Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 98
Filtrar
1.
Clin Gastroenterol Hepatol ; 22(5): 994-1004.e10, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38184096

RESUMO

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is an immune-mediated disease of the pancreas with distinct pathophysiology and manifestations. Our aims were to characterize type 1 AIP in a large pan-European cohort and study the effectiveness of current treatment regimens. METHODS: We retrospectively analyzed adults diagnosed since 2005 with type 1 or not-otherwise-specified AIP in 42 European university hospitals. Type 1 AIP was uniformly diagnosed using specific diagnostic criteria. Patients with type 2 AIP and those who had undergone pancreatic surgery were excluded. The primary end point was complete remission, defined as the absence of clinical symptoms and resolution of the index radiologic pancreatic abnormalities attributed to AIP. RESULTS: We included 735 individuals with AIP (69% male; median age, 57 years; 85% White). Steroid treatment was started in 634 patients, of whom 9 (1%) were lost to follow-up. The remaining 625 had a 79% (496/625) complete, 18% (111/625) partial, and 97% (607/625) cumulative remission rate, whereas 3% (18/625) did not achieve remission. No treatment was given in 95 patients, who had a 61% complete (58/95), 19% partial (18/95), and 80% cumulative (76/95) spontaneous remission rate. Higher (≥0.4 mg/kg/day) corticosteroid doses were no more effective than lower (<0.4 mg/kg/day) doses (odds ratio, 0.428; 95% confidence interval, 0.054-3.387) and neither was a starting dose duration >2 weeks (odds ratio, 0.908; 95% confidence interval, 0.818-1.009). Elevated IgG4 levels were independently associated with a decreased chance of complete remission (odds ratio, 0.639; 95% confidence interval, 0.427-0.955). Relapse occurred in 30% of patients. Relapses within 6 months of remission induction were independent of the steroid-tapering duration, induction treatment duration, and total cumulative dose. CONCLUSIONS: Patients with type 1 AIP and elevated IgG4 level may need closer monitoring. For remission induction, a starting dose of 0.4 mg/kg/day for 2 weeks followed by a short taper period seems effective. This study provides no evidence to support more aggressive regimens.


Assuntos
Pancreatite Autoimune , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Estudos Retrospectivos , Pancreatite Autoimune/tratamento farmacológico , Pancreatite Autoimune/diagnóstico , Europa (Continente) , Idoso , Resultado do Tratamento , Adulto , Esteroides/uso terapêutico , Esteroides/administração & dosagem , Idoso de 80 Anos ou mais
2.
Am J Gastroenterol ; 119(4): 671-681, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37934190

RESUMO

INTRODUCTION: The study aimed to develop international consensus recommendations on the safe use of lumen-apposing metal stents (LAMSs) for on- and off-label indications. METHODS: Based on the available literature, statements were formulated and grouped into the following categories: general safety measures, peripancreatic fluid collections, endoscopic ultrasound (EUS)-biliary drainage, EUS-gallbladder drainage, EUS-gastroenterostomy, and gastric access temporary for endoscopy. The evidence level of each statement was determined using the Grading of Recommendations Assessment, Development, and Evaluation methodology.International LAMS experts were invited to participate in a modified Delphi process. When no 80% consensus was reached, the statement was modified based on expert feedback. Statements were rejected if no consensus was reached after the third Delphi round. RESULTS: Fifty-six (93.3%) of 60 formulated statements were accepted, of which 35 (58.3%) in the first round. Consensus was reached on the optimal learning path, preprocedural imaging, the need for airway protection and essential safety measures during the procedure, such as the use of Doppler, and measurement of the distance between the gastrointestinal lumen and the target structure. Specific consensus recommendations were generated for the different LAMS indications, covering, among others, careful patient selection, the preferred size of the LAMS, the need for antibiotics, the preferred anatomic location of the LAMS, the need for coaxial pigtail placement, and the appropriate management of LAMS-related adverse events. DISCUSSION: Through a modified international Delphi process, we developed general and indication-specific experience- and evidence-based recommendations on the safe use of LAMS.


