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Hepatic lipid deposition and inflammation represent risk factors for hepatocellular carcinoma (HCC). The mRNA-binding protein tristetraprolin (TTP, gene name ZFP36) has been suggested as a tumor suppressor in several malignancies, but it increases insulin resistance. The aim of this study was to elucidate the role of TTP in hepatocarcinogenesis and HCC progression. Employing liver-specific TTP-knockout (lsTtp-KO) mice in the diethylnitrosamine (DEN) hepatocarcinogenesis model, we observed a significantly reduced tumor burden compared to wild-type animals. Upon short-term DEN treatment, modelling early inflammatory processes in hepatocarcinogenesis, lsTtp-KO mice exhibited a reduced monocyte/macrophage ratio as compared to wild-type mice. While short-term DEN strongly induced an abundance of saturated and poly-unsaturated hepatic fatty acids, lsTtp-KO mice did not show these changes. These findings suggested anti-carcinogenic actions of TTP deletion due to effects on inflammation and metabolism. Interestingly, though, investigating effects of TTP on different hallmarks of cancer suggested tumor-suppressing actions: TTP inhibited proliferation, attenuated migration, and slightly increased chemosensitivity. In line with a tumor-suppressing activity, we observed a reduced expression of several oncogenes in TTP-overexpressing cells. Accordingly, ZFP36 expression was downregulated in tumor tissues in three large human data sets. Taken together, this study suggests that hepatocytic TTP promotes hepatocarcinogenesis, while it shows tumor-suppressive actions during hepatic tumor progression.
COPA syndrome is a newly discovered hereditary immunodeficiency affecting the lung, kidneys, and joints. The mutated gene encodes the α subunit of the coatomer complex I, a protein transporter from the Golgi back to the endoplasmic reticulum. The impaired return of proteins leads to intracellular stress. The syndrome is an autoimmune and autoinflammatory disease that can be grouped among the interferonopathies. The knowledge about COPA syndrome and its treatment is still limited. In this paper, we describe an additional patient, a 15-year-old girl with rheumatoid factor-positive polyarthritis and rheumatoid nodules since the age of 2, who developed interstitial lung disease. The detected mutation c.698G>A was causing the disease. The patient presented with symmetric polyarthritis on wrists, fingers, and hip and ankle joints, with significant functional impairment, and high disease activity. Laboratory parameters demonstrated chronic inflammation, hypergammaglobulinemia, high titre ANA (antinuclear antibodies) and CCP (anti-citrullinated protein) antibodies, and rheumatoid factors. Therapies with various DMARDs (Disease Modifying Anti-Rheumatic Drugs) and biologicals failed. Upon baricitinib application, the clinical activity decreased dramatically with disappearance of joint pain and morning stiffness and significant decrease of joint swelling. A low disease activity was reached after 12 months, with complete disappearance of rheumatoid nodules. In contrast to IL-1 (interleukin-1), IL-6, and TNF (tumor necrosis factor) inhibitors, baricitinib was very successful, probably because baricitinib acts as a JAK-1/2 (janus kinase-1/2) inhibitor in the IFNα/β (inteferone α/β) pathway. A relatively higher dose in children is necessary. COPA syndrome represents a novel disorder of intracellular transport. Reviewing published literature on COPA syndrome, in addition to our patient, there were 31 cases further described.
Up to 50% of patients initially treated for prostate cancer in a curative intent experience biochemical recurrence, possibly requiring adjuvant treatment. However, salvage treatment decisions, such as lymph node dissection or radiation therapy, are typically based on prostate specific antigen (PSA) recurrence. Importantly, common imaging modalities (e.g., computed tomography [CT], magnetic resonance imaging, and bone scan) are limited and the detection of recurrent disease is particularly challenging if PSA is low. Prostate specific membrane antigen (PSMA) positron-emission tomography/computed tomography (PET/CT) is a novel and promising imaging modality which aims to overcome the incapability of early identification of distant and regional metastases. Within this review, we summarize the current evidence related to PSMA-PET/CT in prostate cancer men diagnosed with biochemical recurrence after local treatment with curative intent. We discuss detection rates of PSMA-PET/CT stratified by PSA-levels and its impact on clinical decision making. Furthermore, we compare different imagefusion techniques such as PSMA-PET vs. F-/C-Choline-PET scans vs. PSMA-single photon emission computed tomography/CT. Finally, we touch upon the contemporary role of radio-guided-PSMA salvage lymphadenectomy.
