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Loss of hepatocyte nuclear factor 4α (HNF4α) expression is frequently observed in end-stage liver disease and associated with loss of vital liver functions, thus increasing mortality. Loss of HNF4α expression is mediated by inflammatory cytokines, such as transforming growth factor (TGF)-ß. However, details of how HNF4α is suppressed are largely unknown to date. Herein, TGF-ß did not directly inhibit HNF4α but contributed to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CREB-binding protein/p300 to the HNF4α promoter. The recruitment of CREB-binding protein/p300 is indispensable for CCAAT/enhancer-binding protein α (C/EBPα) binding, another essential requirement for constitutive HNF4α expression in hepatocytes. Consistent with the in vitro observation, 67 of 98 patients with hepatic HNF4α expressed both phospho-SMAD2 and C/EBPα, whereas 22 patients without HNF4α expression lacked either phospho-SMAD2 or C/EBPα. In contrast to the observed induction of HNF4α, SMAD2/3 inhibited C/EBPα transcription. Long-term TGF-ß incubation resulted in C/EBPα depletion, which abrogated HNF4α expression. Intriguingly, SMAD2/3 inhibitory binding to the C/EBPα promoter was abolished by insulin. Two-thirds of patients without C/EBPα lacked membrane glucose transporter type 2 expression in hepatocytes, indicating insulin resistance. Taken together, these data indicate that hepatic insulin sensitivity is essential for hepatic HNF4α expression in the condition of inflammation.
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Proteína de Unión a CREB , Insulina , Humanos , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Proteína de Unión a CREB/metabolismo , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Factor de Crecimiento Transformador beta/farmacología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
INTRODUCTION: WNT1-inducible signalling pathway protein 1 (WISP1) promotes progression of several tumor entities often correlating with worse prognosis. Here its expression regulation and role in the progression of chronic liver diseases (CLD) was investigated. METHODS: WISP1 expression was analyzed in human HCC datasets, in biopsies and serum samples and an HCC patient tissue microarray (TMA) including correlation to clinicopathological parameters. Spatial distribution of WISP1 expression was determined using RNAscope analysis. Regulation of WISP1 expression was investigated in cytokine-stimulated primary mouse hepatocytes (PMH) by array analysis and qRT-PCR. Outcome of WISP1 stimulation was analyzed by IncuCyte S3-live cell imaging, qRT-PCR, and immunoblotting in murine AML12 cells. RESULTS: In a TMA, high WISP1 expression was positively correlated with early HCC stages and male sex. Highest WISP1 expression levels were detected in patients with cirrhosis as compared to healthy individuals, patients with early fibrosis, and non-cirrhotic HCC in liver biopsies, expression datasets and serum samples. WISP1 transcripts were predominantly detected in hepatocytes of cirrhotic rather than tumorous liver tissue. High WISP1 expression was associated with better survival. In PMH, AML12 and HepaRG, WISP1 was identified as a specific TGF-ß1 target gene. Accordingly, expression levels of both cytokines positively correlated in human HCC patient samples. WISP1-stimulation induced the expression of Bcl-xL, PCNA and p21 in AML12 cells. CONCLUSIONS: WISP1 expression is induced by TGF-ß1 in hepatocytes and is associated with cirrhotic liver disease. We propose a crucial role of WISP1 in balancing pro- and anti-tumorigenic effects during premalignant stages of CLD.
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Transforming growth factor (TGF)-ß and toll-like receptors (TLRs) have been shown to independently modulate the proliferation of hepatocellular carcinoma (HCC). Since a direct cross-talk between these two signalling pathways in HCC has not been clearly described before, we aimed here to explore the possibility of such interaction. A human HCC tissue array (n = 20 vs. four control samples), human HCC samples (n = 10) and steatohepatitis-driven murine HCC samples (control, NASH and HCC; n = 6/group) were immunostained for TGFßR1, pSMAD2, TRAF6, IRAK1 and PCNA. The results were confirmed by immunoblotting. Effects of constant activation of the SMAD pathway by constitutive expression of ALK5 or knockdown of mediators of TLR signalling, IRAK1 and MyD88, on HCC proliferation, were investigated in the HCC cell line (HUH-7) after treatment with TGFß1 cytokine or TGFßR1 kinase inhibitor (LY2157299) using PCNA and MTS assay. TGFßR1 expression is decreased in human and murine HCC and associated with downregulated pSMAD2, but increased IRAK1, TRAF6 and PCNA staining. TGFßR1 kinase inhibition abolished the cytostatic effects of TGFß1 and led to the induction of IRAK1, pIRAK1 and elevated mRNA levels of TLR-9. Overexpression of ALK5 and knockdown of MyD88 or IRAK1 augmented the cytostatic effects of TGFß1 on HUH-7. In another epithelial HCC cell line, that is, HepG2, TGFßR1 kinase inhibitor similarly elevated cellular proliferation. There is a balance between the canonical SMAD-driven tumour-suppressing arm and the non-canonical tumour-promoting arm of TGFß signalling. Disruption of this balance, by inhibition of the canonical pathway, induces HCC proliferation through TLR signalling.