Assuntos
Endossonografia , Uso Off-Label , Humanos , Consenso , Estudos Retrospectivos , Stents/efeitos adversos , Endoscopia Gastrointestinal , Drenagem/métodos
3.
J Cardiovasc Electrophysiol ; 34(1): 82-89, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36321661

RESUMO

INTRODUCTION: Aim of this study was to evaluate the incidence of ablation-induced endoscopically detected esophageal lesions (EDEL) and gastroparesis in patients undergoing high-power short-duration (HPSD) atrial fibrillation (AF) ablation using different target ablation index (AI) values. METHODS AND RESULTS: Consecutive patients undergoing AF ablation were included. Radiofrequency (RF) ablation was performed using HPSD ablation (50 W, target AI of 320 and 350 (group 1) and 380 (group 2) at posterior wall). Postablation endoscopy was performed in all patients. In total, 233 patients (66.8 ± 10 years; 52% male) were included consecutively (n = 137 patients in group 1 and n = 96 patients in group 2). Mean AI values und RF time at posterior wall was significantly higher and longer in group 2 compared to group 1 patients (413 ± 9 vs. 392 ± 19 AI, p < 0.01; 9.0 ± 0.8 s vs. 7.8 ± 0.7 s, p < 0.01). Esophageal endoscopy revealed esophageal lesions or gastroparesis in 43 of 233 patients (18.5%) in the total cohort (13.1% in group 1 and 26.0% in group 2; p = 0.02). Incidence of EDEL was 8.0% and 13.5% in group 1 and group 2, respectively. According to logistic analysis incidence of EDEL and/or gastroparesis was significantly lower in patients with a higher body mass index and higher in group 2 patients compared to group 1 patients. CONCLUSION: The incidence of EDEL or gastroparesis in patients undergoing HPSD AF ablation was 18.5% in the total cohort. The risk of EDEL and gastroparesis was associated with a higher AI target value of 380 compared to 320 and 350 at posterior wall and was reversely associated with body mass index.


Assuntos
Fibrilação Atrial , Ablação por Cateter , Gastroparesia , Veias Pulmonares , Humanos , Masculino , Feminino , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/epidemiologia , Fibrilação Atrial/cirurgia , Incidência , Gastroparesia/diagnóstico , Gastroparesia/epidemiologia , Gastroparesia/etiologia , Esôfago/diagnóstico por imagem , Esôfago/cirurgia , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Veias Pulmonares/cirurgia , Resultado do Tratamento
4.
Cell Mol Life Sci ; 80(1): 12, 2022 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-36534167

RESUMO

Targeting KRAS downstream signaling remains an important therapeutic approach in pancreatic cancer. We used primary pancreatic ductal epithelial cells and mouse models allowing the conditional expression of oncogenic KrasG12D, to investigate KRAS signaling integrators. We observed that the AP1 family member FRA1 is tightly linked to the KRAS signal and expressed in pre-malignant lesions and the basal-like subtype of pancreatic cancer. However, genetic-loss-of-function experiments revealed that FRA1 is dispensable for KrasG12D-induced pancreatic cancer development in mice. Using FRA1 gain- and loss-of-function models in an unbiased drug screen, we observed that FRA1 is a modulator of the responsiveness of pancreatic cancer to inhibitors of the RAF-MEK-ERK cascade. Mechanistically, context-dependent FRA1-associated adaptive rewiring of oncogenic ERK signaling was observed and correlated with sensitivity to inhibitors of canonical KRAS signaling. Furthermore, pharmacological-induced degradation of FRA1 synergizes with MEK inhibitors. Our studies establish FRA1 as a part of the molecular machinery controlling sensitivity to MAPK cascade inhibition allowing the development of mechanism-based therapies.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Proteínas Proto-Oncogênicas c-fos , Animais , Camundongos , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Mutação , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras) , Proteínas Proto-Oncogênicas c-fos/metabolismo , Neoplasias Pancreáticas
5.
Pancreatology ; 21(5): 912-919, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33824054

