RESUMO
BACKGROUND: Ecthyma gangrenosum (EG) is a cutaneous infectious disease characterized by eschar-like skin ulcers typically caused by Pseudomonas aeruginosa. Here, we report a case of relapsing EG in a patient who had returned from a trip to Colombia, thus establishing EG as an important differential diagnosis of tropical diseases, and demonstrating that even long-term antibiotic treatment can result in only partial remission of EG. CASE PRESENTATION: A 77-year-old man with underlying chronic lymphocytic leukemia (CLL) on ibrutinib treatment was admitted because of a superinfected mosquito bite on the left ear and multiple partially necrotic skin lesions disseminated all over the entire body five days after returning from a trip to Colombia. The initial clinical suspicion of a tropical disease (leishmaniosis, systemic mycosis, or others) could not be confirmed. During the diagnostic workup, microbiological cultures of the skin biopsies and bronchoalveolar lavage revealed Pseudomonas aeruginosa, leading to a diagnosis of EG. Initial antibiotic treatment resulted in partial remission. However, the patient had to be re-admitted due to a relapse 3-4 weeks after the first episode. Finally, the patient was successfully treated with a combined approach consisting of antibiotics, recurrent surgical incisions, and administration of immunoglobulins. CONCLUSIONS: In conclusion, EG should be considered as a differential diagnosis in immunosuppressed patients presenting with eschar-like skin ulcers. A combined treatment approach seems to be the best choice to achieve clinical cure and avoid relapse.
Assuntos
Ectima/diagnóstico , Úlcera Cutânea/diagnóstico , Adenina/análogos & derivados , Adenina/uso terapêutico , Administração Intravenosa , Idoso , Antibacterianos/uso terapêutico , Líquido da Lavagem Broncoalveolar/microbiologia , Colômbia , Diagnóstico Diferencial , Ectima/tratamento farmacológico , Ectima/microbiologia , Ectima/cirurgia , Humanos , Hospedeiro Imunocomprometido , Imunoglobulinas/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Piperidinas/uso terapêutico , Pseudomonas aeruginosa/isolamento & purificação , Úlcera Cutânea/microbiologia , Úlcera Cutânea/cirurgiaRESUMO
BACKGROUND & AIMS: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice. METHODS: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions. RESULTS: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germ-free housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development. CONCLUSIONS: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal microenvironment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.
Assuntos
Adenocarcinoma/patologia , Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Microbioma Gastrointestinal/fisiologia , Interleucina-8/metabolismo , Obesidade/patologia , Adenocarcinoma/imunologia , Adulto , Idoso , Animais , Esôfago de Barrett/imunologia , Carcinogênese/imunologia , Carcinogênese/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Progressão da Doença , Neoplasias Esofágicas/imunologia , Esôfago/imunologia , Esôfago/patologia , Fezes/microbiologia , Feminino , Voluntários Saudáveis , Humanos , Interleucina-8/genética , Interleucina-8/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/imunologia , Organoides , Soro/imunologia , Soro/metabolismo , Fatores de Tempo , Técnicas de Cultura de TecidosRESUMO
BACKGROUND/OBJECTIVES: According to the widely accepted "Cambridge Classification", one of the morphological criteria for chronic pancreatitis (CP) is enlargement of the pancreas. Increased size seems to be an obvious feature of an inflammatory disease. However, it has never been validated so far, if CP is indeed accompanied by significant enlargement of the pancreas. METHODS: In this retrospective study, reference values for the size of the pancreas (head, body and tail measured in the transverse plane by transabdominal ultrasound) were established from 921 patients without pancreatic disease. Measurements were performed by a single investigator. Subsequently, the size of the pancreas from 72 patients with CP was compared to age- and sex-matched controls. RESULTS: Calculating the 5th and 95th percentile, reference values of the pancreatic size were as follows: head 1.5-3.1 cm (mean: 2.2); body 0.6-1.6 cm (mean: 1.1); tail 1.4-3.0 cm (mean: 2.1). The size of the pancreas correlated significantly with body height, weight and body mass index. Patients with CP had only a slightly but statistically significantly larger pancreas than controls. Mean values from the CP group were still between the 5th and 95th percentile of matched controls. CONCLUSIONS: Although the pancreas from patients with CP was statistically significantly larger compared to controls, the difference was only marginally. According to these data, it is at least questionable if pancreatic size is a helpful parameter for sonographic evaluation to discriminate chronic pancreatitis from healthy pancreas.
