA resulted in a set of three genes (NRM, STAG3, and SNHG20). Patients were then divided in to 4 groups based on the CTA tree cutoff values. The Kaplan-Meier analysis showed significantly reduced DFS in groups 1, 2, and 3 (median DFS: 29.7 months, 16.1 months, and 11.7 months, p < 0.01) compared to group 0 (median not reached). Similar results were observed when overall survival (OS) was analyzed. On multivariate Cox regression, higher scores were associated with significantly shorter DFS (1 point: HR 2.57 (1.38-4.80), 2 points: 3.91 (2.11-7.24), and 3 points: 5.09 (2.70-9.58), p < 0.01). Conclusion: Long-term outcomes of patients with HCC can be predicted using a simplified scoring system based on tumor mRNA gene expression levels. This tool could assist clinicians and researchers in identifying patients at increased risks for recurrence to tailor specific treatment and follow-up strategies for individual patients.

2.
Cancers (Basel) ; 13(23)2021 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-34885240

RESUMO

Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation within the tumor microenvironment coincide with tumor progression and metastatic spread and are thought to be the key mediators of this complex process. Amongst many infiltrating cells, neutrophils have recently emerged as an important player in fueling tumor progression, both in animal models and cancer patients. The production of Neutrophil Extracellular Traps (NETs) is particularly important in the pathogenesis of the metastatic cascade. NETs are composed of web-like DNA structures with entangled proteins that are released in response to inflammatory cues in the environment. NETs play an important role in driving tumor progression both in experimental and clinical models. In this review, we aim to summarize the current advances in understanding the role of NETs in cancer, with a specific focus on their role in promoting premetastatic niche formation, interaction with circulating cancer cells, and in epithelial to mesenchymal transition during cancer metastasis. We will furthermore discuss the possible role and different treatment options for targeting NETs to prevent tumor progression.

3.
Front Immunol ; 12: 785222, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899751

RESUMO

While neutrophil extracellular traps (NETs) are important for directly promoting cancer growth, little is known about their impact on immune cells within the tumor microenvironment (TME). We hypothesize that NETs can directly interact with infiltrating T cells to promote an immunosuppressive TME. Herein, to induce a NET-rich TME, we performed liver Ischemia/Reperfusion (I/R) in an established cancer metastasis model or directly injected NETs in subcutaneous tumors. In this NET-rich TME, the majority of CD4+ and CD8+ tumor infiltrating lymphocytes expressed multiple inhibitory receptors, in addition these cells showed a functional and metabolic exhausted phenotype. Targeting of NETs in vivo by treating mice with DNAse lead to decreased tumor growth, decreased NET formation and higher levels of functioning T cells. In vitro, NETs contained the immunosuppressive ligand PD-L1 responsible for T cell exhaustion and dysfunction; an effect abrogated by using PD-L1 KO NETs or culturing NETs with PD-1 KO T cells. Furthermore, we found elevated levels of sPDL-1 and MPO-DNA, a NET marker, in the serum of patients undergoing surgery for colorectal liver metastases resection. Neutrophils isolated from patients after surgery were primed to form NETs and induced exhaustion and dysfunction of human CD4+ and CD8+ T cells. We next targeted PD-L1 in vivo by injecting a blocking antibody during liver I/R. A single dose of anti-PD-L1 during surgery lead to diminished tumors at 3 weeks and functional T cells in the TME. Our data thus reveal that NETs have the capability of suppressing T cell responses through metabolic and functional exhaustion and thereby promote tumor growth. Furthermore, targeting of PD-L1 containing NETs at time of surgery with DNAse or anti-PD-L1 lead to diminished tumor growth, which represents a novel and viable strategy for sustaining immune competence within the TME.

4.
Mol Med ; 27(1): 65, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34167455

RESUMO

BACKGROUND: Bacterial lipopolysaccharide (LPS) induces a multi-organ, Toll-like receptor 4 (TLR4)-dependent acute inflammatory response. METHODS: Using network analysis, we defined the spatiotemporal dynamics of 20, LPS-induced, protein-level inflammatory mediators over 0-48 h in the heart, gut, lung, liver, spleen, kidney, and systemic circulation, in both C57BL/6 (wild-type) and TLR4-null mice. RESULTS: Dynamic Network Analysis suggested that inflammation in the heart is most dependent on TLR4, followed by the liver, kidney, plasma, gut, lung, and spleen, and raises the possibility of non-TLR4 LPS signaling pathways at defined time points in the gut, lung, and spleen. Insights from computational analyses suggest an early role for TLR4-dependent tumor necrosis factor in coordinating multiple signaling pathways in the heart, giving way to later interleukin-17A-possibly derived from pathogenic Th17 cells and effector/memory T cells-in the spleen and blood. CONCLUSIONS: We have derived novel, systems-level insights regarding the spatiotemporal evolution acute inflammation.