The multifaceted p21 (Cip1/Waf1/CDKN1A) in cell differentiation, migration and cancer therapy
(2019)
Loss of cell cycle control is characteristic of tumorigenesis. The protein p21 is the founding member of cyclin-dependent kinase inhibitors and an important versatile cell cycle protein. p21 is transcriptionally controlled by p53 and p53-independent pathways. Its expression is increased in response to various intra- and extracellular stimuli to arrest the cell cycle ensuring genomic stability. Apart from its roles in cell cycle regulation including mitosis, p21 is involved in differentiation, cell migration, cytoskeletal dynamics, apoptosis, transcription, DNA repair, reprogramming of induced pluripotent stem cells, autophagy and the onset of senescence. p21 acts either as a tumor suppressor or as an oncogene depending largely on the cellular context, its subcellular localization and posttranslational modifications. In the present review, we briefly mention the general functions of p21 and summarize its roles in differentiation, migration and invasion in detail. Finally, regarding its dual role as tumor suppressor and oncogene, we highlight the potential, difficulties and risks of using p21 as a biomarker as well as a therapeutic target.
Function of p21 (Cip1/Waf1/CDKN1A) in migration and invasion of cancer and trophoblastic cells
(2019)
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and perinatal mortality and morbidity. Like in tumor cells, most pathways, in which p21 is involved, are deregulated in trophoblasts of preeclamptic placentas. The aim of the present study was to enlighten p21’s role in tumorigenic choriocarcinoma and trophoblastic cell lines. We show that knockdown of p21 induces defects in chromosome movement during mitosis, though hardly affecting proliferation and cell cycle distribution. Moreover, suppression of p21 compromises the migration and invasion capability of various trophoblastic and cancer cell lines mediated by, at least partially, a reduction of the extracellular signal-regulated kinase 3, identified using transcriptome-wide profiling, real-time PCR, and Western blot. Further analyses show that downregulation of p21 is associated with reduced matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2. This work evinces that p21 is involved in chromosome movement during mitosis as well as in the motility and invasion capacity of trophoblastic and cancer cell lines.
Purpose: To evaluate the prevalence of peri‐implantitis (PI) and peri‐implant mucositis (PM) in a long‐term follow‐up with comparison among different PI and PM definitions, and to report on the incidence of PI.
Materials and Methods: In a retrospective clinical study five different PI and PM definitions were applied onto a population with 274 implants 17 to 23 years postimplant placement. Recommendations by the Eighth European Workshop on Periodontology (EWOP) were used as base reference. Clinical and radiological measurements were considered. Risk factors were evaluated in a regression analysis.
Results: After an average observation period of 18.9 years, 40.1% of the implants were diagnosed with PM and 15.0% with PI (Eighth EWOP). PI incidence reached 7.9% on implant level and 13.2% on patient level. Implants diagnosed with PI and progressive bone loss displayed exceptionally vertical bone defect configuration (BDC). Diabetes mellitus, smoking, regular maintenance, or a former periodontal infection did not show significant influence on the prevalence of peri‐implant diseases. Patients with bruxism displayed significantly less PM and PI.
Conclusions: Vertical BDC seems to correspond with active PI, wherefore we estimate such a defining factor of importance. Diagnosis of PM and evaluation of probing pocket depths might be only of descriptive interest as they could lead to false‐positive results.
Background: Chronic hepatitis C is a major public health burden. With new interferon-free direct-acting agents (showing sustained viral response rates of more than 98%), elimination of HCV seems feasible for the first time. However, as HCV infection often remains undiagnosed, screening is crucial for improving health outcomes of HCV-patients. Our aim was to assess the long-term cost-effectiveness of a nationwide screening strategy in Germany.