RESUMO

BACKGROUND: Oncogenic Kras initiates and drives carcinogenesis in the pancreas by complex signaling networks, including activation of the NFκB pathway. Although recent evidence has shown that oncogenic gains in Nfκb2 collaborate with Kras in the carcinogenesis, no data at the level of genetics for the contribution of Nfκb2 is available so far. METHODS: We used Nfkb2 knock-out mice to decipher the role of the gene in Kras-driven carcinogenesis in vivo. RESULTS: We show that the Nfkb2 gene is needed for cancer initiation and progression in KrasG12D-driven models and this requirement of Nfkb2 is mechanistically connected to proliferative pathways. In contrast, Nfκb2 is dispensable in aggressive pancreatic ductal adenocarcinoma (PDAC) models relying on the simultaneous expression of the Kras oncogene and the mutated tumor suppressor p53. CONCLUSIONS: Our data add to the understanding of context-dependent requirements of oncogenic Kras signaling during pancreatic carcinogenesis.


Assuntos
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Animais , Carcinogênese/genética , Carcinoma Ductal Pancreático/genética , Genes ras , Camundongos , Pâncreas , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
6.
Surg Endosc ; 35(4): 1741-1748, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-32323015

RESUMO

BACKGROUND: Lumen apposing metal stent (LAMS) allows an easy access to peripancreatic fluid collections (PPFCs) and the possibility of performing direct endoscopic necrosectomy (DEN). The aim of our study was to evaluate the safety and efficacy of a new 20-mm LAMS in the management of PPFCs. This novel stent represents the largest diameter LAMS available on the market to date. METHODS: This is an international, multicenter retrospective study involving 20 centers. Consecutive patients who underwent EUS-guided PPFC drainage using a 20-mm LAMS were included. Primary outcomes were technical and clinical success. Secondary outcomes were rate and the severity of adverse events. RESULTS: A total 105 patients underwent PPFC drainage using the new 20-mm LAMS and 106 LAMS were placed. Technical success was 100% (106/106). 7/105 patients died due to causes not related to the stent. Clinical success was achieved in 92/98 patients (93.9%). Significant adverse events occurred in 8/98 patients (8.16%): 4 cases (4.08%) of bleeding, 3 cases (3.06%) of suprainfection, 1 case of gastric outlet obstruction. CONCLUSIONS: This multicenter study demonstrated acceptable rates of technical and clinical success using a new 20-mm LAMS for PPFC, including walled-off pancreatic necrosis (WOPN). The results of our study suggest that a new 20-mm LAMS is non-inferior in terms of safety, efficacy, and adverse events as compared to smaller diameter LAMS in the management of PPFCs, including pancreatic psuedocysts (PP) and WOPN. Randomized controlled studies will be needed to determine the ideal size of LAMS need to achieve the greatest clinical benefit with the minimized risk exposure for this high-risk patient population.


Assuntos
Líquidos Corporais/química , Endoscopia , Internacionalidade , Pâncreas/patologia , Pâncreas/cirurgia , Stents/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Drenagem , Endossonografia , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Pâncreas/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Adulto Jovem
7.
Endoscopy ; 52(3): 211-219, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32000275