Assuntos
Pâncreas/diagnóstico por imagem , Pancreatite Crônica/diagnóstico por imagem , Adulto , Estatura , Índice de Massa Corporal , Peso Corporal , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatite Crônica/diagnóstico , Valores de Referência , Estudos Retrospectivos , UltrassonografiaRESUMO
BACKGROUND AND STUDY AIM: The aim of the study was to compare the latest narrow-band imaging (NBI) device with high-definition white light (HDWL) endoscopy for accuracy of real-time optical diagnosis of small colorectal polyps. PATIENTS AND METHODS: We conducted a randomized, prospective, multicenter trial at three study sites in Germany. In the NBI arm, endoscopists used NBI for the prediction of polyp pathology on the basis of the NBI International Colorectal Endoscopic classification. In the HDWL arm, NBI was not used for optical classification of polyp histology. The primary outcome was accuracy of optical diagnoses (neoplastic vs. non-neoplastic) in small polyps measuring <â10âmm. Secondary end points included sensitivity and negative predictive value (NPV). RESULTS: A total of 380 patients were randomized 1:1 to either the NBI or HDWL arm. A total of 421 polyps measuring <â10âmm were detected (55.8â% neoplastic, 44.2â% non-neoplastic). Accuracy, sensitivity, and NPV were 73.7â%, 82.4â%, and 75.5â%, respectively, in the NBI arm and 79.2â%, 79.8â%, and 73.4â%, respectively, in the HDWL arm (Pâ=â0.225, Pâ=â0.667, Pâ=â0.765). More polyps were assessed with high confidence in the HDWL arm (82.6â%) than in the NBI arm (73.7â%; Pâ=â0.038). The NPV of the prediction of neoplastic histology in diminutive polyps (≤â5âmm) rated with high confidence was 90.3â% in the NBI arm. We detected significant differences between the participating study sites in the performance data of predictions. CONCLUSION: The levels of accuracy for real-time prediction of polyp histology (<â10âmm) did not differ between NBI and HDWL for optical diagnosis. Variation in the performance of optical diagnosis was apparent between study centers. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02009774).
Assuntos
Pólipos do Colo , Colonoscopia , Erros de Diagnóstico/prevenção & controle , Imagem de Banda Estreita , Transiluminação , Adulto , Idoso , Biópsia/métodos , Biópsia/normas , Pólipos do Colo/diagnóstico , Pólipos do Colo/diagnóstico por imagem , Pólipos do Colo/patologia , Colonoscopia/métodos , Colonoscopia/normas , Pesquisa Comparativa da Efetividade , Precisão da Medição Dimensional , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Imagem de Banda Estreita/métodos , Imagem de Banda Estreita/normas , Valor Preditivo dos Testes , Transiluminação/métodos , Transiluminação/normas , Carga TumoralRESUMO
BACKGROUND AND STUDY AIM: The use of magnetic endoscope imaging (MEI) has been previously shown to facilitate colonoscopy procedures. We aimed to evaluate the benefits of MEI in terms of reduction in propofol dosage in patients undergoing routine colonoscopy. METHODS: We conducted a randomized prospective trial in a university hospital in Germany. Endoscopists were randomly assigned 1:1 to use MEI during colonoscopy (MEI arm) or to conduct colonoscopy without the use of MEI (standard arm). The desired level of sedation was conscious sedation as assessed using the Observer's Assessment of Alertness and Sedation scores. After complete recovery, patient satisfaction was assessed using a numeric rating scale (NRS) ranging from 1 to 10 points. The primary outcome was total propofol dosage. Secondary outcome measures were patient satisfaction, patients' cooperation, and complication rates, as well as cecal intubation time and adenoma detection. RESULTS: Among 334 randomized patients, no severe adverse events were observed. Median propofol dosage was significantly lower in the MEI arm compared with the standard arm (150âmg vs. 180 mg; Pâ=â0.04). Deep sedation was observed in 7.8â% of patients in the MEI group and 3.6â% in the standard arm (Pâ=â0.10). Patient satisfaction scores were higher in the MEI arm compared with standard procedures (9.0 vs. 8.5; Pâ=â0.04). No significant differences in patients' cooperation, cecal intubation time, and adenoma detection were observed between the study arms. CONCLUSION: The use of MEI may be useful in reducing propofol dosage for colonoscopy and improving patient satisfaction.ClinicalTrials.gov identifier: NCT02121704.