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Antineoplásicos , Carcinoma Hepatocelular , Citostáticos , Neoplasias Hepáticas , Animales , Humanos , Ratones , Carcinoma Hepatocelular/patología , Proliferación Celular , Neoplasias Hepáticas/patología , Factor 88 de Diferenciación Mieloide/genética , Factor 88 de Diferenciación Mieloide/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Receptores Toll-Like/metabolismo , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: Panel gene sequencing is an established diagnostic tool for precision oncology of solid tumors, but its utility for the treatment of cancers of the digestive system in clinical routine is less well documented. METHODS: We retrospectively identified patients with advanced or metastatic gastrointestinal, pancreaticobiliary or hepatic cancers who received panel gene sequencing at a tertiary university hospital from 2015 to 2022. For these cases, we determined the spectrum of genetic alterations, clinicopathological parameters and treatment courses. Assessment of actionability of genetic alterations was based on the OncoKB database, cancer-specific ESMO treatment guidelines, and recommendations of the local molecular tumor board. RESULTS: In total, 155 patients received panel gene sequencing using either the Oncomine Focus (62 cases), Comprehensive (91 cases) or Childhood Cancer Research Assay (2 cases). The mean age of patients was 61 years (range 24-90) and 37% were female. Most patients suffered from either colorectal cancer (53%) or cholangiocellular carcinoma (19%). 327 genetic alterations were discovered in 123 tumor samples, with an average number of 2.1 alterations per tumor. The most frequently altered genes were TP53, KRAS and PIK3CA. Actionable gene alterations were detected in 13.5-56.8% of tumors, according to ESMO guidelines or the OncoKB database, respectively. Thirteen patients were treated with targeted therapies based on identified molecular alterations, with a median progression-free survival of 8.8 months. CONCLUSIONS: Actionable genetic alterations are frequently detected by panel gene sequencing in patients with advanced cancers of the digestive tract, providing clinical benefit in selected cases. However, for the majority of identified actionable alterations, sufficient clinical evidence for targeted treatments is still lacking.
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Neoplasias del Sistema Digestivo , Humanos , Femenino , Masculino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Adulto Joven , Neoplasias del Sistema Digestivo/genética , Neoplasias del Sistema Digestivo/patología , Neoplasias del Sistema Digestivo/terapia , Mutación , Medicina de Precisión/métodos , Terapia Molecular Dirigida/métodos , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: Hepatocellular carcinoma (HCC) remains a significant global health burden with a high mortality rate. Over the past 40 years, significant progress has been achieved in the prevention and management of HCC. SUMMARY: Hepatitis B vaccination programs, the development of direct acting antiviral drugs for Hepatitis C, and effective surveillance strategies provide a profound basis for the prevention of HCC. Advanced surgery and liver transplantation along with local ablation techniques potentially offer cure for the disease. Also, just recently, the introduction of immunotherapy opened a new chapter in systemic treatment. Finally, the introduction of the BCLC classification system for HCC, clearly defining patient groups and assigning reasonable treatment options, has standardized treatment and become the basis of almost all clinical trials for HCC. With this review, we provide a comprehensive overview of the evolving landscape of HCC management and also touch on current challenges. KEY MESSAGE: A comprehensive and multidisciplinary approach is crucial for effective HCC management. Continued research and clinical trials are imperative to further enhance treatment options and will ultimately reduce the global burden of this devastating disease.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patología , Inmunoterapia/métodos , Antivirales/uso terapéuticoRESUMEN
INTRODUCTION: Postprocedural bleeding is a major adverse event after endoscopic resection of colorectal lesions, but the optimal surveillance time after endoscopy is unclear. In this study, we determined onset time and characteristics of postprocedural bleeding events. METHODS: We retrospectively screened patients who underwent endoscopic resection of colorectal lesions at three German hospitals between 2010 and 2019 for postprocedural bleeding events using billing codes. Only patients who required re-endoscopy were included for analysis. For identified patients, we collected demographic data, clinical courses, characteristics of colorectal lesions, and procedure-related variables. Factors associated with late-onset bleeding were determined by univariate and multivariate logistic regression analysis. RESULTS: From a total of 6,820 patients with eligible billing codes, we identified 113 cases with postprocedural bleeding after endoscopic mucosal (61.9%) or snare resection (38.1%) that required re-endoscopy. The median size of the culprit lesion was 20 mm (interquartile range 14-30 mm). The median onset time of postprocedural bleeding was day 3 (interquartile range: 1-6.5 days), with 48.7% of events occurring within 48 h. Multivariate logistic regression analysis demonstrates that a continued intake of antiplatelet drugs (OR: 3.98, 95% CI: 0.89-10.12, p = 0.025) and a flat morphology of the colorectal lesion (OR: 2.98, 95% CI: 1.08-8.01, p = 0.031) were associated with an increased risk for late postprocedural bleeding (>48 h), whereas intraprocedural bleeding was associated with a decreased risk (OR: 0.12, 95% CI: 0.04-0.50, p = 0.001). CONCLUSION: Significant postprocedural bleeding can occur up to 18 days after endoscopic resection of colorectal lesions, but was predominantly observed within 48 h. Continued intake of antiplatelet drugs and a flat polyp morphology are associated with risk for late postprocedural bleeding.