RESUMO

BACKGROUNDS: Endoscopic ultrasound (EUS)-guided placement of lumen-apposing metal stents (LAMSs) has gained popularity for the treatment of pancreatic walled-off necrosis (WON). We compared the 20-mm and 15-mm LAMSs for the treatment of symptomatic WON in terms of clinical success and adverse events. METHODS: We conducted a retrospective, case-matched study of 306 adults at 22 tertiary centers from 04/2014 to 10/2018. A total of 102 patients with symptomatic WON who underwent drainage with 20-mm LAMS (cases) and 204 patients who underwent drainage with 15-mm LAMS (controls) were matched by age, sex, and drainage approach. Conditional logistic regression analysis was performed to compare clinical success (resolution of WON on follow-up imaging without reintervention) and adverse events (according to American Society for Gastrointestinal Endoscopy criteria). RESULTS: Clinical success was achieved in 92.2 % of patients with 20-mm LAMS and 91.7 % of patients with 15-mm LAMS (odds ratio 0.92; P = 0.91). Patients with 20-mm LAMS underwent fewer direct endoscopic necrosectomy (DEN) sessions (mean 1.3 vs. 2.1; P < 0.001), despite having larger WON collections (transverse axis 118.2 vs. 101.9 mm, P = 0.003; anteroposterior axis 95.9 vs. 80.1 mm, P = 0.01). There was no difference in overall adverse events (21.6 % vs. 15.2 %; P = 0.72) and bleeding events (4.9 % vs. 3.4 %; P = 0.54) between the 20-mm and 15-mm LAMS groups, respectively. CONCLUSIONS: The 20-mm LAMS showed comparable clinical success and safety profile to the 15-mm LAMS, with the need for fewer DEN sessions for WON resolution.


Assuntos
Drenagem , Stents , Adulto , Humanos , Necrose/etiologia , Estudos Retrospectivos , Resultado do Tratamento , Ultrassonografia de Intervenção
8.
Gut ; 68(1): 25-39, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29730603

RESUMO

OBJECTIVE: Vedolizumab, a monoclonal antibody directed against the integrin heterodimer α4ß7, is approved for the treatment of Crohn's disease and ulcerative colitis. The efficacy of vedolizumab has been suggested to result from inhibition of intestinal T cell trafficking although human data to support this conclusion are scarce. We therefore performed a comprehensive analysis of vedolizumab-induced alterations in mucosal and systemic immunity in patients with inflammatory bowel disease (IBD), using anti-inflammatory therapy with the TNFα antibody infliximab as control. DESIGN: Immunophenotyping, immunohistochemistry, T cell receptor profiling and RNA sequencing were performed using blood and colonic biopsies from patients with IBD before and during treatment with vedolizumab (n=18) or, as control, the anti-TNFα antibody infliximab (n=20). Leucocyte trafficking in vivo was assessed using single photon emission computed tomography and endomicroscopy. RESULTS: Vedolizumab was not associated with alterations in the abundance or phenotype of lamina propria T cells and did not affect the mucosal T cell repertoire or leucocyte trafficking in vivo. Surprisingly, however, α4ß7 antibody treatment was associated with substantial effects on innate immunity including changes in macrophage populations and pronounced alterations in the expression of molecules involved in microbial sensing, chemoattraction and regulation of the innate effector response. These effects were specific to vedolizumab, not observed in response to the TNFα antibody infliximab, and associated with inhibition of intestinal inflammation. CONCLUSION: Our findings suggest that modulation of innate immunity contributes to the therapeutic efficacy of vedolizumab in IBD. TRIAL REGISTRATION NUMBER: NCT02694588.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Adulto , Biópsia , Estudos de Casos e Controles , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Infliximab/uso terapêutico , Integrinas/antagonistas & inibidores , Masculino , Fenótipo , Estudos Prospectivos , Análise de Sequência de RNA , Linfócitos T/imunologia , Tomografia Computadorizada de Emissão de Fóton Único
9.
Gut ; 68(3): 445-452, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29298872