Methods: We used a Markov cohort model to simulate disease progression and examine long-term population outcomes, HCV associated costs and cost-effectiveness of HCV screening. The model divides the total population into three subpopulations: general population (GEP), people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM), with total infection numbers being highest in GEP, but new infections occurring only in PWIDs and MSM. The model compares four alternative screening strategies (no/basic/advanced/total screening) differing in participation and treatment rates.
Results: Total number of HCV-infected patients declined from 275,000 in 2015 to between 125,000 (no screening) and 14,000 (total screening) in 2040. Similarly, lost quality adjusted life years (QALYs) were 320,000 QALYs lower, while costs were 2.4 billion EUR higher in total screening compared to no screening. While incremental cost-effectiveness ratio (ICER) increased sharply in GEP and MSM with more comprehensive strategies (30,000 EUR per QALY for total vs. advanced screening), ICER decreased in PWIDs (30 EUR per QALY for total vs. advanced screening).
Conclusions: Screening is key to have an efficient decline of the HCV-infected population in Germany. Recommendation for an overall population screening is to screen the total PWID subpopulation, and to apply less comprehensive advanced screening for MSM and GEP.
A case of Lymphangioleiomyomatosis (LAM) of the lung in a patient with a history of breast cancer
(2019)
Background: Lymphangioleiomyomatosis (LAM) is a rare progressive cystic and nodular disease of the lung characterized by smooth muscle cell proliferation. LAM predominantly affects young premenopausal women. This report is of a case of LAM presenting in a 47-year-old woman with a past history of breast cancer and discusses the possibility of an association between the two conditions.
Case report: A 47-year-old woman presented as an emergency with an exacerbation of a four-month history of shortness of breath and dry cough. Her symptoms began following the start of anti-hormonal treatment with letrozole and goserelin acetate for a moderately differentiated (grade 2) invasive ductal carcinoma of the breast (pT2, pN0, M0) which was positive for expression of estrogen receptor (ER+), progesterone receptor (PR+), and human epidermal growth factor receptor 2 (HER2+). Until the previous four months, she had breast-conserving treatment with radiotherapy and tamoxifen therapy. Following hospital admission, she was found to be in type I respiratory failure. Chest X-ray, lung computed tomography (CT), and positron-emission tomography (PET) showed diffuse cystic and nodular lung lesions, consistent with a diagnosis of LAM, and antihormonal therapy was discontinued. She developed pericarditis that was treated with the anti-inflammatory agent, colchicine. Treatment with letrozole and sirolimus improved her respiratory symptoms.
Conclusions: A rare case of LAM is presented in a woman with a recent history of breast cancer. Because both tumors were hormone-dependent, this may support common underlying gene associations and signaling pathways between the two types of tumor.
Endothelial to mesenchymal transition in cardiovascular disease : JACC state-of-the-art review
(2019)
Endothelial to mesenchymal transition (EndMT) is a process whereby an endothelial cell undergoes a series of molecular events that lead to a change in phenotype toward a mesenchymal cell (e.g., myofibroblast, smooth muscle cell). EndMT plays a fundamental role during development, and mounting evidence indicates that EndMT is involved in adult cardiovascular diseases (CVDs), including atherosclerosis, pulmonary hypertension, valvular disease, and fibroelastosis. Therefore, the targeting of EndMT may hold therapeutic promise for treating CVD. However, the field faces a number of challenges, including the lack of a precise functional and molecular definition, a lack of understanding of the causative pathological role of EndMT in CVDs (versus being a “bystander-phenomenon”), and a lack of robust human data corroborating the extent and causality of EndMT in adult CVDs. Here, we review this emerging but exciting field, and propose a framework for its systematic advancement at the molecular and translational levels.