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Pólipos del Colon , Neoplasias Colorrectales , Humanos , Estudios Retrospectivos , Inhibidores de Agregación Plaquetaria , Hemorragia , Pólipos del Colon/patología , Endoscopía Gastrointestinal , Neoplasias Colorrectales/cirugía , Neoplasias Colorrectales/patología , ColonoscopíaRESUMEN
INTRODUCTION AND OBJECTIVES: Autoimmune liver diseases (AILDs) are rare and require precise evaluation, which is often challenging for medical providers. Chatbots are innovative solutions to assist healthcare professionals in clinical management. In our study, ten liver specialists systematically evaluated four chatbots to determine their utility as clinical decision support tools in the field of AILDs. MATERIALS AND METHODS: We constructed a 56-question questionnaire focusing on AILD evaluation, diagnosis, and management of Autoimmune Hepatitis (AIH), Primary Biliary Cholangitis (PBC), and Primary Sclerosing Cholangitis (PSC). Four chatbots -ChatGPT 3.5, Claude, Microsoft Copilot, and Google Bard- were presented with the questions in their free tiers in December 2023. Responses underwent critical evaluation by ten liver specialists using a standardized 1 to 10 Likert scale. The analysis included mean scores, the number of highest-rated replies, and the identification of common shortcomings in chatbots performance. RESULTS: Among the assessed chatbots, specialists rated Claude highest with a mean score of 7.37 (SDâ¯=â¯1.91), followed by ChatGPT (7.17, SDâ¯=â¯1.89), Microsoft Copilot (6.63, SDâ¯=â¯2.10), and Google Bard (6.52, SDâ¯=â¯2.27). Claude also excelled with 27 best-rated replies, outperforming ChatGPT (20), while Microsoft Copilot and Google Bard lagged with only 6 and 9, respectively. Common deficiencies included listing details over specific advice, limited dosing options, inaccuracies for pregnant patients, insufficient recent data, over-reliance on CT and MRI imaging, and inadequate discussion regarding off-label use and fibrates in PBC treatment. Notably, internet access for Microsoft Copilot and Google Bard did not enhance precision compared to pre-trained models. CONCLUSIONS: Chatbots hold promise in AILD support, but our study underscores key areas for improvement. Refinement is needed in providing specific advice, accuracy, and focused up-to-date information. Addressing these shortcomings is essential for enhancing the utility of chatbots in AILD management, guiding future development, and ensuring their effectiveness as clinical decision-support tools.
