Papers by Rinat Abramovitch
Supplemental Figures and Tables
Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which ... more Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2−/−) mouse model to elucidate potential roles of IL6 in chronic hepatitis–associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling–deficient Mdr2−/− strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These find...
Expression levels of genes in CXCR4 overexpressing cell lines
Supplementary figure 4. FACS analysis of BCL-2 expression on the native SK-N-BE(2) cell line (pur... more Supplementary figure 4. FACS analysis of BCL-2 expression on the native SK-N-BE(2) cell line (purple) and on SK-N-BE(2) cells transduced to overexpress CXCR4 (green).
miR-15a and miR-16-1 levels following transfection into NB cells
miR-15a and miR-16-1 expression following antagomiR transfection
CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we desc... more CXCR4 expression in neuroblastoma tumors correlates with disease severity. In this study, we describe mechanisms by which CXCR4 signaling controls neuroblastoma tumor growth and response to therapy. We found that overexpression of CXCR4 or stimulation with CXCL12 supports neuroblastoma tumorigenesis. Moreover, CXCR4 inhibition with the high-affinity CXCR4 antagonist BL-8040 prevented tumor growth and reduced survival of tumor cells. These effects were mediated by the upregulation of miR-15a/16-1, which resulted in downregulation of their target genes BCL-2 and cyclin D1, as well as inhibition of ERK. Overexpression of miR-15a/16-1 in cells increased cell death, whereas antagomirs to miR-15a/16-1 abolished the proapoptotic effects of BL-8040. CXCR4 overexpression also increased miR-15a/16-1, shifting their oncogenic dependency from the BCL-2 to the ERK signaling pathway. Overall, our results demonstrate the therapeutic potential of CXCR4 inhibition in neuroblastoma treatment and prov...
International Journal of Molecular Sciences
Obstructive sleep apnea (OSA) is a highly prevalent condition, characterized by intermittent hypo... more Obstructive sleep apnea (OSA) is a highly prevalent condition, characterized by intermittent hypoxia (IH), sleep disruption, and altered autonomic nervous system function. OSA has been independently associated with dyslipidemia, insulin resistance, and metabolic syndrome. Brown adipose tissue (BAT) has been suggested as a modulator of systemic glucose tolerance through adaptive thermogenesis. Reductions in BAT mass have been associated with obesity and metabolic syndrome. No studies have systematically characterized the effects of chronic IH on BAT. Thus, we aimed to delineate IH effects on BAT and concomitant metabolic changes. C57BL/6J 8-week-old male mice were randomly assigned to IH during sleep (alternating 90 s cycles of 6.5% FIO2 followed by 21% FIO2) or normoxia (room air, RA) for 10 weeks. Mice were subjected to glucose tolerance testing and 18F-FDG PET–MRI towards the end of the exposures followed by BAT tissues analyses for morphological and global transcriptomic changes....
Cells
Liver resection is a common treatment for various conditions and often requires blood transfusion... more Liver resection is a common treatment for various conditions and often requires blood transfusions to compensate for operative blood loss. As partial hepatectomy (PHx) is frequently performed in patients with a pre-damaged liver, avoiding further injury is of paramount clinical importance. Our aim was to study the impact of red blood cell (RBC) resuscitation on liver regeneration. We assessed the impact of RBC storage time on liver regeneration following 50% PHx in rats and explored possible contributing molecular mechanisms using immunohistochemistry, RNA-Seq, and macrophage depletion. The liver was successfully regenerated after PHx when rats were transfused with fresh RBCs (F-RBCs). However, in rats resuscitated with stored RBCs (S-RBCs), the regeneration process was disrupted, as detected by delayed hepatocyte proliferation and lack of hypertrophy. The delayed regeneration was associated with elevated numbers of hemorrhage-activated liver macrophages (Mhem) secreting HO-1. Deple...