Assuntos
Neoplasias do Ceco , Colonoscopia , Imageamento por Ressonância Magnética/métodos , Propofol , Adulto , Idoso , Neoplasias do Ceco/diagnóstico por imagem , Neoplasias do Ceco/patologia , Colonoscopia/métodos , Colonoscopia/psicologia , Sedação Profunda/métodos , Relação Dose-Resposta a Droga , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Aumento da Imagem/métodos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Satisfação do Paciente , Propofol/administração & dosagem , Propofol/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Growth factors have been implicated in pancreatic carcinogenesis. In this study we analyzed the effect of Tgfa overexpression in addition to mutant Kras(G12D) by crossing Elastase-Tgfa mice with p48(+/Cre);Kras(+/LSL-G12D) mice. We show that concomitant expression of TGFalpha and Kras(G12D) accelerates the progression of mPanIN lesions to metastatic pancreatic cancer and leads to the development of cystic papillary lesions resembling human intraductal papillary mucinous neoplasms (IPMN). Microarray data in mice revealed an IPMN signature and IPMNs expressed MUC1 and MUC5AC but not MUC2, similar to human pancreatobiliary IPMNs. Invasive ductal adenocarcinoma developed from PanINs and IPMNs, suggesting precursor lines for both lesion types in this model. In conclusion, Egfr signaling in synergy with oncogenic Kras may be a prerequisite for IPMN development and progression to pancreatic cancer.
Assuntos
Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Proteína Oncogênica p21(ras)/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Fator de Crescimento Transformador alfa/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Diferenciação Celular , Genes ras , Humanos , Camundongos , Camundongos Transgênicos , Mutação , Proteína Oncogênica p21(ras)/genética , Elastase Pancreática/genética , Neoplasias Pancreáticas/genética , Lesões Pré-Cancerosas/genética , Regiões Promotoras Genéticas , Transdução de Sinais , Fator de Crescimento Transformador alfa/genéticaRESUMO
BACKGROUND: Cardiac Index (CI) is a key-parameter of hemodynamic monitoring. Indicator-dilution is considered as gold standard and can be obtained by pulmonary arterial catheter or transpulmonary thermodilution (TPTD; CItd). Furthermore, CI can be estimated by Pulse-Contour-Analysis (PCA) using arterial wave-form analysis (CIpc). Obviously, adjustment of CIpc to CItd initially improves the accuracy of CIpc. Despite uncertainty after which time accuracy of CIpc might be inappropriate, recalibration by TPTD is suggested after a maximum of 8 h. We hypothesized that accuracy of CIpc might not only depend on time to last TPTD, but also on changes of the arterial wave curve detectable by PCA itself. Therefore, we tried to prospectively characterize predictors of accuracy and precision of CIpc (primary outcome). In addition to "time to last TPTD" we evaluated potential predictors detectable solely by pulse-contour-analysis. Finally, the study aimed to develop a pulse-contour-derived "calibration-index" suggesting recalibration and to validate these results in an independent collective. METHODS: In 28 intensive-care-patients with PiCCO-monitoring (Pulsion Medical-Systems, Germany) 56 datasets were recorded. CIpc-values at baseline and after intervals of 1 h, 2 h, 4 h, 6 h and 8 h were compared to CItd derived from immediately subsequent TPTD. Results from this evaluation-collective were validated in an independent validation-collective (49 patients, 67 datasets). RESULTS: Mean bias values CItd-CIpc after different intervals ranged between -0.248 and 0.112 L/min/m(2). Percentage-error after different intervals to last TPTD ranged between 18.6% (evaluation, 2 h-interval) and 40.3% (validation, 6 h-interval). In the merged data, percentage-error was below 30% after 1 h, 2 h, 4 h and 8 h, and exceeded 30% only after 6 h. "Time to last calibration" was neither associated to accuracy nor to precision of CIpc in any uni- or multivariate analysis. By contrast, the height of CIpc and particularly changes in CIpc compared to last thermodilution-derived CItd(base) univariately and independently predicted the bias CItd-CIpc in both collectives. Relative changes of CIpc compared to CItd(base) exceeding thresholds derived from the evaluation-collective (-11.6% < CIpc-CItd(base)/CItd(base) < 7.4%) were confirmed as significant predictors of a bias |CItd-CIpc| ≥ 20% in the validation-collective. CONCLUSION: Recalibration triggered by changes of CIpc compared to CItd(base) derived from last calibration should be preferred to fixed intervals.