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Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the third leading cause of cancer-associated deaths worldwide. Most cases arise in patients with cirrhosis, and early detection through periodic screening can make it potentially curable. The presence of extrahepatic metastases (EHM) affects treatment decisions and curability. The lungs are the most common site for EHM, followed by lymph nodes, bones, and the adrenal glands. Interestingly, approximately only 15 cases of HCC metastasizing to the pituitary gland have been reported so far.The most common symptoms of pituitary metastasis (PM) arising from HCC are nerve palsies affecting the third, fourth, and sixth cranial nerves. Other symptoms, such as diabetes insipidus or pituitary insufficiencies, are present in a minority of cases. Detecting PM is difficult given its rarity. Gold-standard treatments for these patients have not yet been established, but the prognosis is dismal, with a median overall survival of only 4.5 months. In this paper, we present an interesting case of PM as the first symptom of an HCC in a 75-year-old female. We also present an overview of all cases reported to date with emphasis on symptom presentation and survival after diagnosis.Given the improvement of systemic therapy, more cases are diagnosed in both oligometastatic and palliative conditions. Therefore, better approaches and treatment modalities for extrahepatic metastases due to HCC should be defined.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Neoplasias Hipofisarias , Humanos , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/secundario , Carcinoma Hepatocelular/patología , Femenino , Anciano , Neoplasias Hipofisarias/secundario , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapia , Neoplasias Hipofisarias/diagnóstico , Diagnóstico Diferencial , Resultado del TratamientoRESUMEN
OBJECTIVE: Multidrug resistance protein 2 (MRP2) is a bottleneck in bilirubin excretion. Its loss is sufficient to induce hyperbilirubinaemia, a prevailing characteristic of acute liver failure (ALF) that is closely associated with clinical outcome. This study scrutinises the transcriptional regulation of MRP2 under different pathophysiological conditions. DESIGN: Hepatic MRP2, farnesoid X receptor (FXR) and Forkhead box A2 (FOXA2) expression and clinicopathologic associations were examined by immunohistochemistry in 14 patients with cirrhosis and 22 patients with ALF. MRP2 regulatory mechanisms were investigated in primary hepatocytes, Fxr -/- mice and lipopolysaccharide (LPS)-treated mice. RESULTS: Physiologically, homeostatic MRP2 transcription is mediated by the nuclear receptor FXR/retinoid X receptor complex. Fxr-/- mice lack apical MRP2 expression and rapidly progress into hyperbilirubinaemia. In patients with ALF, hepatic FXR expression is undetectable, however, patients without infection maintain apical MRP2 expression and do not suffer from hyperbilirubinaemia. These patients express FOXA2 in hepatocytes. FOXA2 upregulates MRP2 transcription through binding to its promoter. Physiologically, nuclear FOXA2 translocation is inhibited by insulin. In ALF, high levels of glucagon and tumour necrosis factor α induce FOXA2 expression and nuclear translocation in hepatocytes. Impressively, ALF patients with sepsis express low levels of FOXA2, lose MRP2 expression and develop severe hyperbilirubinaemia. In this case, LPS inhibits FXR expression, induces FOXA2 nuclear exclusion and thus abrogates the compensatory MRP2 upregulation. In both Fxr -/- and LPS-treated mice, ectopic FOXA2 expression restored apical MRP2 expression and normalised serum bilirubin levels. CONCLUSION: FOXA2 replaces FXR to maintain MRP2 expression in ALF without sepsis. Ectopic FOXA2 expression to maintain MRP2 represents a potential strategy to prevent hyperbilirubinaemia in septic ALF.
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Factor Nuclear 3-beta del Hepatocito , Fallo Hepático Agudo , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos , Animales , Ratones , Bilirrubina , Factor Nuclear 3-beta del Hepatocito/metabolismo , Hepatocitos/metabolismo , Hiperbilirrubinemia/metabolismo , Hiperbilirrubinemia/patología , Lipopolisacáridos/metabolismo , Hígado/metabolismo , Fallo Hepático Agudo/metabolismo , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos/metabolismo , Miembro 4 de la Subfamilia B de Casete de Unión a ATPRESUMEN
BACKGROUND AND AIMS: It remains unknown how patients with liver failure maintain essential albumin levels. Here, we delineate a hierarchical transcription regulatory network that ensures albumin expression under different disease conditions. APPROACH AND RESULTS: We examined albumin levels in liver tissues and serum in 157 patients, including 84 with HCC, 38 decompensated cirrhosis, and 35 acute liver failure. Even in patients with liver failure, the average serum albumin concentrations were 30.55 g/L. In healthy subjects and patients with chronic liver diseases, albumin was expressed in hepatocytes. In patients with massive hepatocyte loss, albumin was expressed in liver progenitor cells (LPCs). The albumin gene (ALB) core promoter possesses a TATA box and nucleosome-free area, which allows constitutive RNA polymerase II binding and transcription initiation. Chromatin immunoprecipitation assays revealed that hepatocyte nuclear factor 4 alpha (HNF4α), CCAAT/enhancer-binding protein alpha (C/EBPα), and forkhead box A2 (FOXA2) bound to the ALB enhancer. Knockdown of either of these factors reduced albumin expression in hepatocytes. FOXA2 acts as a pioneer factor to support HNF4α and C/EBPα. In hepatocytes lacking HNF4α and C/EBPα expression, FOXA2 synergized with retinoic acid receptor (RAR) to maintain albumin transcription. RAR nuclear translocation was induced by retinoic acids released by activated HSCs. In patients with massive hepatocyte loss, LPCs expressed HNF4α and FOXA2. RNA sequencing and quantitative PCR analyses revealed that lack of HNF4α and C/EBPα in hepatocytes increased hedgehog ligand biosynthesis. Hedgehog up-regulates FOXA2 expression through glioblastoma family zinc finger 2 binding to the FOXA2 promoter in both hepatocytes and LPCs. CONCLUSIONS: A hierarchical regulatory network formed by master and pioneer transcription factors ensures essential albumin expression in various pathophysiological conditions.