5.
Sci Rep ; 11(1): 9703, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33958628

RESUMO

Systemic inflammation is complex and likely drives clinical outcomes in critical illness such as that which ensues following severe injury. We obtained time course data on multiple inflammatory mediators in the blood of blunt trauma patients. Using dynamic network analyses, we inferred a novel control architecture for systemic inflammation: a three-way switch comprising the chemokines MCP-1/CCL2, MIG/CXCL9, and IP-10/CXCL10. To test this hypothesis, we created a logical model comprising this putative architecture. This model predicted key qualitative features of systemic inflammation in patient sub-groups, as well as the different patterns of hospital discharge of moderately vs. severely injured patients. Thus, a rational transition from data to data-driven models to mechanistic models suggests a novel, chemokine-based mechanism for control of acute inflammation in humans and points to the potential utility of this workflow in defining novel features in other complex diseases.


Assuntos
Quimiocinas/metabolismo , Inflamação/metabolismo , Ferimentos e Lesões/metabolismo , Adulto , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Índice de Gravidade de Doença
6.
J Immunother ; 44(5): 185-192, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33935273

RESUMO

Despite its increased application in pancreatic ductal adenocarcinoma (PDAC), complete response to neoadjuvant therapy (NAT) is rare. Given the critical role of host immunity in regulating cancer, we sought to correlate baseline inflammatory profiles to significant response to NAT. PDAC patients receiving NAT were classified as responders (R) or nonresponders (NR) by carbohydrate antigen 19-9 response, pathologic tumor size, and lymph node status in the resected specimen. Baseline (treatment-naive) plasma was analyzed to determine levels of 27 inflammatory mediators. Logistic regression was used to correlate individual mediators with response. Network analysis and Pearson correlation maps were derived to determine baseline inflammatory mediator profiles. Forty patients (20R and 20NR) met study criteria. The R showed significantly higher overall survival (59.4 vs. 21.25 mo, P=0.002) and disease-free survival (50.97 vs. 10.60 mo, P=0.005), compared with NR. soluble interleukin-2 receptor alpha was a significant predictor of no response to NAT (P=0.045). Analysis of inflammatory profiles using the Pearson heat map analysis followed by network analysis depicted increased inflammatory network complexity in NR compared with R (1.69 vs. 1), signifying a more robust baseline inflammatory status of NR. A panel of inflammatory mediators identified by logistic regression and Fischer score analysis was used to create a potential decision tree to predict NAT response. We demonstrate that baseline inflammatory profiles are associated with response to NAT in PDAC, and that an upregulated inflammatory status is associated with a poor response to NAT. Further analysis into the role of inflammatory mediators as predictors of chemotherapy response is warranted.

7.
Hepatology ; 73(6): 2494-2509, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32924145

RESUMO

BACKGROUND AND AIMS: Liver ischemia/reperfusion injury (IRI) induces local and systemic inflammation in which neutrophil extracellular traps (NETs) are major drivers. IRI markedly augments metastatic growth, which is consistent with the notion that the liver IRI can serve as a premetastatic niche. Exercise training (ExT) confers a sustainable protection, reducing IRI in some animal models, and has been associated with improved survival in patients with cancer; however, the impact of ExT on liver IRI or development of hepatic metastases is unknown. APPROACH AND RESULTS: Mice were randomized into exercise (ExT) and sedentary groups before liver IRI and tumor injection. Computerized dynamic network analysis of 20 inflammatory mediators was used to dissect the sequence of mediator interactions after ischemia/reperfusion (I/R) that induce injury. ExT mice showed a significant decrease in hepatic IRI and tissue necrosis. This coincided with disassembly of complex networks among inflammatory mediators seen in sedentary mice. Neutrophil infiltration and NET formation were decreased in the ExT group, which suppressed the expression of liver endothelial cell adhesion molecules. Concurrently, ExT mice revealed a distinct population of infiltrating macrophages expressing M2 phenotypic genes. In a metastatic model, fewer metastases were present 3 weeks after I/R in the ExT mice, a finding that correlated with a marked increase in tumor-suppressing T cells within the tumor microenvironment. CONCLUSIONS: ExT preconditioning mitigates the inflammatory response to liver IRI, protecting the liver from injury and metastases. In light of these findings, potential may exist for the reduction of liver premetastatic niches induced by liver IRI through the use of ExT as a nonpharmacologic therapy before curative surgical approaches.