RESUMO

OBJECTIVES: Sedation has been established for GI endoscopic procedures in most countries, but it is also associated with an added risk of complications. Reported complication rates are variable due to different study methodologies and often limited sample size. DESIGNS: Acute sedation-associated complications were prospectively recorded in an electronic endoscopy documentation in 39 study centres between December 2011 and August 2014 (median inclusion period 24 months). The sedation regimen was decided by each study centre. RESULTS: A total of 368 206 endoscopies was recorded; 11% without sedation. Propofol was the dominant drug used (62% only, 22.5% in combination with midazolam). Of the sedated patients, 38 (0.01%) suffered a major complication, and overall mortality was 0.005% (n=15); minor complications occurred in 0.3%. Multivariate analysis showed the following independent risk factors for all complications: American Society of Anesthesiologists class >2 (OR 2.29) and type and duration of endoscopy. Of the sedation regimens, propofol monosedation had the lowest rate (OR 0.75) compared with midazolam (reference) and combinations (OR 1.0-1.5). Compared with primary care hospitals, tertiary referral centres had higher complication rates (OR 1.61). Notably, compared with sedation by a two-person endoscopy team (endoscopist/assistant; 53.5% of all procedures), adding another person for sedation (nurse, physician) was associated with higher complication rates (ORs 1.40-4.46), probably due to higher complexity of procedures not evident in the multivariate analysis. CONCLUSIONS: This large multicentre registry study confirmed that severe acute sedation-related complications are rare during GI endoscopy with a very low mortality. The data are useful for planning risk factor-adapted sedation management to further prevent sedation-associated complications in selected patients. TRIAL REGISTRATION NUMBER: DRKS00007768; Pre-results.


Assuntos
Sedação Consciente/efeitos adversos , Endoscopia Gastrointestinal/efeitos adversos , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Sedação Consciente/mortalidade , Endoscopia Gastrointestinal/métodos , Endoscopia Gastrointestinal/mortalidade , Endoscopia Gastrointestinal/estatística & dados numéricos , Feminino , Alemanha/epidemiologia , Humanos , Hipnóticos e Sedativos/efeitos adversos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Propofol/efeitos adversos , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Adulto Jovem
10.
Gastrointest Endosc ; 89(2): 311-319.e1, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30179609

RESUMO

BACKGROUND AND AIMS: Postoperative pancreatic leakage and fistulae (POPF) are a leading adverse event after partial pancreatic resection. Treatment algorithms are currently not standardized. Evidence regarding the role of endoscopy is scarce. METHODS: One hundred ninety-six POPF patients with (n = 132) and without (n = 64) concomitant pancreatic fluid collections (PFCs) from centers in Berlin, Kiel, and Dresden were analyzed retrospectively. Clinical resolution was used as the primary endpoint of analysis. RESULTS: Analysis was stratified by the presence or absence of a PFC because these patients differed in treatment pathway and the presence of systemic inflammation with a median C-reactive protein of 30.7 mg/dL in patients without a PFC versus 131.0 mg/dL in patients with a PFC (P = 3.4 × 10-4). In patients with PFCs, EUS-guided intervention led to resolution in a median of 8 days as compared with 25 days for percutaneous drainage and 248 days for surgery (P = 3.75 × 10-14). There was a trend toward a higher success rate of EUS-guided intervention as a primary treatment modality with 85% (P = .034), followed by percutaneous drainage (64%) and surgery (41%). When applied as a rescue intervention (n = 24), EUS led to clinical resolution in 96% of cases. In patients without PFCs, EUS-guided internalization in a novel endoscopic technique led to resolution after a median of 4 days as compared with 51 days for a remaining surgical drainage (P = 9.3 × 10-9). CONCLUSIONS: In this retrospective analysis, EUS-guided drainage of POPF led to a more rapid resolution. EUS may be considered as a viable option in the management of PFCs and POPF and should be evaluated in prospective studies.