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Carcinoma Hepatocelular , Fallo Hepático , Neoplasias Hepáticas , Humanos , Animales , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Erizos/metabolismo , Neoplasias Hepáticas/metabolismo , Factor Nuclear 4 del Hepatocito/genética , Factor Nuclear 4 del Hepatocito/metabolismo , Hepatocitos/metabolismo , Hígado/metabolismo , Proteína alfa Potenciadora de Unión a CCAAT/metabolismo , Albúminas , Fallo Hepático/metabolismoRESUMEN
BACKGROUND AND AIMS: In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. APPROACH AND RESULTS: Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-ß superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. CONCLUSIONS: These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.
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Activinas/genética , Folistatina/metabolismo , Factor Nuclear 4 del Hepatocito/metabolismo , Fallo Hepático Agudo/metabolismo , Activinas/metabolismo , Insuficiencia Hepática Crónica Agudizada/sangre , Adulto , Anciano , Animales , Coagulación Sanguínea , Línea Celular , Factor V/genética , Femenino , Folistatina/sangre , Estudios de Seguimiento , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Factor Nuclear 4 del Hepatocito/genética , Hepatocitos/metabolismo , Humanos , Fallo Hepático Agudo/inducido químicamente , Fallo Hepático Agudo/patología , Fallo Hepático Agudo/cirugía , Regeneración Hepática , Trasplante de Hígado , Masculino , Metronidazol , Ratones , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas , Estudios Prospectivos , Protrombina/genética , Transducción de Señal , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína smad3/genética , Proteína smad3/metabolismo , Proteína Smad4/genética , Células Madre/metabolismo , Factor de Crecimiento Transformador beta1/genética , Pez CebraRESUMEN
BACKGROUND: Complications in chronic pancreatitis (CP) can be grouped in inflammatory (ICC) and fibrotic (FCC) clusters and pancreatic insufficiency cluster (PIC). However, the association between etiological risk factors and the development of complication clusters remains obscure. In this study, the impact of the etiology and disease duration on disease onset and development of complications was investigated. METHODS: This cross-sectional study recruited patients with CP from Mannheim/Germany (n = 870), Gießen/Germany (n = 100) und Donetsk/Ukraine (n = 104). Etiological risk factors, disease stage, age at disease onset, complications, need for hospitalization and surgery were noted. RESULTS: In 1074 patients diagnosed with CP, main risk factors were alcohol and nicotine abuse. An earlier onset of the disease was observed upon nicotine abuse (-4.0 years). Alcohol abuse was only associated with an earlier onset of the definite stage of CP. Alcohol abuse was the major risk factor for the development of ICC (p < 0.0001, multiple regression modeling). Abstinence of alcohol reduced ICC, whereas abstinence of nicotine showed no association. PIC correlated with efferent duct abnormalities and the disease duration. In contrast, FCC was mainly dependent on the disease duration (p < 0.0001; t-test). The presence of any complication cluster correlated with the need for surgery (p < 0.01; X2-test). However, only ICC correlated with a prolonged hospital stay (p < 0.05; t-test). CONCLUSIONS: ICC is mainly dependent on alcohol abuse. In contrast, FCC and PIC are mainly dependent on the disease duration. The etiology and disease duration can be used as predictors of the course of disease to provide individual treatment and surveillance strategies.
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Alcoholismo , Insuficiencia Pancreática Exocrina , Pancreatitis Crónica , Humanos , Alcoholismo/complicaciones , Nicotina , Estudios Transversales , Pancreatitis Crónica/complicaciones , Pancreatitis Crónica/diagnóstico , Factores de Riesgo , Insuficiencia Pancreática Exocrina/etiologíaRESUMEN
GOAL: The aim of this study was to investigate the network of biopsychosocial factors and quality of life (QoL) in persons with inflammatory bowel diseases (IBDs) and explore the influence of psychological factors on the course of the disease. BACKGROUND: QoL of persons with IBD depends on disease activity but also on numerous interacting psychosocial factors. The influence of psychosocial factors on the disease course in controversially discussed. MATERIALS AND METHODS: In 2 independent IBD samples (sample 1: n=209, anonymous internet survey; sample 2: n=84, outpatients with active disease), we measured QoL, anxiety, depression, illness identity, self-esteem, loneliness, childhood trauma, and visceral sensitivity with questionnaires. In addition, fatigue, hemoglobin levels, and response to therapy were assessed in sample 2. We estimated multiple regularized partial correlation networks and conducted accuracy and stability tests of the networks. RESULTS: In both samples, QoL had the strongest relationships with visceral sensitivity and the illness identity engulfment. Depression was the most central factor in the networks. Baseline depression scores, visceral sensitivity, and engulfment were associated with response to therapy in sample 2. CONCLUSIONS: This first network study to assess the interplay between biopsychosocial factors and QoL in IBD reveals a comparable network structure in 2 samples. Results partly replicate findings from previous studies with regard to the importance of depression and yield information on the central role of the newly introduced concepts of illness identity and visceral sensitivity. Preliminary findings point to an influence of these parameters on the disease course, which indicates their role as a possible target in individualized therapy.