Nephrology Dialysis Transplantation, May 1, 2022
Journal of Hepatology, 2018
Cancer Research, 2021
Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which ... more Hepatocellular carcinoma (HCC) typically develops on a background of chronic hepatitis for which the proinflammatory cytokine IL6 is conventionally considered a crucial driving factor. Paradoxically, IL6 also acts as a hepatoprotective factor in chronic liver injury. Here we used the multidrug-resistant gene 2 knockout (Mdr2−/−) mouse model to elucidate potential roles of IL6 in chronic hepatitis–associated liver cancer. Long-term analysis of three separate IL6/Stat3 signaling–deficient Mdr2−/− strains revealed aggravated liver injury with increased dysplastic nodule formation and significantly accelerated tumorigenesis in all strains. Tumorigenesis in the IL6/Stat3-perturbed models was strongly associated with enhanced macrophage accumulation and hepatosteatosis, phenotypes of nonalcoholic steatohepatitis (NASH), as well as with significant reductions in senescence and the senescence-associated secretory phenotype (SASP) accompanied by increased hepatocyte proliferation. These find...
Journal of Hepatology, 2019
Journal of Hepatology, 2017
Journal of Hepatology, 2015
British journal of cancer, Jan 7, 2012
The poor prognosis of patients with colorectal-cancer liver metastases (CRLM) and the insufficien... more The poor prognosis of patients with colorectal-cancer liver metastases (CRLM) and the insufficiency of available treatments have raised the need for alternative curative strategies. We aimed to assess the therapeutic potential of TL-118, a new anti-angiogenic drug combination, for CRLM treatment, in a mouse model. The therapeutic potential of TL-118 was evaluated and compared with B20-4.1.1 (B20; anti-VEGF antibody) and rapamycin in CRLM-bearing mice. Tumour progression and the vascular changes were monitored by MRI. Additionally, mice survival, cell proliferation, apoptosis and vessel density were evaluated. This study demonstrated an unequivocal advantage to TL-118 therapy by significantly prolonging survival (threefold) and reducing metastasis perfusion and vessel density (ninefold). The underlying mechanism for TL-118-treatment success was associated with hepatic perfusion attenuation resulting from reduced nitric-oxide (NO) serum levels as elucidated by using hemodynamic respon...
Cell, 2006
Adult neovascularization relies on the recruitment of circulating cells, but their angiogenic rol... more Adult neovascularization relies on the recruitment of circulating cells, but their angiogenic roles and recruitment mechanisms are unclear. We show that the endothelial growth factor VEGF is sufficient for organ homing of circulating mononuclear myeloid cells and is required for their perivascular positioning and retention. Recruited bone marrow-derived circulating cells (RBCCs) summoned by VEGF serve a function distinct from endothelial progenitor cells. Retention of RBCCs in close proximity to angiogenic vessels is mediated by SDF1, a chemokine induced by VEGF in activated perivascular myofibroblasts. RBCCs enhance in situ proliferation of endothelial cells via secreting proangiogenic activities distinct from locally induced activities. Precluding RBCCs strongly attenuated the proangiogenic response to VEGF and addition of purified RBCCs enhanced angiogenesis in excision wounds. Together, the data suggest a model for VEGF-programmed adult neovascularization highlighting the essential paracrine role of recruited myeloid cells and a role for SDF1 in their perivascular retention.
Calcified Tissue International, 2004
Bone injury occurs in human hemolytic disorders associated with thrombosis, such as betathalassem... more Bone injury occurs in human hemolytic disorders associated with thrombosis, such as betathalassemia and sickle cell disease. Exposure of rats to 2butoxyethanol (BE) has been associated with hemolytic anemia, disseminated thrombosis, and infarction in multiple organs including bone. This rat model apparently mimics acute hemolysis and thrombosis in humans. To elucidate the extent of bone injury, male and female Fischer F344 rats were given 4 daily doses of 250 mg BE/5 ml water/kg of body weight. Tail vertebrae were studied by histopathology and magnetic resonance imaging (MRI). Thrombosis and infarction were seen in both sexes, but females were more severely affected. Lesions were characterized by extensive medullary fat necrosis, granulomatous inflammation, fibroplasia, growth plate degeneration, and new woven bone formation adjacent to necrotic bone trabeculae. MRI mean and standard deviation tissue-density data for both sexes indicated a significant (P £ 0.05) decrease following 4-days treatment and a significant increase (P £ 0.05) following an additional 24 days without treatment. Thus, MRI was useful in revealing BE-induced bone injury, which was predominantly necrotic initially and subsequently regenerative with proliferation of connective tissue and bone following postischemia recovery.
Supplemental Experimental Materials and Methods
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Papers by Rinat Abramovitch