Assuntos
Fístula Anastomótica/cirurgia , Drenagem/métodos , Endoscopia do Sistema Digestório/métodos , Pancreatectomia , Fístula Pancreática/cirurgia , Complicações Pós-Operatórias/cirurgia , Idoso , Endossonografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Cirurgia Assistida por Computador
11.
Biochim Biophys Acta Mol Cell Res ; 1864(5): 782-796, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28188806

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) represents one of the deadliest cancers. From a clinical view, the transcription factor NF-κB is of particular importance, since this pathway confers apoptosis resistance and limits drug efficacy. Whereas the role of the most abundant NF-κB subunit p65/RelA in therapeutic resistance is well documented, only little knowledge of the RelA downstream targets and their functional relevance in TRAIL mediated apoptosis in PDAC is available. In the present study TRAIL resistant and sensitive PDAC cell lines were analyzed for differentially expressed RelA target genes, to define RelA downstream targets mediating TRAIL resistance. The most upregulated target gene was then further functionally characterized. Unbiased genome-wide expression analysis demonstrated that the chemokine CCL20 represents the strongest TRAIL inducible direct RelA target gene in resistant PDAC cells. Unexpectedly, targeting CCL20 by siRNA, blocking antibodies or by downregulation of the sole CCL20 receptor CCR6 had no effect on PDAC cell death or cancer cell migration, arguing against an autocrine role of CCL20 in PDAC. However, by using an ex vivo indirect co-culture system we were able to show that CCL20 acts paracrine to recruit immune cells. Importantly, CCL20-recruited immune cells further increase TRAIL resistance of CCL20-producing PDAC cells. In conclusion, our data show a functional role of a RelA-CCL20 pathway in PDAC TRAIL resistance. We demonstrate how the therapy-induced cross-talk of cancer cells with immune cells affects treatment responses, knowledge needed to tailor novel bi-specific treatments, which target tumor cell as well as immune cells.


Assuntos
Carcinoma Ductal Pancreático , Quimiocina CCL20/fisiologia , Quimiotaxia de Leucócito/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pancreáticas , Ligante Indutor de Apoptose Relacionado a TNF/uso terapêutico , Adulto , Animais , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/patologia , Células Cultivadas , Quimiocina CCL20/antagonistas & inibidores , Quimiocina CCL20/genética , Quimiotaxia de Leucócito/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/imunologia , Humanos , Linfócitos/efeitos dos fármacos , Linfócitos/fisiologia , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , RNA Interferente Pequeno/farmacologia
12.
Br J Cancer ; 118(3): 366-377, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29384525

RESUMO

BACKGROUND: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. METHODS: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures. RESULTS: Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup. CONCLUSIONS: Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.


Assuntos
Carcinoma Ductal Pancreático/metabolismo , Sistema de Sinalização das MAP Quinases , Neoplasias Pancreáticas/metabolismo , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Animais , Antineoplásicos/farmacologia , Benzoxazóis/farmacologia , Bortezomib/farmacologia , Camptotecina/farmacologia , Carcinoma Ductal Pancreático/genética , Linhagem Celular Tumoral , Sobrevivência Celular , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Camundongos , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores
13.
Int J Mol Sci ; 19(6)2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29867042

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant neoplasms and registers rising death rates in western countries. Due to its late detection in advanced stages, its extremely aggressive nature and the minimal effectiveness of currently available therapies, PDAC is a challenging problem in the clinical field. One characteristic of PDAC is a distinct desmoplasia consisting of fibroblasts, endothelial and immune cells as well as non-cellular components, contributing to therapy resistance. It is well established that the NF-κB signaling pathway controls inflammation, cancer progression and apoptosis resistance in PDAC. This study attempts to identify NF-κB target genes mediating therapy resistance of humane PDAC cell lines towards death ligand induced apoptosis. By using a genome wide unbiased approach the chemokine CX3CL1 was established as a central NF-κB target gene mediating therapy resistance. While no direct impact of CX3CL1 expression on cancer cell apoptosis was identified in co-culture assays it became apparent that CX3CL1 is acting in a paracrine fashion, leading to an increased recruitment of inflammatory cells. These inflammatory cells in turn mediate apoptosis resistance of PDAC cells. Therefore, our data dissect a bifunctional cross-signaling pathway in PDAC between tumor and immune cells giving rise to therapy resistance.