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Enfermedades Inflamatorias del Intestino , Calidad de Vida , Humanos , Calidad de Vida/psicología , Enfermedades Inflamatorias del Intestino/complicaciones , Ansiedad/psicología , Encuestas y Cuestionarios , Fatiga , DepresiónRESUMEN
OBJECTIVES OF THE ARTICLE: Liver cirrhosis is the end-stage liver disease associated with poor prognosis and cardiovascular comorbidity could significantly impact mortality of cirrhotic patients. We conducted a large, retrospective study to investigate the survival impact of cardiovascular co-medications in patients with liver cirrhosis. MATERIALS AND METHODS: A study-specific R package was processed on the local databases of partner institutions within the Observational Health Data Sciences and Informatics consortium, namely Columbia University, New York City (NYC), USA and Ajou University School of Medicine (AUSOM), South Korea. Patients with cirrhosis diagnosed between 2000 and 2020 were included. Final analysis of the anonymous survival data was performed at Medical Faculty Mannheim, Heidelberg University. RESULTS: We investigated a total of 32,366 patients with liver cirrhosis. Our data showed that administration of antiarrhythmics amiodarone or digoxin presented as a negative prognostic indicator (p = 0.000 in both cohorts). Improved survival was associated with angiotensin-converting enzyme inhibitor ramipril (p = 0.005 in NYC cohort, p = 0.075 in AUSOM cohort) and angiotensin II receptor blocker losartan (p = 0.000 in NYC cohort, p = 0.005 in AUSOM cohort). Non-selective beta blocker carvedilol was associated with a survival advantage in the NYC (p = 0.000) cohort but not in the AUSOM cohort (p = 0.142). Patients who took platelet inhibitor clopidogrel had a prolonged overall survival compared to those without (p = 0.000 in NYC cohort, p = 0.003 in AUSOM cohort). CONCLUSION: Concomitant cardiovascular medications are associated with distinct survival difference in cirrhotic patients. Multidisciplinary management is needed for a judicious choice of proper cardiovascular co-medications in cirrhotic patients.
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Cirrosis Hepática , Losartán , Humanos , Estudios Retrospectivos , Cirrosis Hepática/complicaciones , Comorbilidad , CarvedilolRESUMEN
BACKGROUND: Alcoholic liver disease (ALD) is still increasing and leads to acute liver injury but also liver cirrhosis and subsequent complications such as liver failure or hepatocellular carcinoma (HCC). As most patients fail to achieve alcohol abstinence, it is essential to identify alternative treatment options in order to improve the outcome of ALD patients. METHODS: Evaluating two large cohorts of patients with ALD from the USA and Korea with a total of 12,006 patients, we investigated the effect on survival of aspirin, metformin, metoprolol, dopamine, and dobutamine drugs in patients with ALD between 2000 and 2020. Patient data were obtained through the "The Observational Health Data Sciences and Informatics consortium," an open-source, multi-stakeholder, and interdisciplinary collaborative effort. RESULTS: The use of aspirin (p = 0.000, p = 0.000), metoprolol (p = 0.002, p = 0.000), and metformin (p = 0.000, p = 0.000) confers a survival benefit for both AUSOM- and NY-treated cohorts. Need of catecholamines dobutamine (p = 0.000, p = 0.000) and dopamine (p = 0.000, p = 0.000) was strongly indicative of poor survival. ß-Blocker treatment with metoprolol (p = 0.128, p = 0.196) or carvedilol (p = 0.520, p = 0.679) was not shown to be protective in any of the female subgroups. CONCLUSION: Overall, our data fill a large gap in long-term, real-world data on patients with ALD, confirming an impact of metformin, acetylsalicylic acid, and ß-blockers on ALD patient's survival. However, gender and ethnic background lead to diverse efficacy in those patients.
