L. N Driessen, Stappers, B. W, Tremou, E. , Fender, R. P, Woudt, P. A, Armstrong, R. , Bloemen, S. , Groot, P. , Heywood, I. , Horesh, A. , van der Horst, A. J, Koerding, E. , McBride, V. A, Miller-Jones, J. CA, Mooley, K. P, Rowlinson, A. , ו Wijers, R. AMJ. 2022.
“21 New Long-Term Variables In The Gx 339-4 Field: Two Years Of Meerkat Monitoring”. \Mnras, 512, Pp. 5037-5066. doi:10.1093/mnras/stac756.
C Bergmann, Poli, A, Agache, I, Bianchini, R, Bax, HJ, Castells, M, Crescioli, S, Dombrowicz, D, Ferastraoaru, D, Fiebiger, E, Gould, HJ, Hartmann, K, Izquierdo, E, Jordakieva, G, Josephs, DH, Jutel, M, Levi-Schaffer, F, de Las Vecillas, L, Lotze, MT, Osborn, G, Pascal, M, Redegeld, F, Rosenstreich, D, Roth-Walter, F, Schmidt-Weber, CB, Shamji, M, Steveling, EH, Turner, MC, Untersmayr, E, Jensen-Jarolim, E, ו Karagiannis, SN. 2022.
“Allergooncology: Danger Signals In Allergology And Oncology. A European Academy Of Allergy And Clinical Immunology (Eaaci) Position Paper.”. Allergy. doi:10.1111/all.15255.
תקציר The immune system interacts with many nominal 'danger' signals, endogenous danger-associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)-associated molecular pattern molecules. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs, and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regards to clinical responses to anti-cancer immune and targeted therapies. Cross-disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes.
O. Vorontsov, Levitt, L. , Lilleri, D. , Vainer, G. W. , Kaplan, O. , Schreiber, L. , Arossa, A. , Spinillo, A. , Furione, M. , Alfi, O. , Oiknine-Djian, E. , Kupervaser, M. , Nevo, Y. , Elgavish, S. , Yassour, M. , Zavattoni, M. , Bdolah-Abram, T. , Baldanti, F. , Geal-Dor, M. , Zakay-Rones, Z. , Yanay, N. , Yagel, S. , Panet, A. , ו Wolf, D. G.. 2022.
“Amniotic Fluid Biomarkers Predict The Severity Of Congenital Cytomegalovirus Infection”. J Clin Invest, 132.
תקציר BACKGROUNDCytomegalovirus (CMV) is the most common intrauterine infection, leading to infant brain damage. Prognostic assessment of CMV-infected fetuses has remained an ongoing challenge in prenatal care, in the absence of established prenatal biomarkers of congenital CMV (cCMV) infection severity. We aimed to identify prognostic biomarkers of cCMV-related fetal brain injury.METHODSWe performed global proteome analysis of mid-gestation amniotic fluid samples, comparing amniotic fluid of fetuses with severe cCMV with that of asymptomatic CMV-infected fetuses. The levels of selected differentially excreted proteins were further determined by specific immunoassays.RESULTSUsing unbiased proteome analysis in a discovery cohort, we identified amniotic fluid proteins related to inflammation and neurological disease pathways, which demonstrated distinct abundance in fetuses with severe cCMV. Amniotic fluid levels of 2 of these proteins - the immunomodulatory proteins retinoic acid receptor responder 2 (chemerin) and galectin-3-binding protein (Gal-3BP) - were highly predictive of the severity of cCMV in an independent validation cohort, differentiating between fetuses with severe (n = 17) and asymptomatic (n = 26) cCMV, with 100%-93.8% positive predictive value, and 92.9%-92.6% negative predictive value (for chemerin and Gal-3BP, respectively). CONCLUSIONAnalysis of chemerin and Gal-3BP levels in mid-gestation amniotic fluids could be used in the clinical setting to profoundly improve the prognostic assessment of CMV-infected fetuses.FUNDINGIsrael Science Foundation (530/18 and IPMP 3432/19); Research Fund - Hadassah Medical Organization.
N. Rosenberg, Van Haele, M. , Lanton, T. , Brashi, N. , Bromberg, Z. , Adler, H. , Giladi, H. , Peled, A. , Goldenberg, D. S. , Axelrod, J. H. , Simerzin, A. , Chai, C. , Paldor, M. , Markezana, A. , Yaish, D. , Shemulian, Z. , Gross, D. , Barnoy, S. , Gefen, M. , Amran, O. , Claerhout, S. , Fernandez-Vaquero, M. , Garcia-Beccaria, M. , Heide, D. , Shoshkes-Carmel, M. , Schmidt Arras, D. , Elgavish, S. , Nevo, Y. , Benyamini, H. , Tirnitz-Parker, J. E. E. , Sanchez, A. , Herrera, B. , Safadi, R. , Kaestner, K. H. , Rose-John, S. , Roskams, T. , Heikenwalder, M. , ו Galun, E.. 2022.
“Combined Hepatocellular-Cholangiocarcinoma Derives From Liver Progenitor Cells And Depends On Senescence And Il6 Trans-Signaling”. J Hepatol.
תקציר BACKGROUND AND AIMS: Primary liver cancers include: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA) and combined HCC-CCA tumors (cHCC-CCA). It has been suggested, but not unequivocally proven, that hepatic progenitor cells (HPCs) can contribute to hepatocarcinogenesis. We aimed to determine whether HPCs contribute to HCC, cHCC-CCA or both types of tumors. METHOD: To trace progenitor cells during hepatocarcinogenesis, we generated Mdr2-KO mice that harbor an YFP reporter gene driven by the Foxl1 promoter which is expressed specifically in progenitor cells. These mice (Mdr2-KO(Foxl1-CRE;RosaYFP)) develop chronic inflammation and HCCs by the age of 14-16 months, followed by cHCC-CCA tumors at the age of 18 months, as we have first observed. RESULTS: In this Mdr2-KO(Foxl1-CRE;RosaYFP) mouse model, liver progenitor cells are the source of cHCC-CCA tumors, but not the source of HCC. Ablating the progenitors, caused reduction of cHCC-CCA tumors but did not affect HCCs. RNA-seq revealed enrichment of the IL6 signaling pathway in cHCC-CCA tumors compared to HCC tumors. ScRNA-seq analysis revealed that IL6 is expressed from immune and parenchymal cells in senescence, and that IL6 is part of the senescence-associated secretory phenotype (SASP). Administration of anti-IL6 Ab to Mdr2-KO(Foxl1-CRE;RosaYFP) mice, inhibited the development of cHCC-CCA tumors. By blocking IL6 trans-signaling, cHCC-CCA tumors decreased in number and size, indicating that cHCC-CCA is dependent on IL6 trans-signaling. Furthermore, the administration of a senolytic agent inhibited IL6 and the development of cHCC-CCA tumors. CONCLUSION: Our results demonstrate that cHCC-CCA, but not HCC tumors, originate from HPCs, and that IL6, which derives in part from cells in senescence, plays an important role in this process via IL6 trans-signaling. These findings could enhance new therapeutic approaches for cHCC-CCA liver cancer. LAY SUMMARY: Combined hepatocellular carcinoma - cholangiocarcinoma is the third prevalent liver cancer. We show that the source of this tumor is the liver tissue stem cells and that, this tumor type is dependent on an inflammatory signaling of IL6 and can be inhibited by blocking IL6 signaling or using a senolytic agent.