Assuntos
Débito Cardíaco/fisiologia , Pulso Arterial/normas , Algoritmos , Pressão Sanguínea/fisiologia , Calibragem , Cuidados Críticos , Feminino , Frequência Cardíaca/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica , Estudos Prospectivos , Sensibilidade e Especificidade , Termodiluição/métodos , Resistência Vascular/fisiologiaRESUMO
BACKGROUND & AIMS: The transcription factor nuclear factor-κB (NF-κB) (a heterodimer of NF-κB1p50 and RelA) is activated rapidly in acute pancreatitis (AP). However, it is not clear whether NF-κB promotes or protects against AP. We used the NF-κB inhibitor protein, inhibitor of κB (IκB)α, to study the roles of NF-κB in the development of AP in mice. METHODS: IκBα or the combination of IκBα and RelA selectively were deleted from pancreas of mice using the Cre/locus of cross-over P strategy; cerulein or L-arginine were used to induce AP. We performed microarray analyses of the IκBα- and RelA-deficient pancreata. DNA from healthy individuals and patients with acute or chronic pancreatitis were analyzed for variants in coding regions of alpha-1-antichymotrypsin. RESULTS: Mice with pancreas-specific deletion of IκBα had constitutive activation of RelA and a gene expression profile consistent with NF-κB activation; development of AP in these mice was attenuated and trypsin activation was impaired. However, AP was fully induced in mice with pancreas-specific deletion of IκBα and RelA. By using genome-wide expression analysis, we identified a cluster of NF-κB-regulated genes that might protect against the development of AP. The serine protease inhibitor 2A (Spi2a) was highly up-regulated in IκBα-deficient mice. Lentiviral-mediated expression of Spi2A reduced the development of AP in C57BL/6 and RelA-deficient mice. However, we did not correlate any variants of alpha-1-antichymotrypsin, the human homologue of Spi2a, with acute or chronic pancreatitis. CONCLUSIONS: Pancreas-specific deletion of IκBα results in nuclear translocation of RelA and reduces AP induction and trypsin activation in mice after administration of cerulein or L-arginine. Constitutive activation of RelA up-regulates Spi2A, which protects mice against the development of AP.
Assuntos
Proteínas I-kappa B/genética , NF-kappa B/metabolismo , Pancreatite/genética , Pancreatite/metabolismo , Serpinas/genética , Fator de Transcrição RelA/genética , alfa 1-Antiquimotripsina/genética , Células Acinares , Animais , Arginina , Ceruletídeo , Citosol/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Vetores Genéticos , Genótipo , Proteínas I-kappa B/metabolismo , Lentivirus , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Inibidor de NF-kappaB alfa , Proteínas Nucleares/metabolismo , Pâncreas/enzimologia , Pancreatite/induzido quimicamente , Pancreatite/patologia , Fosforilação , Serpinas/metabolismo , Transdução de Sinais , Fator de Transcrição RelA/metabolismo , Tripsina/metabolismo , Regulação para CimaRESUMO
The ontogenic relationship between the common dendritic cell (DC) progenitor (CDP), the committed conventional DC precursor (pre-cDC), and cDC subpopulations in lymphoid and nonlymphoid tissues has been largely unraveled. In contrast, the sequential steps of plasmacytoid DC (pDC) development are less defined, and it is unknown at which developmental stage and location final commitment to the pDC lineage occurs. Here we show that CCR9(-) pDCs from murine BM which enter the circulation and peripheral tissues have a common DC precursor function in vivo in the steady state, in contrast to CCR9(+) pDCs which are terminally differentiated. On adoptive transfer, the fate of CCR9(-) pDC-like precursors is governed by the tissues they enter. In the BM and liver, most transferred CCR9(-) pDC-like precursors differentiate into CCR9(+) pDCs, whereas in peripheral lymphoid organs, lung, and intestine, they additionally give rise to cDCs. CCR9(-) pDC-like precursors which are distinct from pre-cDCs can be generated from the CDP. Thus, CCR9(-) pDC-like cells are novel CDP-derived circulating DC precursors with pDC and cDC potential. Their final differentiation into functionally distinct pDCs and cDCs depends on tissue-specific factors allowing adaptation to local requirements under homeostatic conditions.
Assuntos
Diferenciação Celular , Células Dendríticas/fisiologia , Células-Tronco/fisiologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Movimento Celular/genética , Células Cultivadas , Células Dendríticas/metabolismo , Feminino , Perfilação da Expressão Gênica , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Tecido Linfoide/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mucosa/citologia , Mucosa/metabolismo , Mucosa/fisiologia , Especificidade de Órgãos/genética , Receptores CCR/metabolismo , Organismos Livres de Patógenos Específicos , Células-Tronco/metabolismoRESUMO
Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared with normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K, or MEK1 using Seahorse measurements, nuclear magnetic resonance metabolome analysis, mass spectrometry, isotope tracing, and RNA sequencing analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione (GSH) but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis. Significance: Metabolic reprogramming from oxidative phosphorylation to glycolysis mediated by MYC plays a crucial role in the development of pancreatic cancer, revealing a mechanism driving tumorigenesis and potential therapeutic targets. See related commentary by Storz, p. 2225.