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Carcinoma Hepatocelular , Hepatopatías Alcohólicas , Neoplasias Hepáticas , Humanos , Femenino , Carcinoma Hepatocelular/complicaciones , Metoprolol , Dobutamina , Dopamina , Neoplasias Hepáticas/complicaciones , Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/tratamiento farmacológicoRESUMEN
INTRODUCTION: The Laurén classification is widely used for Gastric Cancer (GC) histology subtyping. However, this classification is prone to interobserver variability and its prognostic value remains controversial. Deep Learning (DL)-based assessment of hematoxylin and eosin (H&E) stained slides is a potentially useful tool to provide an additional layer of clinically relevant information, but has not been systematically assessed in GC. OBJECTIVE: We aimed to train, test and externally validate a deep learning-based classifier for GC histology subtyping using routine H&E stained tissue sections from gastric adenocarcinomas and to assess its potential prognostic utility. METHODS: We trained a binary classifier on intestinal and diffuse type GC whole slide images for a subset of the TCGA cohort (N = 166) using attention-based multiple instance learning. The ground truth of 166 GC was obtained by two expert pathologists. We deployed the model on two external GC patient cohorts, one from Europe (N = 322) and one from Japan (N = 243). We assessed classification performance using the Area Under the Receiver Operating Characteristic Curve (AUROC) and prognostic value (overall, cancer specific and disease free survival) of the DL-based classifier with uni- and multivariate Cox proportional hazard models and Kaplan-Meier curves with log-rank test statistics. RESULTS: Internal validation using the TCGA GC cohort using five-fold cross-validation achieved a mean AUROC of 0.93 ± 0.07. External validation showed that the DL-based classifier can better stratify GC patients' 5-year survival compared to pathologist-based Laurén classification for all survival endpoints, despite frequently divergent model-pathologist classifications. Univariate overall survival Hazard Ratios (HRs) of pathologist-based Laurén classification (diffuse type versus intestinal type) were 1.14 (95% Confidence Interval (CI) 0.66-1.44, p-value = 0.51) and 1.23 (95% CI 0.96-1.43, p-value = 0.09) in the Japanese and European cohorts, respectively. DL-based histology classification resulted in HR of 1.46 (95% CI 1.18-1.65, p-value < 0.005) and 1.41 (95% CI 1.20-1.57, p-value < 0.005), in the Japanese and European cohorts, respectively. In diffuse type GC (as defined by the pathologist), classifying patients using the DL diffuse and intestinal classifications provided a superior survival stratification, and demonstrated statistically significant survival stratification when combined with pathologist classification for both the Asian (overall survival log-rank test p-value < 0.005, HR 1.43 (95% CI 1.05-1.66, p-value = 0.03) and European cohorts (overall survival log-rank test p-value < 0.005, HR 1.56 (95% CI 1.16-1.76, p-value < 0.005)). CONCLUSION: Our study shows that gastric adenocarcinoma subtyping using pathologist's Laurén classification as ground truth can be performed using current state of the art DL techniques. Patient survival stratification seems to be better by DL-based histology typing compared with expert pathologist histology typing. DL-based GC histology typing has potential as an aid in subtyping. Further investigations are warranted to fully understand the underlying biological mechanisms for the improved survival stratification despite apparent imperfect classification by the DL algorithm.
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Adenocarcinoma , Aprendizaje Profundo , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Estudios Retrospectivos , Pronóstico , Modelos de Riesgos Proporcionales , Adenocarcinoma/patologíaRESUMEN
BACKGROUND: Health-related quality of life (hrQoL) may be the most important patient-reported outcome for patients with chronic disorders. The Short Health Scale (SHS) is a brief four-item instrument to assess hrQoL in patients with bowel disorders. This study examined the validity, reliability and sensitivity of the German translation of the SHS in a cohort of outpatients with inflammatory bowel diseases (IBD). METHODS: The study was preregistered in April 2021 (https://doi.org/10.17605/OSF.IO/S82D9). Outpatients with IBD (n=225) in different stages of disease activity (as determined by the Harvey-Bradshaw index or partial Mayo score) completed the German SHS and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) as an established measure of hrQoL to examine the convergent validity. To assess reliability, a subset of patients (n=30) in remission completed the same questionnaires after 4-8 weeks. Sensitivity to change was established from questionnaires of patients with either decreased (n=15) or increased (n=16) disease activity after 3-6 months. RESULTS: The internal consistency of the German SHS was high (Cronbach's α=0.860). SHS total scores correlated strongly with sIBDQ scores (ρ=-0.760, p<0.001) and disease activity (ρ=0.590, p<0.001). Retest reliability was high (ρ=0.695, p<0.001). Sensitivity to change was statistically significant for patients with decreased (p=0.013) but not increased (p=0.134) disease activity. CONCLUSION: The German version of the SHS is a valid and reliable tool to measure hrQoL in persons with IBD.