Assuntos
Apoptose , Carcinoma Ductal Pancreático/metabolismo , Quimiocina CX3CL1/metabolismo , NF-kappa B/metabolismo , Transdução de Sinais , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/fisiopatologia , Carcinoma Ductal Pancreático/terapia , Linhagem Celular Tumoral , Quimiocina CX3CL1/imunologia , Humanos
15.
Hum Mol Genet ; 23(14): 3883-90, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24556216

RESUMO

Genome-wide association studies (GWAS) have revealed genetic determinants of iron metabolism, but correlation of these with clinical phenotypes is pending. Homozygosity for HFE C282Y is the predominant genetic risk factor for hereditary hemochromatosis (HH) and may cause liver cirrhosis. However, this genotype has a low penetrance. Thus, detection of yet unknown genetic markers that identify patients at risk of developing severe liver disease is necessary for better prevention. Genetic loci associated with iron metabolism (TF, TMPRSS6, PCSK7, TFR2 and Chr2p14) in recent GWAS and liver fibrosis (PNPLA3) in recent meta-analysis were analyzed for association with either liver cirrhosis or advanced fibrosis in 148 German HFE C282Y homozygotes. Replication of associations was sought in additional 499 Austrian/Swiss and 112 HFE C282Y homozygotes from Sweden. Only variant rs236918 in the PCSK7 gene (proprotein convertase subtilisin/kexin type 7) was associated with cirrhosis or advanced fibrosis (P = 1.02 × 10(-5)) in the German cohort with genotypic odds ratios of 3.56 (95% CI 1.29-9.77) for CG heterozygotes and 5.38 (95% CI 2.39-12.10) for C allele carriers. Association between rs236918 and cirrhosis was confirmed in Austrian/Swiss HFE C282Y homozygotes (P = 0.014; ORallelic = 1.82 (95% CI 1.12-2.95) but not in Swedish patients. Post hoc combined analyses of German/Swiss/Austrian patients with available liver histology (N = 244, P = 0.00014, ORallelic = 2.84) and of males only (N = 431, P = 2.17 × 10(-5), ORallelic = 2.54) were consistent with the premier finding. Association between rs236918 and cirrhosis was not confirmed in alcoholic cirrhotics, suggesting specificity of this genetic risk factor for HH. PCSK7 variant rs236918 is a risk factor for cirrhosis in HH patients homozygous for the HFE C282Y mutation.


Assuntos
Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Cirrose Hepática/genética , Proteínas de Membrana/genética , Subtilisinas/genética , Idoso , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Hemocromatose/complicações , Hemocromatose/patologia , Proteína da Hemocromatose , Homozigoto , Humanos , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco
16.
Eur Surg Res ; 57(3-4): 155-170, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27434375

RESUMO

BACKGROUND: The aim of this study was to compare arterial embolization (AE) with portal vein embolization (PVE) for the induction of segmental hypertrophy regarding procedural efficacy, safety and outcome. METHODS: A total of 29 mini pigs were subjected to PVE, AE or assigned to the sham (SO) group. Correspondingly, 75% of the hepatic artery or portal vein branches were embolized. Growth and atrophy of the liver lobes, calculating the liver-to-body weight index (LBWI), laboratory data, arteriography, portography, Doppler ultrasound (US) and histopathology were analyzed. RESULTS: After PVE, 2 animals had to be excluded due to technical problems. After AE, 4 animals had to be excluded because of technical problems and early sacrifice. Postprocedural US demonstrated effective AE and PVE of the respective lobes. Four weeks after PVE, portography showed a slow refilling of the embolized lobe by collateral portal venous vessels. Four weeks after AE, arteriography revealed a slight revascularization of the embolized lobes by arterial neovascularization. Segmental AE led to extensive necrotic and inflammatory alterations in the liver and bile duct parenchyma. Significant hypertrophy of the non-embolized lobe was only noted in the PVE group (LBWI: 0.91 ± 0.28%; p = 0.001). There was no increase in the non-embolized lobe in the AE (LBWI: 0.45 ± 0.087%) and SO group (LBWI: 0.45 ± 0.13%). CONCLUSION: PVE is safe and effective to induce segmental hypertrophy. Portal reperfusion by collateral vessels may limit hypertrophy. AE did not increase the segmental hepatic volume but carries the risk of extensive necrotic inflammatory damage.