Assuntos
Metaplasia , Neoplasias Pancreáticas , Animais , Humanos , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/genética , Camundongos , Metaplasia/metabolismo , Metaplasia/patologia , Glicólise , Carcinogênese/metabolismo , Células Acinares/metabolismo , Células Acinares/patologia , Fosforilação Oxidativa , Glutationa/metabolismo , Reprogramação Celular , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Masculino , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Reprogramação MetabólicaRESUMO
Caveolin-1 (Cav1), a scaffold protein of membrane caveolae and coactivator of peroxisome proliferator-activated receptor gamma (PPARg), inhibits oncogenic signaling through Ras and wingless. However, the in vivo role of Cav1 in colorectal cancer (CRC) remained unknown. To test whether loss of Cav1 accelerates tumorigenesis, we generated a novel mouse model of CRC by crossing C57BL/6 Apc(min/+) with B6129 Cav1 knockout (Cav1-/-) mice. Apc(min/+) Cav1-/- mice developed large, microinvasive and vascularized intraepithelial adenocarcinomas in the distal colon and rectum with higher incidence than Apc(min/+) Cav1+/- and Apc(min/+) Cav1+/+ littermates. Intratumoral gene signatures related to Ras and wingless signaling were elevated, nuclear localization of PPARg protein and expression of PPARg-target genes were reduced independently of Cav1. The PPARg-agonist rosiglitazone prevented tumor formation in mice irrespectively of the Cav1 status and upregulated expression of the Ras-inhibitory protein docking protein-1. Thus, codeficiency of Cav1 and adenomatous polyposis coli facilitated formation of CRC, and activation of PPARg may offer novel strategies for treatment of CRC.
Assuntos
Carcinogênese/genética , Caveolina 1/genética , Neoplasias Colorretais/genética , Terapia de Alvo Molecular , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Animais , Caveolina 1/deficiência , Neoplasias Colorretais/patologia , Genes ras/genética , Humanos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Transdução de Sinais , Proteína Wnt1/genética , Proteína Wnt1/metabolismoRESUMO
BACKGROUND & AIMS: Chemotherapy modestly prolongs survival of patients with advanced gastric cancer, but strategies are needed to increase its efficacy. Histone deacetylase (HDAC) inhibitors modify chromatin and can block cancer cell proliferation and promote apoptosis. METHODS: Gastric cancer cell lines were incubated with the HDAC inhibitor LBH589 (Panobinostat, Novartis, Germany); levels of proliferation, apoptosis, histone acetylation, and gene expression were determined. We identified factors downstream of HDAC that regulated chemoresistance. The effects of combination chemotherapy of HDAC inhibitors and anthracyclines were studied in CEA424/SV40 T-antigen (CEA/Tag) transgenic mice, which develop gastric tumors. We analyzed gastric tumor samples from patients using immunohistochemistry. RESULTS: HDAC2 was expressed in human gastric cancer cell lines and tumor samples, as well as in gastric tumors from CEA/Tag mice, compared with non-neoplastic gastric tissue. LBH589 inhibited proliferation of cancer cells in vitro. LBH589 down-regulated expression of genes that mediate anthracycline resistance by activating expression of Cbp/p300-interacting transactivator, with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a gene that mediates sensitivity to chemotherapeutics. Pre-incubation of cells with an HDAC inhibitor and overexpression of CITED2-sensitized gastric cell lines to anthracycline-mediated cell death. In CEA/Tag mice, LBH589 induced tumor-cell expression of CITED2 and increased the efficacy of anthracycline to reduce tumor growth. Levels of CITED2 were increased in gastric tumor samples from patients who had complete responses to epirubicin. CONCLUSIONS: The HDAC inhibitor LBH589 can overcome the resistance of mouse gastric cancer cells to anthracyclines by inducing expression of CITED2. Levels of CITED2 in gastric tumors correlate with patients' response to epirubicin. LBH589 might be used to increase the response of patients to anthracyclines.
Assuntos
Antraciclinas/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Ácidos Hidroxâmicos/farmacologia , Proteínas Repressoras/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Transativadores/genética , Animais , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Epirubicina/farmacologia , Expressão Gênica , Humanos , Indóis , Camundongos , Camundongos Transgênicos , PanobinostatRESUMO
Whereas the final differentiation of conventional dendritic cells (CDCs) from committed precursors occurs locally in secondary lymphoid or peripheral tissues, plasmacytoid dendritic cells (PDCs) are thought to fully develop in the bone marrow from common DC progenitors before migrating to the periphery. In our study, we define, for the first time, a subpopulation of CCR9(-) major histocompatibility complex class II(low) PDCs in murine bone marrow, which express E2-2 and are immediate precursors of CCR9(+) fully differentiated PDCs. However, CCR9(-) PDCs have the plasticity to acquire the phenotype and function of CD11b(+) CD8α(-) major histocompatibility complex class II(high) CDC-like cells under the influence of soluble factors produced by intestinal epithelial cells or recombinant GM-CSF. This deviation from the PDC lineage commitment is regulated on the level of transcription factors reflected by down-regulation of E2-2 and up-regulation of ID2, PU.1, and BATF3. Thus, CCR9(-) PDCs are immediate PDC precursors that can be reprogrammed to differentiate into CDC-like cells with higher antigen-presenting and cytokine-producing capacity under the influence of the local tissue microenvironment.