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Enfermedades Inflamatorias del Intestino , Calidad de Vida , Humanos , Reproducibilidad de los Resultados , Enfermedades Inflamatorias del Intestino/diagnóstico , Encuestas y CuestionariosRESUMEN
Colorectal cancer (CRC) is a high-incidence malignancy worldwide which still needs better therapy options. Therefore, the aim of the present study was to investigate the responses of normal or malignant human intestinal epithelium to bone morphogenetic protein (BMP)-9 and to find out whether the application of BMP-9 to patients with CRC or the enhancement of its synthesis in the liver could be useful strategies for new therapy approaches. In silico analyses of CRC patient cohorts (TCGA database) revealed that high expression of the BMP-target gene ID1, especially in combination with low expression of the BMP-inhibitor noggin, is significantly associated with better patient survival. Organoid lines were generated from human biopsies of colon cancer (T-Orgs) and corresponding non-malignant areas (N-Orgs) of three patients. The N-Orgs represented tumours belonging to three different consensus molecular subtypes (CMS) of CRC. Overall, BMP-9 stimulation of organoids promoted an enrichment of tumour-suppressive gene expression signatures, whereas the stimulation with noggin had the opposite effects. Furthermore, treatment of organoids with BMP-9 induced ID1 expression (independently of high noggin levels), while treatment with noggin reduced ID1. In summary, our data identify the ratio between ID1 and noggin as a new prognostic value for CRC patient outcome. We further show that by inducing ID1, BMP-9 enhances this ratio, even in the presence of noggin. Thus, BMP-9 is identified as a novel target for the development of improved anti-cancer therapies of patients with CRC.
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Neoplasias del Colon , Neoplasias Colorrectales , Factor 2 de Diferenciación de Crecimiento , Proteína Morfogenética Ósea 2 , Proteína Morfogenética Ósea 4/farmacología , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Neoplasias Colorrectales/genética , Factor 2 de Diferenciación de Crecimiento/genética , Humanos , Proteína 1 Inhibidora de la Diferenciación , Hígado/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: At the entry site of respiratory virus infections, the oropharyngeal microbiome has been proposed as a major hub integrating viral and host immune signals. Early studies suggested that infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with changes of the upper and lower airway microbiome, and that specific microbial signatures may predict coronavirus disease 2019 (COVID-19) illness. However, the results are not conclusive, as critical illness can drastically alter a patient's microbiome through multiple confounders. METHODS: To study oropharyngeal microbiome profiles in SARS-CoV-2 infection, clinical confounders, and prediction models in COVID-19, we performed a multicenter, cross-sectional clinical study analyzing oropharyngeal microbial metagenomes in healthy adults, patients with non-SARS-CoV-2 infections, or with mild, moderate, and severe COVID-19 (n = 322 participants). RESULTS: In contrast to mild infections, patients admitted to a hospital with moderate or severe COVID-19 showed dysbiotic microbial configurations, which were significantly pronounced in patients treated with broad-spectrum antibiotics, receiving invasive mechanical ventilation, or when sampling was performed during prolonged hospitalization. In contrast, specimens collected early after admission allowed us to segregate microbiome features predictive of hospital COVID-19 mortality utilizing machine learning models. Taxonomic signatures were found to perform better than models utilizing clinical variables with Neisseria and Haemophilus species abundances as most important features. CONCLUSIONS: In addition to the infection per se, several factors shape the oropharyngeal microbiome of severely affected COVID-19 patients and deserve consideration in the interpretation of the role of the microbiome in severe COVID-19. Nevertheless, we were able to extract microbial features that can help to predict clinical outcomes.
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COVID-19 , Microbiota , Adulto , Enfermedad Crítica , Estudios Transversales , Disbiosis , Haemophilus , Humanos , Neisseria , SARS-CoV-2RESUMEN
Epigenetic dysregulation is an important feature of colorectal cancer (CRC). Combining epigenetic drugs with other antineoplastic agents is a promising treatment strategy for advanced cancers. Here, we exploited the concept of synthetic lethality to identify epigenetic targets that act synergistically with histone deacetylase (HDAC) inhibitors to reduce the growth of CRC. We applied a pooled CRISPR-Cas9 screen using a custom sgRNA library directed against 614 epigenetic regulators and discovered that knockout of the euchromatic histone-lysine N-methyltransferases 1 and 2 (EHMT1/2) strongly enhanced the antiproliferative effect of clinically used HDAC inhibitors. Using tissue microarrays from 1066 CRC samples with different tumor stages, we showed that low EHMT2 protein expression is predominantly found in advanced CRC and associated with poor clinical outcome. Cotargeting of HDAC and EHMT1/2 with specific small molecule inhibitors synergistically reduced proliferation of CRC cell lines. Mechanistically, we used a high-throughput Western blot assay to demonstrate that both inhibitors elicited distinct cellular mechanisms to reduce tumor growth, including cell cycle arrest and modulation of autophagy. On the epigenetic level, the compounds increased H3K9 acetylation and reduced H3K9 dimethylation. Finally, we used a panel of patient-derived CRC organoids to show that HDAC and EHMT1/2 inhibition synergistically reduced tumor viability in advanced models of CRC.