8.
Cytokine ; 139: 154344, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-29954675

RESUMO

Acute inflammation following sterile injury is both inevitable and necessary to restore homeostasis and promote tissue repair. However, when excessive, inflammation can jeopardize the viability of organs and cause detrimental systemic effects. Identifying key-regulators of the immune cascade induced by surgery is vital to attenuating excessive inflammation and its subsequent effects. In this review, we describe the emerging role of IL-17A as a key-regulator in acute inflammation. The role of IL-17A in chronic disease states, such as rheumatoid arthritis, psoriasis and cancer has been well documented, but its significance in acute inflammation following surgery, sepsis, or traumatic injury has not been well studied. We aim to highlight the role of IL-17A in acute inflammation caused by trauma, liver ischemia, and organ transplantation, as well as in post-operative surgical infections. Further investigation of the roles of this cytokine in acute inflammation may stimulate novel therapies or diagnostic modalities.

9.
HPB (Oxford) ; 23(1): 144-153, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32646806

RESUMO

BACKGROUND: Cholangitis due to anastomotic stricture of the hepaticojejunostomy (HJ) following pancreaticoduodenectomy (PD), while uncommon, adversely affects postoperative quality-of-life. While prior studies have identified patient-related risk factors for these biliary complications, technical risk factors have not been systematically examined. Video review of surgical procedures has helped define technical details predictive of postoperative complications in bariatric and hepato-pancreato-biliary (HPB) surgery. Similarly, the present study utilized video review to identify technical factors associated with cholangitis and anastomotic biliary stricture following robotic PD. METHODS: This was an observational study. A blinded experienced HPB surgeon reviewed videos of post-learning-curve HJs performed during robotic PD and extracted 20 technical variables. Other demographic and clinical variables were collected from a prospectively maintained database. RESULTS: 241 robotic PD videos were reviewed. 29 (12.0%) developed cholangitis and/or biliary stricture, with a median time-to-event of 189 (IQR 78-365) days. Several clinical and technical factors were independently predictive of cholangitis and/or biliary stricture: preoperative radiotherapy, small duct size (<10 mm diameter), increased distance of the HJ (>10 mm) from the hilar plate, and continuous suturing technique. CONCLUSION: Post-hoc video review of HJ is a powerful method to predict biliary complications. Moreover, altering specific technical factors might enable surgeons to improve postoperative outcomes.


Assuntos
Colangite , Colestase , Procedimentos Cirúrgicos Robóticos , Colangite/diagnóstico por imagem , Colangite/etiologia , Colestase/diagnóstico por imagem , Colestase/etiologia , Constrição Patológica , Humanos , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias/etiologia , Procedimentos Cirúrgicos Robóticos/efeitos adversos
10.
Clin Transplant ; 34(10): e14106, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33091178
11.
Ann Surg ; 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773624

RESUMO

OBJECTIVE: The aim of the study was to quantify the risk of incarceration of incisional hernias. BACKGROUND: Operative repair is the definitive treatment for incisional ventral hernias but is often deferred if the perceived risk of elective operation is elevated secondary to comorbid conditions. The risk of incarceration during nonoperative management (NOM) factors into shared decision making by patient and surgeon; however, the incidence of acute incarceration remains largely unknown. METHODS: A retrospective analysis of adult patients with an International Classification of Diseases, Ninth Revision or Tenth Revision diagnosis of incisional hernia was conducted from 2010 to 2017 in 15 hospitals of a single healthcare system. The primary outcome was incarceration necessitating emergent operation. The secondary outcome was 30-, 90-, and 365-day mortality. Univariate and multivariate analyses were used to determine independent predictors of incarceration. RESULTS: Among 30,998 patients with an incisional hernia (mean age 58.1 ±â€Š15.9 years; 52.7% female), 23,022 (78.1%) underwent NOM of whom 540 (2.3%) experienced incarceration, yielding a 1- and 5-year cumulative incidence of 1.24% and 2.59%, respectively. Independent variables associated with incarceration included: age older than 40 years, female sex, current smoker, body mass index 30 or greater, and a hernia-related inpatient admission. All-cause mortality rates at 30, 90, and 365 days were significantly higher in the incarceration group at 7.2%, 10%, and 14% versus 1.1%, 2.3%, and 5.3% in patients undergoing successful NOM, respectively. CONCLUSIONS: Incarceration is an uncommon complication of NOM but is associated with a significant risk of death. Tailored decision making for elective repair and considering the aforementioned risk factors for incarceration provides an initial step toward mitigating the excess morbidity and mortality of an incarceration event.