Assuntos
Diferenciação Celular , Células Dendríticas/citologia , Células Dendríticas/fisiologia , Receptores CCR/metabolismo , Células-Tronco/fisiologia , Animais , Apresentação de Antígeno/fisiologia , Antígeno CD11b/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Separação Celular/métodos , Células Cultivadas , Células Dendríticas/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fenótipo , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
Pancreatic cancer is one of the most fatal malignancies lacking effective therapies. Notch signaling is a key regulator of cell fate specification and pancreatic cancer development; however, the role of individual Notch receptors and downstream signaling is largely unknown. Here, we show that Notch2 is predominantly expressed in ductal cells and pancreatic intraepithelial neoplasia (PanIN) lesions. Using genetically engineered mice, we demonstrate the effect of conditional Notch receptor ablation in KrasG12D-driven pancreatic carcinogenesis. Deficiency of Notch2 but not Notch1 stops PanIN progression, prolongs survival, and leads to a phenotypical switch toward anaplastic pancreatic cancer with epithelial-mesenchymal transition. By expression profiling, we identified increased Myc signaling regulated by Notch2 during tumor development, placing Notch2 as a central regulator of PanIN progression and malignant transformation. Our study supports the concept of distinctive roles of individual Notch receptors in cancer development.
Assuntos
Adenocarcinoma/patologia , Carcinoma in Situ/patologia , Carcinoma Ductal Pancreático/patologia , Neoplasias Pancreáticas/patologia , Receptor Notch2/metabolismo , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Animais , Western Blotting , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Knockout , Pâncreas/metabolismo , Pâncreas/patologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Notch2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de SinaisRESUMO
BACKGROUND: Pulmonary carcinoids are rare, low-grade malignant tumors characterized by neuroendocrine differentiation and relatively indolent clinical behavior. Most cases present as a slow-growing polypoidal mass in the major bronchi leading to hemoptysis and pulmonary infection due to blockage of the distal bronchi. Carcinoid syndrome is a paraneoplastic syndrome caused by the systemic release of vasoactive substances that presents in 5% of patients with neuroendocrine tumors. Due to such nonspecific presentation, most patients are misdiagnosed or diagnosed late and may receive several courses of antibiotics to treat recurrent pneumonia before the tumor is diagnosed. CASE SUMMARY: We report the case of a 48-year-old male who presented with cough, dyspnea, a history of recurrent pneumonitis, and therapy-refractory ulcerative colitis that completely subsided after the resection of a pulmonary carcinoid. CONCLUSION: We report and emphasize pulmonary carcinoid as a differential diagnosis in patients with nonresponding inflammatory bowel diseases and recurrent pneumonia.
Assuntos
Adenoma , Tumor Carcinoide , Carcinoma Neuroendócrino , Colite Ulcerativa , Neoplasias Pulmonares , Síndrome do Carcinoide Maligno , Masculino , Humanos , Pessoa de Meia-Idade , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/cirurgia , Síndrome do Carcinoide Maligno/diagnóstico , Síndrome do Carcinoide Maligno/etiologia , Tumor Carcinoide/complicações , Tumor Carcinoide/diagnóstico , Tumor Carcinoide/cirurgia , Intestinos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/cirurgiaRESUMO
BACKGROUND & AIMS: Little is known about how transcription factors might regulate pathogenesis of chronic pancreatitis (CP). We analyzed the in vivo role of RelA/p65, a component of the transcription factor nuclear factor (NF)-κB, in different cell types during development of CP in mice. METHODS: RelA/p65 was functionally inactivated in the pancreas (relaΔpanc), in myeloid cells (relaΔmye), or both (relaΔpanc,Δmye) compartments using the Cre-loxP strategy. Experimental CP was induced with repetitive injections of cerulein over 6 weeks. Pancreata were investigated histologically and biochemically. We created an in vitro coculture assay of pancreatic stellate cells (PSC) and macrophages and performed gene arrays from pancreata and macrophages with functionally inactivated RelA/p65. Tissue samples from patients with CP were analyzed for matrix metalloproteinase (MMP) 10 expression. RESULTS: In contrast to their relaF/F littermates, relaΔpanc displayed typical signs of CP after long-term stimulation with cerulein. Numerous macrophages and activated α-smooth muscle actin (SMA)-positive PSCs were detected. Additional inactivation of RelA/p65 in myeloid cells (relaΔpanc,Δmye) attenuated fibrosis. In vitro, RelA/p65-deficient, lipopolysaccharide (LPS)-stimulated macrophages degraded fibronectin in cocultured PSCs. Using gene expression analysis, MMP-10 was identified as a candidate for this process. Recombinant MMP-10 degraded fibronectin in LPS-stimulated PSCs. In tissue samples from patients with CP, MMP-10 was up-regulated in myeloid cells. CONCLUSIONS: RelA/p65 functions in myeloid cells to promote pathogenesis of CP. In acinar cells, RelA/p65 protects against chronic inflammation, whereas myeloid RelA/p65 promotes fibrogenesis. In macrophage, MMP-10 functions as a RelA/p65-dependent, potentially antifibrogenic factor during progression of CP.