Congenital lower urinary-tract obstruction (LUTO) is caused by anatomical blockage of the bladder outflow tract or by functional impairment of urinary voiding. About three out of 10,000 pregnancies are affected. Although several monogenic causes of functional obstruction have been defined, it is unknown whether congenital LUTO caused by anatomical blockage has a monogenic cause. Exome sequencing in a family with four affected individuals with anatomical blockage of the urethra identified a rare nonsense variant (c.2557C>T [p.Arg853∗]) in BNC2, encoding basonuclin 2, tracking with LUTO over three generations. Re-sequencing BNC2 in 697 individuals with LUTO revealed three further independent missense variants in three unrelated families. In human and mouse embryogenesis, basonuclin 2 was detected in lower urinary-tract rudiments. In zebrafish embryos, bnc2 was expressed in the pronephric duct and cloaca, analogs of the mammalian lower urinary tract. Experimental knockdown of Bnc2 in zebrafish caused pronephric-outlet obstruction and cloacal dilatation, phenocopying human congenital LUTO. Collectively, these results support the conclusion that variants in BNC2 are strongly implicated in LUTO etiology as a result of anatomical blockage.
Background and aims: Patients with gastric cancer often show signs of malnutrition. We sought to evaluate the influence of sarcopenia in patients with locally advanced, not metastasized, gastric or gastro-esophageal junction (GEJ) cancer undergoing curative treatment (perioperative chemotherapy and surgery) on morbidity and mortality in order to identify patients in need for nutritional intervention.
Patients and methods: Two-centre study, conducted in the Frankfurt University Clinic and Krankenhaus Nordwest (Frankfurt) as part of the University Cancer Center Frankfurt (UCT). 47/83 patients were treated in the FLOT trial (NCT01216644). Patients´ charts were reviewed for clinical data. Two consecutive CT scans were retrospectively analyzed to determine the degree of sarcopenia. Survival was calculated using the Kaplan-Meier method, multivariate analysis was performed using the Cox regression.
Results: 60 patients (72.3%) were male and 23 (27.7%) female. 45 patients (54.2%) had GEJ type 1–3 and 38 (45.8%) gastric tumors, respectively. Sarcopenic patients were significantly older than non-sarcopenic patients (mean age 65.1 years vs. 59.5 years, p = 0.042), terminated the chemotherapy significantly earlier (50% vs. 22.6%, p = 0.037) and showed higher Clavien-Dindo scores, indicating more severe perioperative complications (score ≥3 43.3 vs. 17.0%, p = 0.019). Sarcopenic patients had a significantly shorter survival than non-sarcopenic patients (139.6 ± 19.5 [95% CI, 101.3–177.9] vs. 206.7 ± 13.8 [95% CI, 179.5–233.8] weeks, p = 0.004). Multivariate Cox regression analysis showed that, besides UICC stage, sarcopenia significantly influenced survival.
Conclusion: Sarcopenia is present in a large proportion of patients with locally advanced gastric or GEJ cancer and significantly influences tolerability of chemotherapy, surgical complications and survival.
The hepatitis C virus (HCV) RNA replication cycle is a dynamic intracellular process occurring in three-dimensional space (3D), which is difficult both to capture experimentally and to visualize conceptually. HCV-generated replication factories are housed within virus-induced intracellular structures termed membranous webs (MW), which are derived from the Endoplasmatic Reticulum (ER). Recently, we published 3D spatiotemporal resolved diffusion–reaction models of the HCV RNA replication cycle by means of surface partial differential equation (sPDE) descriptions. We distinguished between the basic components of the HCV RNA replication cycle, namely HCV RNA, non-structural viral proteins (NSPs), and a host factor. In particular, we evaluated the sPDE models upon realistic reconstructed intracellular compartments (ER/MW). In this paper, we propose a significant extension of the model based upon two additional parameters: different aggregate states of HCV RNA and NSPs, and population dynamics inspired diffusion and reaction coefficients instead of multilinear ones. The combination of both aspects enables realistic modeling of viral replication at all scales. Specifically, we describe a replication complex state consisting of HCV RNA together with a defined amount of NSPs. As a result of the combination of spatial resolution and different aggregate states, the new model mimics a cis requirement for HCV RNA replication. We used heuristic parameters for our simulations, which were run only on a subsection of the ER. Nevertheless, this was sufficient to allow the fitting of core aspects of virus reproduction, at least qualitatively. Our findings should help stimulate new model approaches and experimental directions for virology.
Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis
(2019)
Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option.
Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection.
Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers.
Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.
Sepsis is characterized by dysregulated gene expression, provoking a hyper-inflammatory response occurring in parallel to a hypo-inflammatory reaction. This is often associated with multi-organ failure, leading to the patient’s death. Therefore, reprogramming of these pro- and anti-inflammatory, as well as immune-response genes which are involved in acute systemic inflammation, is a therapy approach to prevent organ failure and to improve sepsis outcomes. Considering epigenetic, i.e., reversible, modifications of chromatin, not altering the DNA sequence as one tool to adapt the expression profile, inhibition of factors mediating these changes is important. Acetylation of histones by histone acetyltransferases (HATs) and initiating an open-chromatin structure leading to its active transcription is counteracted by histone deacetylases (HDACs). Histone deacetylation triggers a compact nucleosome structure preventing active transcription. Hence, inhibiting the activity of HDACs by specific inhibitors can be used to restore the expression profile of the cells. It can be assumed that HDAC inhibitors will reduce the expression of pro-, as well as anti-inflammatory mediators, which blocks sepsis progression. However, decreased cytokine expression might also be unfavorable, because it can be associated with decreased bacterial clearance.
Background: GLUT1-deficiency-syndrome (G1DS) is an autosomal dominant genetic disorder based on a mutation of the SLC2A1 gene. This mutation can lead to an encephalopathy due to abnormal glucose transport in the brain. G1DS is a rare disease, with an estimated incidence of 1: 90 000.
Case report: We report a case of a 10-year-old female who presented with recurrent fever, headaches, and vertigo for more than 3 days within 2 weeks following pneumonia. A bilateral mastoiditis was proven by a cerebral magnetic resonance imaging and a cranial computed tomography scan. The patient had to undergo mastoidectomy and thus, her first general anesthesia. Half a year previously she was diagnosed with G1DS. According to the standard of care, a ketogenic diet had been administered since the patient’s diagnosis 6 months earlier. Our patient received a total intravenous anesthesia (TIVA) using propofol, fentanyl, and rocuronium administered without any incidents.
Conclusions: We recommend normoglycemia during the perioperative phase and avoidance of glucose-based medication to keep a patient’s ketotic state. Our case highlights that TIVA, with the outlined medication used in this case, was safe when the patient’s ketotic state and periprocedural blood glucose was monitored continuously. Nevertheless, we would suggest using remifentanil instead of fentanyl for future TIVAs due to a reduced increase in blood glucose level in our patient.
Background: Esophageal cancer (EC) is one of the deadliest cancers worldwide. The contemporary strong increase of the adenocarcinomas in Western countries and the high mortality rates require the intensification of prospective multinational studies.
Methods: Therefore, this global health issue has been chosen for the bibliometric review of the global publication output. As source for meta and citation data, the Web of Science has been used and Density Equalizing Maps were applied for visualization.
Results: 17,387 articles on EC could be identified. The years with publication and citation maxima correspond to the appearance of the most prolific articles. China is the most publishing country, followed by Japan and the USA. Germany and the UK ranked 4th and 5th. The analysis of the ratios articles and socio-economic parameters emphasizes the leading position of the Scandinavian countries and Japan. Here, the high-income countries come out on top. The high incidence regions are mainly represented by Chinese and Japanese research. The association of the publication output and the overall research funding could be shown.
Conclusions: A strengthened international network increasingly consisting of the scientifically best positioned countries as well as more of the high incidence countries worldwide is mandatory for future research. The findings deliver scientists, clinicians and decision makers backgrounds for future decisions all over the world.
