The journal retracts the article titled, "HSP70-eIF4G Interaction Promotes Protein Synthesis and Cell Proliferation in Hepatocellular Carcinoma" [...].

Cancer patients frequently suffer from anemia and cancer-related pain, which can be treated by non-opioid analgesics such as diclofenac (DCF) and acetaminophen (APAP) attenuating inflammatory responses. The pro-inflammatory cytokine interleukin (IL)-6 triggers the expression of acute-phase proteins, including the iron regulator hepcidin. Using proteomics and dynamic pathway modeling, we show that DCF and APAP directly impact IL-6 signaling by enhancing the induction of the feedback-inhibitor suppressor of cytokine signaling 3 (SOCS3), reducing signal transducer and activator of transcription (STAT)3 phosphorylation, and decreasing the expression of most acute-phase proteins except for hepcidin. In primary human hepatocytes (PHHs), the impact depends on the patient-specific extent of SOCS3 induction, which is anti-correlated with hepcidin expression. Whereas, in liver cancer cells, DCF and APAP stabilize the interaction of autocrine secreted bone morphogenic protein (BMP) with its receptor, resulting in strongly amplified hepcidin expression. Our studies suggest that co-inhibition of the BMP receptor counteracts excessive hepcidin production upon treatment with pain-relieving drugs and could prevent iron-deficiency-caused anemia in liver cancer. A record of this paper’s transparent peer review process is included in the supplemental information.

Objective and Background:Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an aspartate aminotransferase to platelet ratio combined with an albumin-bilirubin grade (APRI+ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE).Methods:A total of 12,056 patients from the National Surgical Quality Improvement Program database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. The performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2525 patients. In 620 patients, the APRI+ALBI MVM, trained in the National Surgical Quality Improvement Program cohort, was compared with the MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC).Results:A MVM including APRI+ALBI, age, sex, tumor type, and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC: 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for the calculation of the APRI+ALBI MVM was designed.Conclusion:Risk assessment through the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents a universally available and cost-effective risk assessment before hepatectomy, facilitated by a freely available smartphone app.

Einleitung Das unilaterale und multifokale Auftreten von cochleovestibulären Schwannomen (CVS) stellt ein sehr seltenes Phänomen dar. Die Entstehung multifokaler einseitiger CVS im Kleinhirnbrückenwinkel (CPA) oder im inneren Gehörgang (IAC) sowie im Innenohr wurde bisher bei Patienten mit neurofibromatosis 2-related schwannomatosis beschrieben, während ein sporadisches Entstehen von unilateralen multifokalen CVS extrem selten zu sein scheint.

Objective To describe the genetic characteristics and the management of two very rare cases of unilateral multifocal inner ear and internal auditory canal or cerebellopontine angle cochleovestibular schwannomas not being associated to full neurofibromatosis type 2-related schwannomatosis. Patients In a 29-year-old man and a 55-year-old woman with single-sided deafness multifocal unilateral cochleovestibular schwannomas were surgically resected, and hearing was rehabilitated with a cochlear implant (CI). Unaffected tissue was analyzed using next generation sequencing of the NF2 gene. Tumor tissue was analyzed using a 340-parallel sequencing gene panel. Main outcome measures Mutations in the NF2 gene, word recognition score for monosyllables at 65 dB SPL (WRS65) with CI. Results No disease-causing mutation was detected in the examined sequences in blood leucokytes. All tumor samples revealed, among others, somatic pathogenic NF2 mutations. While the anatomically separate tumors in case 1 were likely molecular identical, the tumors in case 2 showed different genetic patterns. WRS65 was 55% at 6 years of follow-up and 60% at 4.5 years of follow-up, respectively. Conclusions The occurrence of multifocal unilateral cochleovestibular schwannomas without pathogenic variants in NF2 in non-affected blood leucocytes can be associated with mosaic NF2-related schwannomatosis (case 1), or with likely sporadic mutations (case 2) and may be overlooked due to their extreme rarity. Although challenging, successful hearing rehabilitation could be achieved through surgical resection of the tumors and cochlear implantation.

Introduction Among cochleovestibular schwannoma (CVS) unilateral multifocality represents a rare phenomenon. While the occurrence of multifocal unilateral CVS in the cerebellopontine angle (CPA) or internal auditory canal (IAC) and the inner ear has been described for patients with neurofibromatosis 2-related schwannomatosis, unilateral sporadic multifocal CVS appear to be extremely rare.

BACKGROUND:There is ongoing debate regarding liver transplantation (LT) versus liver resection (LR) for locally advanced hepatoblastoma. However, comparative studies are lacking. Consequently, a significant evidence gap persists, hindering the establishment of consensus guidelines. This study aimed to compare LT and LR for locally advanced hepatoblastoma, using predefined inclusion criteria to ensure comparable intervention groups. METHODS:According to current Children's Oncology Group (COG) and SIOPEL (European Childhood Liver Tumour Study Group) recommendations, hepatoblastoma that requires LT evaluation was defined as either PRETEXT (PRE-Treatment EXTent of tumor) IV F+, POST-TEXT (POST-Treatment EXTent of tumor) IV, POST-TEXT P+, and/or POST-TEXT V+. A systematic literature search (Medline/Web-of-Science/Embase) was performed. Only patients who met the aforementioned criteria were included. Patient data were extracted individually and pooled. RESULTS:A total of 189 patients with locally advanced hepatoblastoma from 55 studies met the specified criteria, with 111 undergoing LT and 78 LR. There were no significant differences between the two groups in age, alpha-fetoprotein (AFP), and PRETEXT stages. Local recurrence was more common after LR (14% vs. 3% in LT, p = .008), while distant recurrence was more often observed after LT (16% vs. 5% in LR, p = .035). Overall survival (OS) and event-free survival (EFS) did not differ significantly between LT and LR (5-year OS: LT = 75.3% [95% confidence interval: 66.5-85.2], LR = 87.6% [80.4-95.6], p = .140; 5-year EFS: LT = 68.5% [59.3-79.1], LR = 71.1% [60.7-83.3], p = .700). CONCLUSION:Real-life data revealed that a considerable number of patients with locally advanced hepatoblastoma underwent LR. This analysis suggests that outcomes are similar and favorable for both approaches. LR can therefore be considered an effective alternative to LT in selected cases even in locally advanced hepatoblastoma.

Genetic TNFAIP3 (A20) inactivation is a classical somatic lymphoma lesion and the genomic trait in haploinsufficiency of A20 (HA20). In a cohort of 34 patients with HA20, we show that heterozygous TNFAIP3 loss skews immune repertoires toward lymphocytes with classical self-reactive antigen receptors typically found in B and T cell lymphomas. This skewing was mediated by a feed-forward tumor necrosis factor (TNF)/A20/nuclear factor κB (NF-κB) loop that shaped pre-lymphoma transcriptome signatures in clonally expanded B ( CD81 , BACH2 , and NEAT1 ) or T ( GATA3 , TOX , and PDCD1 ) cells. The skewing was reversed by anti-TNF treatment but could also progress to overt lymphoma. Analysis of conditional TNFAIP3 knock-out mice reproduced the wiring of the TNF/A20/NF-κB signaling axis with permissive antigen receptors and suggested a distinct regulation in B and T cells. Together, patients with the genetic disorder HA20 provide an exceptional window into A20/TNF/NF-κB–mediated control of immune homeostasis and early steps of lymphomagenesis that remain clinically unrecognized.

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

BACKGROUND:Hyperphosphorylation and intraneuronal aggregation of the microtubule-associated protein tau is a major pathological hallmark of Alzheimer's disease (AD) brain. Of special interest is the effect of cerebral amyloid beta deposition, the second main hallmark of AD, on human tau pathology. Therefore, studying the influence of cerebral amyloidosis on human tau in a novel human tau knock-in (htau-KI) mouse model could help to reveal new details on their interplay.METHODS:We studied the effects of a novel human htau-KI under fast-progressing amyloidosis in 5xFAD mice in terms of correlation of gene expression data with human brain regions, development of Alzheimer's-like pathology, synaptic transmission, and behavior.RESULTS:The main findings are an interaction of human beta-amyloid and human tau in crossbred 5xFADxhtau-KI observed at transcriptional level and corroborated by electrophysiology and histopathology. The comparison of gene expression data of the 5xFADxhtau-KI mouse model to 5xFAD, control mice and to human AD patients revealed conspicuous changes in pathways related to mitochondria biology, extracellular matrix, and immune function. These changes were accompanied by plaque-associated MC1-positive pathological tau that required the htau-KI background. LTP deficits were noted in 5xFAD and htau-KI mice in contrast to signs of rescue in 5xFADxhtau-KI mice. Increased frequencies of miniature EPSCs and miniature IPSCs indicated an upregulated presynaptic function in 5xFADxhtau-KI.CONCLUSION:In summary, the multiple interactions observed between knocked-in human tau and the 5xFAD-driven progressing amyloidosis have important implications for future model development in AD.

Apoptosis induction, cell proliferation and viability after MAPK inhibitor treatment. (A) Apoptosis was determined in HepG2, Hep3B and Huh-7 cells after treatment with 0.2 (light gray bar), 1 (dark gray bar) or 5µM (black bar) inhibitor or DMSO (white bar) at 48h by measuring the subG1 peak using propidium iodide. (B) Cell division was determined by eFluor670 labeling of HepG2, Hep3B and Huh-7 cells after 96h treatment with the different inhibitor concentrations and detected by flow cytometry. (C) The WST-1 metabolic assay was used to detect the viability/proliferation of the three cell lines after treatment with the respective inhibitors for 72h. Each bar represents the mean {plus minus} SDs from three to six replicates.

BACKGROUND:Evidence on safety and efficacy of different liver transection techniques in pediatric major hepatectomy is completely lacking, as no study has been conducted so far. The use of stapler hepatectomy has never before been reported in children. METHODS:Three liver transection techniques were compared: (1) ultrasonic dissector (CUSA), (2) tissue sealing device (LigaSure™), and (3) stapler hepatectomy. All pediatric hepatectomies performed at a referral center in a 12-year study period were analyzed, patients were pair-matched in a 1:1:1-fashion. Intraoperative weight-adjusted blood loss, operation time, use of inflow occlusion, liver injury (peak-transaminase levels), postoperative complications (CCI), and long-term outcome were compared. RESULTS:Of 57 pediatric liver resections, 15 patients were matched as triples based on age, weight, tumor stage, and extent of resection. Intraoperative blood loss was not significantly different between the groups (p = 0.765). Stapler hepatectomy was associated with significantly shorter operation time (p = 0.028). Neither postoperative death nor bile leakage occurred, and no reoperation due to hemorrhage was needed in any patient. CONCLUSION:This is the first comparison of transection techniques in pediatric liver resection and the first report on stapler hepatectomy in children. All three techniques can be safely applied and may harbor individual advantages in pediatric hepatectomy each.

Background: Liver surgery provides cure in patients with hepatobiliary malignancies and liver metastases to the liver. A recent national evaluation on the outcome after liver surgery in Germany by Filmann et al. in the BJS, however, revealed an unexpected high morbidity and mortality rate following liver resection. In 2019, the German Association for General and Visceral Surgery launched the German liver surgery registry collecting data from certified and volunteer high-volume centers in Germany. This is the first evaluation of the StuDoQ-registry for liver surgery. Methods: Based on a multicentric registry of high-volume centers in Germany, a retrospective outcome analysis of liver surgery was performed between 2019 – 2022. Any tumor type was included. Endpoints included major complications (Dindo-Clavien, ≥3A), postoperative liver failure (PHLF, international study group of liver surgery criteria (ISGLS)), bile leakage (ISGLS), and 90-day mortality. Results: Overall, 4.109 patients underwent liver resection, 1.411 (34%) of those were major resections (≥3 segments). Colorectal liver metastasis (CRLM: 1.209 (29%)) was the most common tumor type, followed by hepatocellular (HCC: 635 (16%)) and intrahepatic cholangiocellular carcinoma (CCC: 605 (15%)). Mean operation time was 225 minutes (±119). Overall, rate of major complications, PHLF and bile leakage was 1.050 (26%), 411 (10%) and 154 (4%). The 90-day mortality was 338 (8%) in total, 153 (11%) of those occurred in minor and 154 (23%) in major resections. Depending on the tumor type, 90-day mortality was 50 (7%) in minor and 40 (9%) in major liver resection for CRLM. In primary liver tumors, 90-day mortality amounted to 27 (7%) in minor and 27 (13%) in major liver resection for HCC. In CCC, 90-day mortality accounted for 11 (6%) in minor and 55 (15%) in major liver resection. Conclusions: This is the first study based on a national registry of high-volume centers in Germany that has determined the outcome after liver surgery. The rate of morbidity and mortality remains high and confirms recent findings of our group. Investigations of roots are inevitable to achieve an improvement of outcomes.

(B) The phosphorylation of the given proteins in lysates of HepG2 (left), Hep3B (middle) and Huh-7 (right) cells after treatment with 0.2, 1, and 5µM GW5074 or sunitinib at different time points. The values represent MFI of 30-60 beads for each kinase and time point. One of two or three representative experiments is shown.

Purpose: Although surgery is associated with an acceptable cure rate, tumor recurrence is still a challenging issue in hepatocellular carcinoma (HCC) patients. Red blood cell distribution width (RDW) is considered an inflammatory marker for predicting overall mortality in a wide spectrum of malignancies. In the current study, the prognostic role of pre- and postoperative RDW in HCC recurrence after liver resection (LRx) is investigated. Patients and Methods: In 395 patients, RDW levels were evaluated preoperatively as well as six and twelve months after curative LRx. The RDW cutoff values were determined using receiver operating characteristic curves (ROCS) according to the recurrence-free survival (RFS). Survival analyses were performed using the Kaplan-Meier, and differences were compared using the Log rank test. Results: The RFS was significantly higher among patients with low RDW at the 6th month and 12th month, postoperatively (P < 0.001 and P = 0.028). RDW levels of higher than 16.15% at the 6th (HR: 2.047, P <0.001) and higher than 15.85% at 12th (HR: 3.105, P < 0.002) months after liver resection were independent predictors of RFS. Conclusion: Postoperative RDW values seem to be predictive of tumor recurrence in HCC patients. RDW levels at the 6th and 12th months postoperatively were independent predictors of recurrence after LRx.

Effects of MAPK inhibitors on JNK, c-Jun, Akt and ATF2 phosphorylation. (A) Kinetics of p-JNK, p-c-Jun, p-Akt and p-ATF2 phosphorylation in HepG2 (left) and Hep3B (right) cell lines after treatment with 6.5µM sorafenib, 5µM AZD6244, U0126 (left) or 5µM PLX4720, PD0325901 (right) or DMSO at the given time points are displayed as MFI.

Alteration of total protein amount of MEK1, ERK1/2, c-Jun, Akt and ATF2 by MAPK inhibition. Total amount of MEK1, ERK1/2, c-Jun, Akt and ATF2 of HepG2 (A), Hep3B (B) and Huh-7 (C) cells after treatment with 0.2, 1 or 5µM sorafenib, PLX4720, U0126, AZD6244, PD0325901, GW5074 or sunitinib at different time points.

Two way ANOVA statistics of phosphorylated MEK1 and ERK1/2 after MAPKi treatment. Values of phosphoplex data of mean fluorescence intensities (MFI) from 30-60 beads for each kinase at each time point were calculated against the respective DMSO value using the 2 way ANOVA statistic. Indicated p-values are defined as *p{less than or equal to}0.05, **p{less than or equal to}0.01, ***p{less than or equal to}0.001, ns= not significant.