12.
Front Immunol ; 11: 987, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32528475

RESUMO

Innate immunity can initiate platelet activation during the development of thrombosis through a process, termed immunothrombosis. Neutrophils form neutrophil extracellular traps (NETs) that have been shown to interact directly with platelets and play pro-coagulant roles in a variety of infectious and sterile inflammatory settings. Hepatic surgical stress initiated by ischemia/reperfusion (I/R) injury has wide systemic consequences on distant organs. However, the mechanisms of this remote injury phenomenon are not well-understood. Here, we sought to determine the role of NETs in causing systemic immunothrombosis and distant organ injury following a local inflammatory insult with liver I/R. Postoperative thromboelastographic revealed that the speed of clot formation (alpha-angle) was significantly increased whereas time to clot formation (R-time) were decreased by in patients undergoing liver resection, indicating a hypercoagulable state after surgery. In mice subjected to liver I/R, circulating platelet activation and platelet-neutrophil aggregates were significantly increased. Injured distant organs such as the lung and kidney displayed NETs and platelet-rich micro-thrombi in the microvasculature following liver I/R. The immune-thrombi and organ damage were dramatically decreased when NETs were inhibited by DNase treatment. Depletion of Tlr4 on platelets limited NET-induced activation of platelets but had no effect on NET formation. Furthermore, platelet-specific TLR4 KO mice had significantly reduced distant organ injury with decreased circulating platelet activation, platelet-neutrophil aggregates following liver I/R in comparison to their control counterparts. These data establish that after an acute local inflammatory process, NET-activated platelets can lead to a systemic pro-coagulant state with resultant remote organ injury by immunothrombosis.


Assuntos
Coagulação Sanguínea , Plaquetas/imunologia , Armadilhas Extracelulares/imunologia , Hepatectomia/efeitos adversos , Neutrófilos/imunologia , Ativação Plaquetária , Traumatismo por Reperfusão/imunologia , Trombose/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Plaquetas/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Proteína-Arginina Desiminase do Tipo 4/deficiência , Proteína-Arginina Desiminase do Tipo 4/genética , Traumatismo por Reperfusão/sangue , Transdução de Sinais , Estresse Fisiológico , Trombose/sangue , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genética , Adulto Jovem
13.
J Gastrointest Surg ; 24(7): 1581-1589, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32410174

RESUMO

BACKGROUND: Long-term complications following pancreatoduodenectomy (PD) can significantly impact quality of life and healthcare utilization. Most reports focus on short-term (within 90 days) PD outcomes; however, the incidence and risk factors for long-term complications (> 90 days) remain to be evaluated. We sought to identify the incidence, outcomes, and risk factors for long-term complications post-PD. METHODS: All PD survivors between 2010 and 2017 were identified from a single-institutional database. Long-term complications (> 90 days post-PD and not resulting from cancer recurrence), including biliary stricture, cholangitis, pancreatitis, peptic ulcer, small bowel obstruction, and incisional hernia, were identified. Logistic regression was used to identify perioperative predictors of long-term complications. RESULTS: Of 906 PDs, 628 long-term survivors met criteria for analysis (mean age of 65.3 years, 47% female). Median follow-up and overall survival were 51.1 months (95% CI 47.6, 55.7) and 68.5 months (95% CI 57.9, 81.4), respectively. A total of 198 (31.5%) experienced at least one long-term complication. Complications included incisional hernia (17.7%), biliary stricture or cholangitis (8.0%), pancreatitis (5.7%), small bowel obstruction (4.3%), and peptic ulcer (3.2%). In total, 108 (17.2%) of the complications required an intervention, nearly half of which were surgical. On multivariable analysis, several predictors of long-term complications were identified: obesity (BMI ≥ 30 kg/m2), postoperative wound infection, prolonged index length of stay, readmission (< 90 days), operative approach (open vs. robotic), and pylorus-preservation. CONCLUSION: Long-term complications occur in nearly a third of PDs and nearly one-fifth of all PDs require re-intervention. Several modifiable predictors of long-term complications were identified.