Assuntos
Células Mieloides/metabolismo , Pâncreas/metabolismo , Pancreatite Crônica/metabolismo , Fator de Transcrição RelA/metabolismo , Actinas/metabolismo , Animais , Estudos de Casos e Controles , Células Cultivadas , Ceruletídeo , Técnicas de Cocultura , Modelos Animais de Doenças , Fibronectinas/metabolismo , Fibrose , Humanos , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Macrófagos/patologia , Metaloproteinase 10 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Células Mieloides/patologia , Pâncreas/patologia , Células Estreladas do Pâncreas/metabolismo , Células Estreladas do Pâncreas/patologia , Pancreatite Crônica/induzido quimicamente , Pancreatite Crônica/genética , Pancreatite Crônica/patologia , Fatores de Tempo , Fator de Transcrição RelA/deficiência , Fator de Transcrição RelA/genéticaRESUMO
INTRODUCTION: Liver failure patients might be at risk for citrate accumulation during continuous venovenous hemodialysis (CVVHD) with regional citrate anticoagulation. The aim of this study was to investigate the predictive capability of baseline liver function parameters regarding citrate accumulation, expressed as an increase in the calcium total/calcium ionized (Ca(tot)/Ca(ion)) ratio ≥ 2.5, and to describe the feasibility of citrate CVVHD in liver failure patients. METHODS: We conducted a prospective observational study in medical ICU patients treated in a German university hospital. We performed 43 CVVHD runs using citrate for regional anticoagulation in 28 critically ill patients with decompensated liver cirrhosis or acute liver failure (maximum of two CVVHD runs per patient). Liver function was characterized before CVVHD using laboratory parameters, calculation of Child-Pugh and Model of End-stage Liver Disease scores, and determination of the plasma disappearance rate of indocyanine green. In addition to blood gas analysis, we measured total calcium and citrate in serum at baseline and after definitive time points for each CVVHD run. RESULTS: Accumulation of citrate in serum correlated with an increase in the Ca(tot)/Ca(ion) ratio. Although the critical upper threshold of Ca(tot)/Ca(ion) ratio ≥ 2.5 was exceeded 10 times in seven different CVVHD runs, equalization of initial metabolic acidosis was possible without major disturbances of acid-base and electrolyte status. Standard laboratory liver function parameters showed poor predictive capabilities regarding citrate accumulation in terms of an elevated Ca(tot)/Ca(ion) ratio ≥ 2.5. In contrast, serum lactate ≥ 3.4 mmol/l and prothrombin time ≤ 26% predicted an increase in the Ca(tot)/Ca(ion) ratio ≥ 2.5 with high sensitivity (86% for both lactate and prothrombin time) and specificity (86% for lactate, 92% for prothrombin time). CONCLUSIONS: Despite substantial accumulation of citrate in serum, CVVHD with regional citrate anticoagulation seems feasible in patients with severely impaired liver function. Citrate accumulation in serum is reflected by an increase in the Ca(tot)/Ca(ion) ratio. To identify patients at risk for citrate accumulation in terms of a Ca(tot)/Ca(ion) ratio ≥ 2.5, baseline serum lactate (threshold ≥ 3.4 mmol/l) and prothrombin time (threshold ≤ 26%) may be useful for risk prediction in daily clinical practice. Careful monitoring of electrolytes and acid-base status is mandatory to ensure patient safety.
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Anticoagulantes/uso terapêutico , Ácido Cítrico/uso terapêutico , Falência Hepática/terapia , Diálise Renal/métodos , Equilíbrio Ácido-Base , Adolescente , Adulto , Idoso , Anticoagulantes/sangue , Cálcio/sangue , Ácido Cítrico/sangue , Eletrólitos/sangue , Feminino , Humanos , Concentração de Íons de Hidrogênio , Falência Hepática/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Primary myelofibrosis belongs to the group of myeloproliferative syndromes. Extramedullary hematopoiesis in the liver can lead to portal hypertension. PATIENT AND METHODS: We report a case of a patient with life-threatening, endoscopically not treatable bleeding from esophageal varices due to extramedullary hematopoiesis of the liver that was successfully treated with placement of a transjugular intrahepatic porto-systemic stent-shunt (TIPS). RESULTS: Therapy of variceal bleeding by TIPS insertion was successful. During a 29-month follow-up, no hepatic failure, hepatic encephalopathy, or further variceal bleeding episode occurred. CONCLUSION: TIPS placement is a well-established procedure for the treatment of complications due to portal hypertension mainly due to liver cirrhosis. This report illustrates that TIPS placement can also be a promising treatment option in patients with primary myelofibrosis and portal hypertension due to extramedullary hematopoiesis.