Chaperone-assisted selective autophagy (CASA) initiated by the cochaperone Bcl2-associated athanogene 3 (BAG3) represents an important mechanism for the disposal of misfolded and damaged proteins in mammalian cells. Under mechanical stress, the cochaperone cooperates with the small heat shock protein HSPB8 and the cytoskeleton-associated protein SYNPO2 to degrade force-unfolded forms of the actin-crosslinking protein filamin. This is essential for muscle maintenance in flies, fish, mice and men. Here, we identify the serine/threonine protein kinase 38 (STK38), which is part of the Hippo signaling network, as a novel interactor of BAG3. STK38 was previously shown to facilitate cytoskeleton assembly and to promote mitophagy as well as starvation and detachment induced autophagy. Significantly, our study reveals that STK38 exerts an inhibitory activity on BAG3-mediated autophagy. Inhibition relies on a disruption of the functional interplay of BAG3 with HSPB8 and SYNPO2 upon binding of STK38 to the cochaperone. Of note, STK38 attenuates CASA independently of its kinase activity, whereas previously established regulatory functions of STK38 involve target phosphorylation. The ability to exert different modes of regulation on central protein homeostasis (proteostasis) machineries apparently allows STK38 to coordinate the execution of diverse macroautophagy pathways and to balance cytoskeleton assembly and degradation.
Yellow fever virus (YFV) represents a re-emerging zoonotic pathogen, transmitted by mosquito vectors to humans from primate reservoirs. Sporadic outbreaks of YFV occur in endemic tropical regions, causing a viral hemorrhagic fever (VHF) associated with high mortality rates. Despite a highly effective vaccine, no antiviral treatments currently exist. Therefore, YFV represents a neglected tropical disease and is chronically understudied, with many aspects of YFV biology incompletely defined including host range, host–virus interactions and correlates of host immunity and pathogenicity. In this article, we review the current state of YFV research, focusing on the viral lifecycle, host responses to infection, species tropism and the success and associated limitations of the YFV-17D vaccine. In addition, we highlight the current lack of available treatments and use publicly available sequence and structural data to assess global patterns of YFV sequence diversity and identify potential drug targets. Finally, we discuss how technological advances, including real-time epidemiological monitoring of outbreaks using next-generation sequencing and CRISPR/Cas9 modification of vector species, could be utilized in future battles against this re-emerging pathogen which continues to cause devastating disease.
Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl4 inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2/Arhgef1/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and in vivo. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl4) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.
Acute‐on‐chronic liver failure (ACLF) is a syndrome with high short‐term mortality. Precipitating events, including hemorrhage and infections, contribute to ACLF development, but the role of surgery remains unknown. We investigated the development of ACLF in patients with cirrhosis undergoing surgery. In total, 369 patients with cirrhosis were included in the study. The clinical and laboratory data were collected prior to and on days 1‐2, 3‐8, and 9‐28, and at 3 and 12 months after surgery. Surgery type was classified as limited or extensive, as well as liver and nonliver surgery. A total of 39 patients had baseline ACLF. Surgery was performed during acute decompensation in 35% of the rest of the 330 patients, and 81 (24.5%) developed ACLF within 28 days after surgery. Surrogate markers of systemic inflammation were similar in patients who developed ACLF or not. Age, sex, serum sodium, baseline bacterial infection, and abdominal nonliver surgery were independent predictors for the development of ACLF after surgery. Patients who developed ACLF within 28 days after surgery had a higher mortality at 3, 6, and 12 months. Survival did not differ between patients with ACLF at surgery and those developing ACLF after surgery. Development of ACLF within 28 days after surgery and elevated alkaline phosphatase and international normalized ratio were independent predictors of 90‐day mortality. Independent predictors of 1‐year all‐cause mortality were alkaline phosphatase, Model for End‐Stage Liver Disease score, and preoperative hepatic encephalopathy, whereas nonliver surgery was associated with improved survival. ACLF frequently develops in patients with cirrhosis undergoing surgery, especially in those with active bacterial infection, lower serum sodium, and kidney or coagulation dysfunction. Prognoses of ACLF both at and after surgery are similarly poor. Patients with cirrhosis should be carefully managed perioperatively.