Assuntos
Embolização Terapêutica/efeitos adversos , Artéria Hepática , Fígado/patologia , Veia Porta , Animais , Peso Corporal , Hipertrofia , Tamanho do Órgão , Suínos , Porco Miniatura , Ultrassonografia Doppler
17.
Chimia (Aarau) ; 70(10): 694-697, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27779926

RESUMO

During our continuous search for new resistance-breaking insecticides applicable to malaria vector control, a new class of α,ß-unsaturated imines was identified by applying the principle of conformational rigidification as a powerful tool for compound optimisation. Herein we describe the successful synthesis of these compounds and their biological test results. Our lead compound 16 from this insecticidal class outperforms market standards, notably for the control of mosquito strains that exhibit either metabolic or target-site resistance to these established insecticides. In our model system for insecticide-treated mosquito nets the compound reveals long-lasting efficacy for up to several months.


Assuntos
Iminas/farmacologia , Insetos Vetores , Inseticidas/farmacologia , Malária/prevenção & controle , Controle de Mosquitos/métodos , Animais , Descoberta de Drogas , Resistência a Inseticidas , Inseticidas/síntese química
20.
J Biol Chem ; 289(4): 1917-29, 2014 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-24311782

RESUMO

Although nuclear factor E2-related factor-2 (Nrf2) protects from carcinogen-induced tumorigenesis, underlying the rationale for using Nrf2 inducers in chemoprevention, this antioxidative transcription factor may also act as a proto-oncogene. Thus, an enhanced Nrf2 activity promotes formation and chemoresistance of colon cancer. One mechanism causing persistent Nrf2 activation is the adaptation of epithelial cells to oxidative stress during chronic inflammation, e.g. colonocytes in inflammatory bowel diseases, and the multifunctional stress response gene immediate early response-3 (IER3) has a crucial role under these conditions. We now demonstrate that colonic tissue from Ier3(-/-) mice subject of dextran sodium sulfate colitis exhibit greater Nrf2 activity than Ier3(+/+) mice, manifesting as increased nuclear Nrf2 protein level and Nrf2 target gene expression. Likewise, human NCM460 colonocytes subjected to shRNA-mediated IER3 knockdown exhibit greater Nrf2 activity compared with control cells, whereas IER3 overexpression attenuated Nrf2 activation. IER3-deficient NCM460 cells exhibited reduced reactive oxygen species levels, indicating increased antioxidative protection, as well as lower sensitivity to TRAIL or anticancer drug-induced apoptosis and greater clonogenicity. Knockdown of Nrf2 expression reversed these IER3-dependent effects. Further, the enhancing effect of IER3 deficiency on Nrf2 activity relates to the control of the inhibitory tyrosine kinase Fyn by the PI3K/Akt pathway. Thus, the PI3K inhibitor LY294002 or knockdown of Akt or Fyn expression abrogated the impact of IER3 deficiency on Nrf2 activity. In conclusion, the interference of IER3 with the PI3K/Akt-Fyn pathway represents a novel mechanism of Nrf2 regulation that may get lost in tumors and by which IER3 exerts its stress-adaptive and tumor-suppressive activity.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Colite/metabolismo , Colo/metabolismo , Células Epiteliais/metabolismo , Proteínas Imediatamente Precoces/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular , Cromonas/farmacologia , Colite/induzido quimicamente , Colite/genética , Colo/patologia , Sulfato de Dextrana/toxicidade , Inibidores Enzimáticos/farmacologia , Células Epiteliais/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Proteínas Imediatamente Precoces/genética , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Morfolinas/farmacologia , Fator 2 Relacionado a NF-E2/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fyn/genética , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA