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Cell-free DNA (cfDNA) in human plasma provides access to molecular information about the pathological processes in the organs or tumors from which it originates. These DNA fragments are derived from fragmented chromatin in dying cells and retain some of the cell-of-origin histone modifications. In this study, we applied chromatin immunoprecipitation of cell-free nucleosomes carrying active chromatin modifications followed by sequencing (cfChIP-seq) to 268 human samples. In healthy donors, we identified bone marrow megakaryocytes, but not erythroblasts, as major contributors to the cfDNA pool. In patients with a range of liver diseases, we showed that we can identify pathology-related changes in hepatocyte transcriptional programs. In patients with metastatic colorectal carcinoma, we detected clinically relevant and patient-specific information, including transcriptionally active human epidermal growth factor receptor 2 (HER2) amplifications. Altogether, cfChIP-seq, using low sequencing depth, provides systemic and genome-wide information and can inform diagnosis and facilitate interrogation of physiological and pathological processes using blood samples.

The oncofetal long noncoding RNA (lncRNA) H19 is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role of H19 in carcinogenesis is a subject of controversy. We aimed to examine the role of H19 in chronic inflammation-mediated hepatocarcinogenesis using the Mdr2/Abcb4 knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generated Mdr2-KO/H19-KO double knockout (dKO) mice and followed spontaneous tumor development in the dKO and control Mdr2-KO mice. Cellular localization of H19 and effects of H19 loss in the liver were determined in young and old Mdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver of dKO versus Mdr2-KO females. The expression levels of H19 and Igf2 were variable in nontumor liver tissues of Mdr2-KO females and were significantly downregulated in most matched tumors. In nontumor liver tissue of aged Mdr2-KO females, H19 was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared to dKO females. At an early age, dKO females displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples, H19 expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated with CTNNB1 (beta-catenin) mutations and patients' survival (in tumors). Our data demonstrate that the lncRNA H19 is pro-oncogenic during the development of chronic inflammation-mediated HCC in the Mdr2-KO mouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.

Cette introduction présente l’intérêt d’étudier la notion d’ethos collectif comme à la fois proche, et différente, de la notion d’ethos telle qu’utilisée en rhétorique et analyse du discours. Elle en dégage les enjeux en indiquant l’importance de ses fonctions sociales. Elle les illustre à travers la présentation des chapitres de l’ouvrage qui traitent de l’ethos.

Simple Summary Liver cancer develops mostly in a chronically inflamed liver. The inflammation process can enhance or suppress the development of liver cancer. H19 is a noncoding RNA that is upregulated in inflamed livers. The role of H19 in liver cancer was intensely investigated, but the reported findings are conflicting. Some reported that H19 is a tumor suppressor and others that it has oncogenic properties. To understand the contribution of H19 to liver cancer development, we investigated miR-675, which is generated from the first exon of the H19 RNA message. Interestingly, we found that miR-675 suppresses liver cancer cell growth by inducing cell death. Following our investigation of the mechanism of this killing effect, we established that miR-675 represses the protein called Fas-associated protein with death domain (FADD) and that this repression leads to the development of a specific type of necrosis named necroptosis. These findings can have future therapeutic implications. Abstract The H19-derived microRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD), a mediator of apoptotic cell death signaling, is downregulated by miR-675 and a negative correlation exists between miR-675 and FADD expression in mouse models of HCC (p = 0.014) as well as in human samples (p = 0.017). We demonstrate in a mouse model of liver inflammation that overexpression of miR-675 promotes necroptosis, which can be inhibited by the necroptosis-specific inhibitor Nec-1/Nec-1s. miR-675 induces the level of both p-MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) and RIP3 (receptor-interacting protein 3), which are key signaling molecules in necroptosis, and enhances MLKL binding to RIP3. miR-675 also inhibits the levels of cleaved caspases 8 and 3, suggesting that miR-675 induces a shift from apoptosis to a necroptotic cellular pathway. In conclusion, downregulation of FADD by miR-675 promotes liver necroptosis in response to inflammatory signals. We propose that this regulation cascade can stimulate and enhance the inflammatory response in the liver, making miR-675 an important regulator in liver inflammation and potentially also in HCC.

SummaryBackgroundSepsis has no proven specific pharmacologic treatment. Reported mortality in sepsis ranges from 30%–45%. This study was designed to determine the safety preliminary efficacy of allogenic apoptotic cells administered for immunomodulation in septic patients.MethodsThe primary aim of this phase IB study was to determine the safety profile of apoptotic cell infusion in subjects presenting to the emergency room with sepsis. Sepsis was determined by clinical infections and Sequential Organ Failure Assessment (SOFA) scores >2. The secondary aims were to measure organ dysfunction, intensive care unit (ICU) and hospital stays, and mortality, that were compared to historical controls. Exploratory endpoints included measuring immune modulator agents to elucidate the mechanism of action using Luminex® analysis.FindingsTen patients were treated with apoptotic cells, administered as a single dose or two sequential doses. All 10 patients had mild-to-moderate sepsis with a SOFA score range of 2–6 upon entering the study. No serious adverse events (SAEs) and no related AEs were reported. All 10 study subjects survived while matched historical controls had a mortality rate of 27%. The study subjects exhibited rapid resolution of organ dysfunction and had significantly shorter ICU lengths of stay compared to matched historical controls (pInterpretationAdministration of apoptotic cells to patients with mild-to-moderate sepsis was safe and had a significant immuno-modulating effect, leading to early resolution of the cytokine storm.Trial registrationClinicalTrials.gov Identifier: NCT03925857FundingThe study was sponsored by Enlivex Therapeutics Ltd.

The H19-derivedmicroRNA-675 (miR-675) has been implicated as both tumor promoter and tumor suppressor and also plays a role in liver inflammation. We found that miR-675 promotes cell death in human hepatocellular carcinoma (HCC) cell lines. We show that Fas-associated protein with death domain (FADD), amediator of apoptotic cell death signaling, is downregulated bymiR-675 and a negative correlation exists betweenmiR-675 and FADD expression inmousemodels ofHCC (p = 0.014) aswell as in human samples (p = 0.017). We demonstrate in amousemodel of liver inflammation that overexpression of miR-675 promotes necroptosis, which can be inhibited by the necroptosis-specific inhibitor Nec-1/Nec-1s. miR-675 induces the level of both p-MLKL (Mixed Lineage Kinase Domain-Like Pseudokinase) and RIP3 (receptor-interacting protein 3), which are key signaling molecules in necroptosis, and enhances MLKL binding to RIP3. miR-675 also inhibits the levels of cleaved caspases 8 and 3, suggesting that miR-675 induces a shift fromapoptosis to a necroptotic cellular pathway. In conclusion, downregulation of FADD bymiR-675 promotes liver necroptosis in response to inflammatory signals. We propose that this regulation cascade can stimulate and enhance the inflammatory response in the liver, making miR-675 an important regulator in liver inflammation and potentially also in HCC.

The oncofetal long noncoding RNA (lncRNA)H19is postnatally repressed in most tissues, and re-expressed in many cancers, including hepatocellular carcinoma (HCC). The role ofH19in carcinogenesis is a subject of controversy. We aimed to examine the role ofH19in chronic inflammation-mediated hepatocarcinogenesis using theMdr2/Abcb4knockout (Mdr2-KO) mouse, a well-established HCC model. For this goal, we have generatedMdr2-KO/H19-KOdouble knockout (dKO) mice and followed spontaneous tumor development in thedKOand controlMdr2-KOmice. Cellular localization ofH19and effects ofH19loss in the liver were determined in young and oldMdr2-KO mice. Tumor incidence and tumor load were both significantly decreased in the liver ofdKOversusMdr2-KOfemales. The expression levels ofH19andIgf2were variable in nontumor liver tissues ofMdr2-KOfemales and were significantly downregulated in most matched tumors. In nontumor liver tissue of agedMdr2-KOfemales,H19was expressed mainly in hepatocytes, and hepatocyte proliferation was increased compared todKOfemales. At an early age,dKOfemales displayed lower levels of liver injury and B-cell infiltration, with higher percentage of binuclear hepatocytes. In human samples,H19expression was higher in females, positively correlated with cirrhosis (in nontumor liver samples) and negatively correlated withCTNNB1(beta-catenin) mutations and patients’ survival (in tumors). Our data demonstrate that the lncRNAH19is pro-oncogenic during the development of chronic inflammation-mediated HCC in theMdr2-KOmouse model, mainly by increasing liver injury and decreasing hepatocyte polyploidy in young mice.

IL-6 signaling via its receptor (IL-6R) and co-receptor (gp130) performs multiple roles in regulating metabolic homeostasis. However, gp130 is also expressed systemically in a soluble form (sgp130), which limits soluble IL-6 receptor (sIL-6R)-mediated signaling – also called trans-signaling. Here we find that transgenic peripheral sgp130-mediated trans-signaling blockade induces mature-onset obesity, while differentially affecting age-dependent behavioral determinants of energy expenditure. In youth, trans-signaling blockade increases feeding associated with reduced leptin sensitivity but increases energy expenditure to maintain metabolic balance. In aging, reduced physical activity predisposes mice to adiposity, adipose tissue macrophage recruitment, hepatosteatosis, hyperglycemia, and insulin resistance. Mechanistically, trans-signaling blockade reduces hepatic Stat3 phosphorylation and suppresses PPARα, associated with miR-21 upregulation, while pharmacological activation of PPARα prevents obesity and hepatosteatosis, and rescues insulin sensitivity. Together these experiments reveal a role for peripheral IL-6 trans-signaling in metabolic homeostasis and provide clinical significance to elevated sgp130 levels found in some obese and diabetic patients.

Nodding syndrome (NS) is a devastating and enigmatic childhood epilepsy. NS is accompanied by multiple neurological impairments and neuroinflammation, and associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. Moreover, NS seems to be an ‘Autoimmune Epilepsy’ since: 1. ~50% of NS patients have neurotoxic cross-reactive Ov/Leimodin-I autoimmune antibodies. 2. Our recently published findings: Most (~86%) of NS patients have glutamate-receptor AMPA-GluR3B peptide autoimmune antibodies that bind, induce Reactive Oxygen Species, and kill both neural cells and T cells. Furthermore, NS patient’s IgG induce seizures, brain multiple damage alike occurring in brains of NS patients, and elevation of T cells and activated microglia and astrocytes, in brains of normal mice. Human Leukocyte antigen (HLA) class I and II molecules are critical for initiating effective beneficial immunity against foreign microorganisms and contributing to proper brain function, but also predispose to detrimental autoimmunity against self-peptides. We analyzed seven HLA loci, either by next-generation-sequencing or Sequence-Specific-Oligonucleotide-Probe, in 48 NS patients and 51 healthy controls from South Sudan. We discovered that NS associates significantly with both protective HLA haplotype: HLA-B*42:01, C*17:01, DRB1*03:02, DQB1*04:02 and DQA1*04:01, and susceptible motif: Ala24, Glu63 and Phe67, in the HLA-B peptide-binding groove. These amino acids create a hydrophobic and sterically closed peptide-binding HLA pocket, favoring proline residue. Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves tentatively associate with protection or susceptibility to NS. Accordingly, different HLA molecules may explain why under similar environmental factors, only some children, within the same families, tribes and districts, develop NS, while others do not., Author summary Nodding syndrome (NS) is a devastating and mysterious neurological disorder affecting 5–15 years old children, primarily in Sudan, Uganda and Tanzania. NS strongly associates with an infection with the parasitic worm Oncocherca Volvulus (Ov), transmitted by the black fly, affecting many people worldwide. Moreover, NS is most probably an 'Autoimmune Epilepsy', especially in view of our recent findings that NS patient’s autoimmune GluR3B antibodies induce ROS and kill both neural cells and T cells. NS patient’s IgG also induce seizures, multiple brain damage and inflammation-inducing cells in the brain. HLA class I genes are expressed on the surface of all nucleated cells and present peptides to cytotoxic CD8+ T cells. HLA class II genes are expressed mainly on the surface of antigen presenting cells and present peptides to helper CD4+ T cells. Analysis of HLA of South-Sudanese NS patients and healthy controls revealed that that few amino acids in HLA peptide-binding grooves associate with either protection or susceptibility to NS. Theses amino acids could be critical in NS by affecting beneficial immunity and/or detrimental autoimmunity.

Background This report highlights a rapidly progressive case of Creutzfeldt-Jakob Disease (CJD) whose time from symptom onset to death spanned less than two months. We also explore the most recently available in-patient demographics data for discharges with CJD in the United States. Methods We reviewed a CJD case and systematically analyzed a retrospective cohort of CJD discharges using the Healthcare Cost and Utilization Project (HCUP) to evaluate the existing national data on the status of CJD demographics and dispositions in the United States in 2016. Results An estimated total of 710 hospital discharges with a diagnosis of CJD were seen across the United States in 2016. According to HCUP, the average age of patients was 66.15 ± 11.54 years with 48.6 % female. Average time to intubation from admission to hospital was 4.71 ± 7.32 days with a rate of intubation of 6.34 %. The mean hospital cost was $19,901.25 ± $18,743.48. The rate of in-hospital mortality was 8.45 %. No significant geographical differences were noted (p = 0.49). No significant differences were seen among incidence in specific ethnic groups (p = 0.33) or income quartiles (p = 0.90). Conclusions Our data shows that the incidence of CJD in 2016 appears to be equally distributed among individuals in the United States by demographic categories. Additionally, our case-study from 2019 illustrates an important example for diagnosing a rapidly-progressing case of CJD.

Background & Aims Development of nonalcoholic steatohepatitis (NASH) is associated with reductions in hepatic microRNA122 (MIR122); the RAR related orphan receptor A (RORA) promotes expression of MIR122. Increasing expression of RORA in livers of mice increases expression of MIR122 and reduces lipotoxicity. We investigated the effects of a RORA agonist in mouse models of NASH. Methods We screened a chemical library to identify agonists of RORA and tested their effects on a human hepatocellular carcinoma cell line (Huh7). C57BL/6 mice were fed a chow or high-fat diet (HFD) for 4 weeks to induce fatty liver. Mice were given hydrodynamic tail vein injections of a MIR122 antagonist (antagomiR-122) or a control antagomiR once each week for 3 weeks while still on the HFD or chow diet, or intraperitoneal injections of the RORA agonist RS-2982 or vehicle, twice each week for 3 weeks. Livers, gonad white adipose, and skeletal muscle were collected and analyzed by reverse-transcription polymerase chain reaction, histology, and immunohistochemistry. A separate group of mice were fed an atherogenic diet, with or without injections of RS-2982 for 3 weeks; livers were analyzed by immunohistochemistry, and plasma was analyzed for levels of aminotransferases. We analyzed data from liver tissues from patients with NASH included in the RNA-sequencing databases GSE33814 and GSE89632. Results Injection of mice with antagomiR-122 significantly reduced levels of MIR122 in plasma, liver, and white adipose tissue; in mice on an HFD, antagomiR-122 injections increased fat droplets and total triglyceride content in liver and reduced β-oxidation and energy expenditure, resulting in significantly more weight gain than in mice given the control microRNA. We identified RS-2982 as an agonist of RORA and found it to increase expression of MIR122 promoter activity in Huh7 cells. In mice fed an HFD or atherogenic diet, injections of RS-2982 increased hepatic levels of MIR122 precursors and reduced hepatic synthesis of triglycerides by reducing expression of biosynthesis enzymes. In these mice, RS-2982 significantly reduced hepatic lipotoxicity, reduced liver fibrosis, increased insulin resistance, and reduced body weight compared with mice injected with vehicle. Patients who underwent cardiovascular surgery had increased levels of plasma MIR122 compared to its levels before surgery; increased expression of plasma MIR122 was associated with increased levels of plasma free fatty acids and levels of RORA. Conclusions We identified the compound RS-2982 as an agonist of RORA that increases expression of MIR122 in cell lines and livers of mice. Mice fed an HFD or atherogenic diet given injections of RS-2982 had reduced hepatic lipotoxicity, liver fibrosis, and body weight compared with mice given the vehicle. Agonists of RORA might be developed for treatment of NASH.

Development of nonalcoholic steatohepatitis (NASH) is associated with reductions in hepatic microRNA122 (MIR122); the RAR related orphan receptor A (RORA) promotes expression of MIR122. Increasing expression of RORA in livers of mice increases expression of MIR122 and reduces lipotoxicity. We investigated the effects of a RORA agonist in mouse models of NASH.

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell–induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapies.

To present our experience treating patients who have undergone dental implantation under no change in their constant anticoagulant treatment. A retrospective study on patients who have undergone dental implantation. The study group consisted of patients under oral anticoagulants for at least 6 months before dental implantation. The control group was consisted of healthy patients with no oral anticoagulant treatment. Bleeding events were recorded and treated during the first 2 weeks postoperatively. A total of 193 patients were included in the study. Seventy-two of them who were under anticoagulants served as a study group and the rest (121 patients) served as a control group. Mean age: 65 years old in the study group and 59 years old in the control group. Gender: male to female ratio was higher in the study group and lower in the control group. Four patients in the study group and 7 patients in the control group presented postoperative bleeding and were treated successfully by additional local hemostasis methods. With the limitation of this study, it can be concluded that patients under oral anticoagulant treatment can undergo dental implantation safely. Bleeding events are rare and can be controlled by local hemostasis. Prior to dental implant insertion, patients under oral anticoagulants can continue their constant medical treatment. The procedure can be performed on outpatient basis under local hemostasis.

Nodding Syndrome (NS) is a fatal pediatric epilepsy of unknown etiology, accompanied by multiple neurological impairments, and associated with Onchocerca volvulus (Ov), malnutrition, war-induced trauma, and other insults. NS patients have neuroinflammation, and ~50% have cross-reactive Ov/Leiomodin-1 neurotoxic autoimmune antibodies. RESULTS: Studying 30 South Sudanese NS patients and a similar number of healthy subjects from the same geographical region, revealed autoimmune antibodies to 3 extracellular peptides of ionotropic glutamate receptors in NS patients: AMPA-GluR3B peptide antibodies (86%), NMDA-NR1 peptide antibodies (77%) and NMDA-NR2 peptide antibodies (87%) (in either 1:10, 1:100 or 1:1000 serum dilution). In contrast, NS patients did not have 26 other well-known autoantibodies that target the nervous system in several autoimmune-mediated neurological diseases. We demonstrated high expression of both AMPA-GluR3 and NMDA-NR1 in human neural cells, and also in normal human CD3+ T cells of both helper CD4+ and cytotoxic CD8+ types. Patient's GluR3B peptide antibodies were affinity-purified, and by themselves precipitated short 70 kDa neuronal GluR3. NS patient's affinity-purified GluR3B peptide antibodies also bound to, induced Reactive Oxygen Species (ROS) in, and killed both human neural cells and T cells within 1-2 hours only. NS patient's purified IgGs, or serum (1:10 or 1:30), induced similar effects. In vivo video EEG experiments in normal mice, revealed that when NS patient's purified IgGs were released continuously (24/7 for 1 week) in normal mouse brain, they induced all the following: 1.Seizures, 2. Cerebellar Purkinje cell loss, 3. Degeneration in the hippocampus and cerebral cortex, and 4. Elevation of CD3+ T cells, and of activated Mac-2+microglia and GFAP+astrocytes in both the gray and white matter of the cerebral cortex, hippocampus, corpus calossum and cerebellum of mice. NS patient's serum cytokines: IL-1β, IL-2, IL-6, IL-8, TNFα, IFNγ, are reduced by 85-99% compared to healthy subjects, suggesting severe immunodeficiency in NS patients. This suspected immunodeficiency could be caused by combined effects of the: 1. Chronic Ov infection, 2. Malnutrition, 3. Killing of NS patient's T cells by patient's own GluR3B peptide autoimmune antibodies (alike the killing of normal human T cells by the NS patient's GluR3B peptide antibodies found herein in vitro). CONCLUSIONS: Regardless of NS etiology, NS patients suffer from 'Dual-targeted Autoimmune Sword': autoimmune AMPA GluR3B peptide antibodies that bind, induce ROS in, and kill both neural cells and T cells. These neurotoxic and immunotoxic GluR3B peptide autoimmune antibodies, and also NS patient's NMDA-NR1/NR2A and Ov/Leiomodin-1 autoimmune antibodies, must be silenced or removed. Moreover, the findings of this study are relevant not only to NS, but also to many more patients with other types of epilepsy, which have GluR3B peptide antibodies in serum and/or CSF. This claim is based on the following facts: 1. The GluR3 subunit is expressed in neural cells in crucial brains regions, in motor neurons in the spinal cord, and also in other cells in the body, among them T cells of the immune system, 2. The GluR3 subunit has diverse neurophysiological role, and its deletion or abnormal function can: disrupt oscillatory networks of both sleep and breathing, impair motor coordination and exploratory activity, and increase the susceptibility to generate seizures, 3. GluR3B peptide antibodies were found so far in ~27% of >300 epilepsy patients worldwide, which suffer from various other types of severe, intractable and enigmatic epilepsy, and which turned out to be 'Autoimmune Epilepsy'. Furthermore, the findings of this study could be relevant to different neurological diseases besides epilepsy, since other neurotransmitter-receptors autoantibodies are present in other neurological and psychiatric diseases, e.g. autoimmune antibodies against other GluRs, Dopamine receptors, GABA receptors, Acetylcholine receptors and others. These neurotransmitter-receptors autoimmune autoantibodies might also act as 'Dual-targeted Autoimmune Sword' and damage both neural cells and T cells (as the AMPA-GluR3B peptide antibodies induced in the present study), since T cells, alike neural cells, express most if not all these neurotransmitter receptors, and respond functionally to the respective neurotransmitters - a scientific and clinical topic we coined 'Nerve-Driven Immunity'.

This article analyses the reactions of Israel’s academic elite to the 1977 political upheaval. Some of Israel’s leading scholars in humanities and social sciences framed the new political situation...

The article describes complications following dental implant dislocation into the maxillary sinus and their management and attempts to elucidate the reasons for these complications and their prevention. This retrospective study presents 55 cases of dental implant migration into the maxillary sinus. Patients were 30 men and 25 women with average age of 58 years. Oroantral communication was found in 46 cases, primarily in cases without prior bone augmentation, in patients aged older than 60 years (mean), and medically compromised patients (ASA > 1). The dislocated implant and the infected tissue were removed from the sinus in most cases by Caldwell-luc intervention. The oroantral communication was closed by local and regional flaps. In most of the cases, the oroantral communication was closed by a single intervention. The conclusion was that oroantral communication and maxillary sinusitis are common findings following dental implant migration and dislocation into the maxillary sinus. The risk factors for these complications were dental implantation in the posterior maxilla without sufficient alveolar bone, implantation without prior maxillary sinus augmentation, and older and medically compromised patients. Successful closure of the communication is usually performed with local or regional flaps.

As simplistic and self-evident as it may seem, the 1977 political upheaval in Israel is important on two different levels, each in itself sufficient for defining it as one of the most dramatic mome...

BACKGROUND: Systemic protumorigenic effects have been noted after radiofrequency ablation (RFA) of normal liver and have been linked to an interleukin 6/signal transducer and activator of transcription 3 (STAT3)/hepatocyte growth factor (HGF)/tyrosine-protein kinase Met (c-Met)/vascular endothelial growth factor (VEGF) cytokinetic pathway. PURPOSE: To elucidate kinetics of RFA protumorigenic effects on intrahepatic metastatic implantation and growth and determine potential molecular targets for pharmacologic suppression of these effects. MATERIALS AND METHODS: An intrahepatic metastasis model was established by implanting CT26 and MC38 tumor cells into 216 7–8-week-old male Balb/C and C57BL6 mice, respectively, by means of splenic injection. Between June 2017 and March 2019, mice underwent tumor injection, followed 24 hours later by either standardized RFA (70°C ± 1, 5 minutes, 1-cm tip) or a sham procedure (needle placement without heating) (12 animals per arm, n = 48). Next, RFA or sham procedures were performed, followed by splenic tumor cell injection at 1 day, 3 days, or 7 days later (six animals per arm, n = 72). Finally, PHA-665752 and S3I-201 were used to block c-Met or STAT3, respectively, prior to either RFA or sham treatment (six animals per arm, n = 96). Livers were harvested at 14 days for CT26 and 21days for MC38 for tumor quantification. Ki-67 and CD34 immunohistochemistry measured proliferative indexes and microvascular density, respectively. Data were compared with analysis of variance and the two-tailed Student t test. RESULTS: RFA performed after tumor cell injection induced increased metastatic tumor number (103 ± 45 vs 52 ± 44 [CT26], P = .009 and 87 ± 51 vs 39 ± 20 [MC38], P = .007), cellular proliferation (P < .001 for both), and intratumoral neovascularization (P < .001 for both), compared with the sham procedure. Tumor cell injection performed 1 day and 3 days after RFA also increased these indexes (P < .05), while no difference was demonstrated for cell injection 7 days after RFA (P > .05). Adjuvant c-Met or STAT3 inhibition reduced intrahepatic metastatic parameters after RFA to baseline (P < .03), equivalent to the sham group (P > .05). CONCLUSION: Radiofrequency ablation of normal liver promotes intrahepatic metastatic implantation and increased growth over a short-lived (1–3 days) temporal window in animal models. This phenomenon can be potentially neutralized with specific inhibition of pathways including hepatocyte growth factor/tyrosine-protein kinase Met and signal transducer and activator of transcription 3. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Nikolic in this issue.

Cet article se propose d’analyser le discours de reparation d’image de la droite israelienne durant la crise militaire de l’ete 2006, qui se deroule peu apres une campagne electorale ou la droite ideologique subit une defaite importante. Utilisant le modele analytique de la rhetorique de reparation d’image, l’analyse s’effectue a l’intersection de deux courants theoriques : l’analyse du discours polemique, telle que developpee dans l’ecole francaise de l’argumentation et de l’analyse du discours, et les approches discursive et rhetorique dans l’etude des mouvements sociaux. A partir d’un corpus d’articles d’opinion, nous explorons ici un aspect peu etudie de la pratique de reparation d’image : les roles de la polarisation et du retravail d’ethos d’un locuteur collectif, et la facon dont cette pratique fonctionne comme instrument de renforcement de la perception de soi qu’a un groupe social.

To determine the role of hepatic radiofrequency ablation (RFA) heating parameters and their activation of heat shock proteins (HSPs) in modulating distant tumor growth.First, to study the effects of RFA dose on distant tumor growth, rats with subcutaneous R3230 adenocarcinoma (10 ± 1 mm) were assigned to 3 different hepatic RF doses (60 °C × 10 min, 70 °C × 5 min or 90 °C × 2 min) that induced identical sized ablation or sham (n = 6/arm). Post-RFA tumor growth rates, cellular proliferation (Ki-67) and microvascular density (MVD) were compared at 7d. Next, the effect of low and high power doses on local HSP70 expression and cellular infiltration (α-SMA + myofibroblasts and CD68 + macrophages), cytokine (IL-6) and growth factor (HGF and VEGF) expression was assessed. Finally, 60 °C × 10 min and 90 °C × 2 min RFA were combined with anti-HSP micellar quercetin (MicQ, 2 mg/ml). A total of 150 animals were used.Lower RF heating (70 °C × 5 min and 60 °C × 10 min) resulted in larger distant tumors at 7d (19.2 ± 0.8 mm for both) while higher RF heating (90 °C × 2) led to less distant tumor growth (16.7 ± 1.5 mm, p .01 for both), though increased over sham (13.5 ± 0.5 mm, p .01). Ki-67 and MVD correlated with tumor growth (p .01 for all). Additionally, lower dose 60 °C × 10 min hepatic RFA had more periablational HSP70 compared to 90 °C × 2 min (rim: 1.106 ± 163 µm vs. 360 ± 18 µm, p .001), with similar trends for periablational α-SMA, CD68 and CDC47 (p .01 for all). Anti-HSP70 MicQ blocked distant tumor growth for lower dose (60 °C × 10: RF/MicQ 14.6 ± 0.4 mm vs. RF alone: 18.1 ± 0.4 mm, p .01) and higher dose RFA (90 °C × 2 min: RF/MicQ 14.6 ± 0.5 mm vs. RF alone: 16.4 ± 0.7 mm, p .01).Hepatic RF heating parameters alter periablational HSP70, which can influence and stimulate distant tumor growth. Modulation of RF heating parameters alone or in combination with adjuvant HSP inhibition can reduce unwanted, off-target systemic tumorigenic effects.

This article explores the modalities by which referring to past discursive performance of adversaries within a continuous polemical exchange is used in ad hominem attacks. Our starting point holds that in the context of lengthy debates, participants and third-party listeners share a rhetorical memory, which, dynamic and subjective as it may be, allows for the evaluation of participants’ characters based on their perceived discursive performances. By analysing opinion articles related to the Israeli political debate, this study shows how drawing inference from adversaries’ prior statements and conduct is used to compromise their credibility as participants in the polemical exchange. It is found that, alongside supporting arguments from inconsistent commitment, previous discursive performance is mobilized to discredit speakers’ epistemic authority (by demonstrating how the adversary’s prior statements were false) and their moral legitimacy (by demonstrating that the adversary failed to act as a fair interlocutor).