Assuntos
Hérnia Incisional , Pancreaticoduodenectomia , Idoso , Feminino , Humanos , Incidência , Masculino , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Qualidade de Vida , Estudos Retrospectivos , Fatores de Risco
14.
JAMA Surg ; 155(6): e200416, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32267474

RESUMO

Importance: Adults with comorbidity have less physiological reserve and an increased rate of postoperative mortality and readmission after the stress of a major surgical intervention. Objective: To assess postoperative mortality and readmission among individuals with diabetes with or without preoperative prescriptions for metformin. Design, Setting, and Participants: This cohort study obtained data from the electronic health record of a multicenter, single health care system in Pennsylvania. Included were adults with diabetes who underwent a major operation with hospital admission from January 1, 2010, to January 1, 2016, at 15 community and academic hospitals within the system. Individuals without a clinical indication for metformin therapy were excluded. Follow-up continued until December 18, 2018. Exposures: Preoperative metformin exposure was defined as 1 or more prescriptions for metformin in the 180 days before the surgical procedure. Main Outcomes and Measures: All-cause postoperative mortality, hospital readmission within 90 days of discharge, and preoperative inflammation measured by the neutrophil to leukocyte ratio were compared between those with and without preoperative prescriptions for metformin. The corresponding absolute risk reduction (ARR) and adjusted hazard ratio (HR) with 95% CI were calculated in a propensity score-matched cohort. Results: Among the 10 088 individuals with diabetes who underwent a major surgical intervention, 5962 (59%) had preoperative metformin prescriptions. A total of 5460 patients were propensity score-matched, among whom the mean (SD) age was 67.7 (12.2) years, and 2866 (53%) were women. In the propensity score-matched cohort, preoperative metformin prescriptions were associated with a reduced hazard for 90-day mortality (adjusted HR, 0.72 [95% CI, 0.55-0.95]; ARR, 1.28% [95% CI, 0.26-2.31]) and hazard of readmission, with mortality as a competing risk at both 30 days (ARR, 2.09% [95% CI, 0.35-3.82]; sub-HR, 0.84 [95% CI, 0.72-0.98]) and 90 days (ARR, 2.78% [95% CI, 0.62-4.95]; sub-HR, 0.86 [95% CI, 0.77-0.97]). Preoperative inflammation was reduced in those with metformin prescriptions compared with those without (mean neutrophil to leukocyte ratio, 4.5 [95% CI, 4.3-4.6] vs 5.0 [95% CI, 4.8-5.3]; P < .001). E-value analysis suggested robustness to unmeasured confounding. Conclusions and Relevance: This study found an association between metformin prescriptions provided to individuals with type 2 diabetes before a major surgical procedure and reduced risk-adjusted mortality and readmission after the operation. This association warrants further investigation.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Readmissão do Paciente/estatística & dados numéricos , Complicações Pós-Operatórias/mortalidade , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Diabetes Mellitus Tipo 2/complicações , Feminino , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Período Pré-Operatório , Medição de Risco , Estresse Fisiológico/efeitos dos fármacos
15.
Front Med (Lausanne) ; 7: 46, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32161760

RESUMO

Purpose: We sought to identify a MODS score parameter that highly correlates with adverse outcomes and then use this parameter to test the hypothesis that multiple severity-based MODS clusters could be identified after blunt trauma. Methods: MOD score across days (D) 2-5 was subjected to Fuzzy C-means Clustering Analysis (FCM) followed by eight Clustering Validity Indices (CVI) to derive organ dysfunction patterns among 376 blunt trauma patients admitted to the intensive care unit (ICU) who survived to discharge. Thirty-one inflammation biomarkers were assayed (Luminex™) in serial blood samples (3 samples within the first 24 h and then daily up to D 5) and were analyzed using Two-Way ANOVA and Dynamic Network analysis (DyNA). Results: The FCM followed by CVI suggested four distinct clusters based on MOD score magnitude between D2 and D5. Distinct patterns of organ dysfunction emerged in each of the four clusters and exhibited statistically significant differences with regards to in-hospital outcomes. Interleukin (IL)-6, MCP-1, IL-10, IL-8, IP-10, sST2, and MIG were elevated differentially over time across the four clusters. DyNA identified remarkable differences in inflammatory network interconnectivity. Conclusion: These results suggest the existence of four distinct organ failure patterns based on MOD score magnitude in blunt trauma patients admitted to the ICU who survive to discharge.