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Varizes Esofágicas e Gástricas/complicações , Varizes Esofágicas e Gástricas/cirurgia , Hemorragia Gastrointestinal/complicações , Hemorragia Gastrointestinal/cirurgia , Hematopoese Extramedular , Derivação Portossistêmica Transjugular Intra-Hepática/instrumentação , Mielofibrose Primária/complicações , Idoso , Humanos , Masculino , Derivação Portossistêmica Transjugular Intra-Hepática/métodos , Mielofibrose Primária/cirurgia , Resultado do TratamentoRESUMO
UNLABELLED: Farnesoid X receptor (FXR/Fxr) is a bile acid-regulated nuclear receptor that promotes hepatic bile acid metabolism, detoxification, and liver regeneration. However, the adaptive pathways under conditions of bile acid stress are not fully elucidated. We found that wild-type but not Fxr knockout mice on diets enriched with chenodeoxycholic acid (CDCA) increase their liver/body weight ratios by 50% due to hepatocellular hypertrophy. Microarray analysis identified Hex (Hematopoietically expressed homeobox), a central transcription factor in vertebrate embryogenesis and liver development, as a novel CDCA- and Fxr-regulated gene. HEX/Hex was also regulated by FXR/Fxr and CDCA in primary mouse hepatocytes and human HepG2 cells. Comparative genomic analysis identified a conserved inverted repeat-1-like DNA sequence within a 300 base pair enhancer element of intron-1 in the human and mouse HEX/Hex gene. A combination of chromatin immunoprecipitation, electromobility shift assay, and transcriptional reporter assays demonstrated that FXR/Fxr binds to this element and mediates HEX/Hex transcriptional activation. CONCLUSION: HEX/Hex is a novel bile acid-induced FXR/Fxr target gene during adaptation of hepatocytes to chronic bile acid exposure.
Assuntos
Ácido Quenodesoxicólico/efeitos adversos , Proteínas de Ligação a DNA/metabolismo , Hepatomegalia/induzido quimicamente , Hepatomegalia/metabolismo , Proteínas de Homeodomínio/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Linhagem Celular Tumoral , Ácido Quenodesoxicólico/farmacologia , Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Feminino , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Hepatomegalia/patologia , Proteínas de Homeodomínio/genética , Humanos , Hipertrofia/induzido quimicamente , Íntrons/genética , Íntrons/fisiologia , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Citoplasmáticos e Nucleares/genética , Fatores de Transcrição/genéticaRESUMO
OBJECTIVE: Most patients with hepatocellular carcinoma are diagnosed at intermediate or advanced stages (BCLC B or C) and undergo palliative local treatments such as transarterial chemoembolization or selective internal radiation therapy, also called radioembolization. In terms of liver function and tumor extent, stages BCLC B and C comprise a wide spectrum of tumor manifestations. Predictors of survival in these patients undergoing transarterial chemoembolization and selective internal radiation therapy might help stratification into different prognostic groups and help to select the optimal treatment modality. METHODS: In this retrospective study, all patients with hepatocellular carcinoma who underwent transarterial chemoembolization between January 2010 and December 2014 and all hepatocellular carcinoma patients who underwent selective internal radiation therapy between August 2012 and December 2016 were recruited. The prognostic value of pretherapeutic clinical and laboratory parameters for the prediction of overall survival was analyzed using uni- and multi-variable Cox regression models. RESULTS: We enrolled 129 patients in the transarterial chemoembolization group and 34 patients in the selective internal radiation therapy group. The predictive value of the albumin-bilirubin grade was validated for both the transarterial chemoembolization and the selective internal radiation therapy group. Multivariable analysis identified albumin-bilirubin grade and tumor size as independent predictors for the transarterial chemoembolization group and tumor size, serum albumin and serum sodium as independent predictors for the selective internal radiation therapy group. CONCLUSION: While measures of liver dysfunction predicted survival similarly in both cohorts, we found tumor size to predict survival differently in transarterial chemoembolization- and selective internal radiation therapy-treated patients. Tumor size might help to select the most appropriate treatment in hepatocellular carcinoma patients, although this finding has to be validated in further studies.