16.
Ann Transl Med ; 7(16): 371, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31555685

RESUMO

Background: The cellular and molecular response of liver cells to hypoxic stress is not fully understood. We used computational modeling to gain insights into the inflammatory response of primary human hepatocytes (HC) to hypoxic stress in vitro. Methods: Primary HC from cancer patients were exposed to hypoxia (1% O2) or normoxia (21% O2) for 1-48 h, and the cell supernatants were assayed for 21 inflammatory mediators. Data were analyzed by Two-Way ANOVA, Dynamic Bayesian Network (DBN) inference, Dynamic Network Analysis (DyNA), and Time-interval Principal Component Analysis (TI-PCA). Results: The chemokines MCP-1/CCL2 and IP-10/CXCL10, along with the cytokines interleukin (IL)-2 and IL-15 were altered significantly over time in hypoxic vs. normoxic HC. DBN inference suggested central, coordinating roles for MCP-1 and IL-8 in regulating a largely conserved inflammatory program in both hypoxic and normoxic HC. DyNA likewise suggested similar network trajectories of decreasing complexity over time in both hypoxic and normoxic HC, though with differential connectivity of MCP-1, IP-10, IL-8, and Eotaxin. TI-PCA pointed to IL-1ß as a central characteristic of inflammation in hypoxic HC across all time intervals, along with IL-15 and IL-10, vs. Eotaxin, IL-7, IL-10, IL-15, and IL-17A in normoxic HC. Conclusions: Thus, diverse human HC appear to respond in a largely conserved fashion to cell culture stress, with distinct characteristics based on the presence or absence of hypoxia.

17.
Cancer Res ; 79(21): 5626-5639, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31519688

RESUMO

Neutrophil infiltration and neutrophil extracellular traps (NET) in solid cancers are associated with poorer prognosis, but the mechanisms are incompletely understood. We hypothesized that NETs enhance mitochondrial function in tumor cells, providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis, and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC1α, TFAM, and NRF-1. In vitro, cancer cells treated with NETs upregulated mitochondrial biogenesis-associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential, and increased the oxygen consumption rate. Furthermore, NETs increased cancer cells' expression of fission and fusion-associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase released from NETs activated TLR4 on cancer cells, leading to PGC1α upregulation, increased mitochondrial biogenesis, and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression. SIGNIFICANCE: Neutrophils through the release of NETs facilitate the growth of stressed cancer cells by altering their bioenergetics, the inhibition of which induces cell death.


Assuntos
Proliferação de Células/fisiologia , Armadilhas Extracelulares/fisiologia , Homeostase/fisiologia , Mitocôndrias/fisiologia , Neutrófilos/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , DNA Mitocondrial/metabolismo , Armadilhas Extracelulares/metabolismo , Células HCT116 , Humanos , Elastase de Leucócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Infiltração de Neutrófilos/fisiologia , Neutrófilos/metabolismo
18.
Sci Rep ; 9(1): 5971, 2019 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-30979951

RESUMO

Acetaminophen (APAP) overdose (APAPo) is predominant in the NIH Pediatric Acute Liver Failure (PALF) Study. We assayed multiple inflammatory mediators in serial serum samples from 13 PALF survivors with APAPo + N-acetylcysteine (NAC, the frontline therapy for APAPo), 8 non-APAPo + NAC, 40 non-APAPo non-NAC, and 12 non-survivors. High Mobility Group Box 1 (HMGB1) was a dominant mediator in dynamic inflammation networks in all sub-groups, associated with a threshold network complexity event at d1-2 following enrollment that was exceeded in non-survivors vs. survivors. We thus hypothesized that differential HMGB1 network connectivity after day 2 is related to the putative threshold event in non-survivors. DyNA showed that HMGB1 is most connected in non-survivors on day 2-3, while no connections were observed in APAPo + NAC and non-APAPo + NAC survivors. Inflammatory dynamic networks, and in particular HMGB1 connectivity, were associated with the use of NAC in the context of APAPo. To recapitulate hepatocyte (HC) damage in vitro, primary C57BL/6 HC and HC-specific HMGB1-null HC were treated with APAP + NAC. Network phenotypes of survivors were recapitulated in C57BL/6 mouse HC and were greatly altered in HMGB1-null HC. HC HMGB1 may thus coordinate a pro-inflammatory program in PALF non-survivors (which is antagonized by NAC), while driving an anti-inflammatory/repair program in survivors.


Assuntos
Acetaminofen/efeitos adversos , Analgésicos não Narcóticos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Proteína HMGB1/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Adolescente , Animais , Biomarcadores/sangue , Criança , Pré-Escolar , Estudos de Coortes , Overdose de Drogas/metabolismo , Proteína HMGB1/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Lactente , Inflamação/induzido quimicamente , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cultura Primária de Células
19.
HPB (Oxford) ; 21(6): 679-686, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30501987

RESUMO

BACKGROUND: Achieving margin negative resection is a significant determinant of outcome in pancreatic adenocarcinoma (PDA). However, because of the fibrotic nature of PDA, it can be difficult to discriminate fibrosis from active disease intra-operatively. We sought to determine if post-hoc video review of robotic pancreatico-duodenectomy (RPD) could predict the portal/superior mesenteric vein (PV/SMV) margin status on final pathology. METHODS: Experienced pancreatic surgeons, blinded to patient and operative variables, reviewed the PV/SMV margin for available RPD videos of consecutive PDA patients from 9/2012 through 6/2017. RESULTS: 107 RPD videos were reviewed. Of 76 patients (71%) predicted to have a negative vein margin on video review, 20 patients (26%) had a pathologic positive margin. 25 of 31 patients (81%) predicted to have positive margin on video review were positive on pathology. The specificity of video prediction was 90.3% with a sensitivity of 55.6% and an accuracy of 75.7%. CONCLUSION: Post-hoc video review prediction is unable to reliably predict a positive (R1) margin at the portal vein/SMV, suggesting that intra-operative clinical assessment may be suboptimal in determining the need for more extensive resections.


Assuntos
Carcinoma Ductal Pancreático/cirurgia , Veias Mesentéricas/cirurgia , Neoplasias Pancreáticas/cirurgia , Pancreaticoduodenectomia/métodos , Veia Porta/cirurgia , Procedimentos Cirúrgicos Robóticos/métodos , Neoplasias Vasculares/patologia , Idoso , Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/patologia , Feminino , Seguimentos , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Invasividade Neoplásica , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Neoplasias Vasculares/cirurgia
20.
J Immunol ; 202(1): 268-277, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30504418

RESUMO

Hepatic ischemia reperfusion (I/R) is a clinically relevant model of acute sterile inflammation leading to a reverberating, self-sustaining inflammatory response with resultant necrosis. We hypothesized that computerized dynamic network analysis (DyNA) of 20 inflammatory mediators could help dissect the sequence of post-I/R mediator interactions that induce injury. Although the majority of measured inflammatory mediators become elevated in the first 24 h, we predicted that only a few would be secreted early in the process and serve as organizational centers of downstream intermediator complexity. In support of this hypothesis, DyNA inferred a central organizing role for IL-17A during the first 3 h of reperfusion. After that, DyNA revealed connections among almost all the inflammatory mediators, representing an ongoing cytokine storm. Blocking IL-17A immediately after reperfusion disassembled the inflammatory networks and protected the liver from injury. Disassembly of the networks was not achieved if IL-17A blockage was delayed two or more hours postreperfusion. Network disassembly was accompanied by decrease in neutrophil infiltration and neutrophil extracellular trap (NET) formation. By contrast, administration of recombinant IL-17A increased neutrophil infiltration, NET formation, and liver necrosis. The administration of DNase, a NET inhibitor, significantly reduced hepatic damage despite prior administration of IL-17A, and DNase also disassembled the inflammatory networks. In vitro, IL-17A was a potent promoter of NET formation. Therefore, computational analysis identified IL-17A's early, central organizing role in the rapid evolution of a network of inflammatory mediators that induce neutrophil infiltration and NET formation responsible for hepatic damage after liver I/R.


Assuntos
Biologia Computacional/métodos , Simulação por Computador , Armadilhas Extracelulares/imunologia , Interleucina-17/metabolismo , Fígado/patologia , Neutrófilos/imunologia , Traumatismo por Reperfusão/imunologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Células Cultivadas , Desoxirribonucleases/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-17/imunologia , Fígado/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Necrose , Infiltração de Neutrófilos , Mapas de Interação de Proteínas
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