Therapeutic efficacy of combining PEGylated liposomal doxorubicin and radiofrequency (RF) ablation: Comparison between slow-drug-releasing, non-thermosensitive and fast-drug-releasing, thermosensitive nano-liposomes
Andriyanov A.V.,Institute for Medical Research Israel Canada |
Koren E.,Institute for Medical Research Israel Canada |
Barenholz Y.,Institute for Medical Research Israel Canada |
Goldberg S.N.,Hebrew University of Jerusalem |
Goldberg S.N.,Beth Israel Deaconess Medical Center
PLoS ONE | Year: 2014
Aims: To determine how the accumulation of drug in mice bearing an extra-hepatic tumor and its therapeutic efficacy are affected by the type of PEGylated liposomal doxorubicin used, treatment modality, and rate of drug release from the liposomes, when combined with radiofrequency (RF) ablation. Materials and Methods: Two nano-drugs, both long-circulating PEGylated doxorubicin liposomes, were formulated: (1) PEGylated doxorubicin in thermosensitive liposomes (PLDTS), having a burst-type fast drug release above the liposomes' solid ordered to liquid disordered phase transition (at 42°C), and (2) non-thermosensitive PEGylated doxorubicin liposomes (PLDs), having a slow and continuous drug release. Both were administered intravenously at 8 mg/kg doxorubicin dose to tumor-bearing mice. Animals were divided into 6 groups: no treatment, PLD, RF, RF+PLD, PLDTS, and PLDTS+RF, for intratumor doxorubicin deposition at 1, 24, and 72 h post-injection (in total 41, mice), and 31 mice were used for randomized survival studies. Results: Non-thermosensitive PLD combined with RF had the least tumor growth and the best end-point survival, better than PLDTS+RF (p<0.005) or all individual therapies (p<0.001). Although at 1 h post-treatment the greatest amount of intra-tumoral doxorubicin was seen following PLDTS+RF (p<0.05), by 24 and 72 h the greatest doxorubicin amount was seen for PLD+RF (p<0.05); in this group the tumor also has the longest exposure to doxorubicin. Conclusion: Optimizing therapeutic efficacy of PLD requires a better understanding of the relationship between the effect of RF on tumor microenvironment and liposome drug release profile. If drug release is too fast, the benefit of changing the microenvironment by RF on tumor drug localization and therapeutic efficacy may be much smaller than for PLDs having slow and temperature-independent drug release. Thus the much longer circulation time of doxorubicin from PLD than from PLDTS may be beneficial in many therapeutic instances, especially in extra-hepatic tumors. © 2014 Andriyanov et al.
Bulvik B.E.,Goldyne Savad Institute of Gene Therapy |
Rozenblum N.,Goldyne Savad Institute of Gene Therapy |
Gourevich S.,Goldyne Savad Institute of Gene Therapy |
Ahmed M.,Beth Israel Deaconess Medical Center |
And 5 more authors.
Radiology | Year: 2016
Purpose: To compare both periablational and systemic effects of two mechanistically different types of ablation: thermal radiofrequency (RF) ablation and electroporative ablation with irreversible electroporation (IRE) in appropriately selected animal models. Materials and Methods: Animal experiments were performed according to a protocol approved by the Animal Care Committee of Hebrew University. Female C57BL/6 mice (n = 165) were randomized to undergo either RF or IRE ablation of noncancerous normal liver. The inflammatory response, cell proliferation, interleukin 6 (IL-6) levels, and intactness of vessels in the liver were assessed at 6, 12, and 24 hours and at 3, 7, and 14 days after ablation (n = 122 for mechanistic experiments). Systemic effects were then assessed by comparing tumor formation in an Mdr2-knockout (KO) mouse model (n = 15) and tumor growth in a remote BNL 1ME hepatoma xenograft tumor (n = 28). Results were averaged and evaluated by using two-tailed t tests. Results: Although RF ablation was associated with a well-defined periablational inflammatory rim, for IRE, the infiltrate penetrated the ablation zone, largely along persistently patent vessels. Peak IL-6 levels (6 hours after ablation) were 10 and three times higher than at baseline for IRE and RF, respectively (P <.03). Mdr2-KO mice that were treated with IRE ablation had more tumors that were 3 mm or larger than mice treated with RF ablation or sham operation (mean, 3.6 ± 1.3 [standard deviation] vs 2.4 ± 1.1 and 2.2 ± 0.8, respectively; P <.05 for IRE vs both RF ablation and sham operation). For BNL 1ME tumors, both RF and IRE liver ablation reduced tumor growth, with a greater effect noted for IRE (1329 mm3 ± 586 and 819 mm3 ± 327 vs 2241 mm3 ± 548 for sham operation; P <.05) that was accompanied by more infiltrating lymphocytes compared with sham operation (7.6 cells per frame ± 1.9 vs 11.2 ± 2.1 vs 0.3 ± 0.1; P <.05). Conclusion: Persistent patency of vasculature within the coagulated zone from IRE increases the area and accumulation of infiltrative cells that is associated with a higher serum IL-6 level than RF ablation. These local changes of IRE induce more robust systemic effects, including both tumorigenic and immunogenic effects. © 2016 RSNA.
Faucher S.P.,Columbia University |
Friedlander G.,Institute for Medical Research Israel Canada |
Livny J.,Cambridge Broad Institute |
Livny J.,Harvard University |
And 2 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010
Legionella pneumophila is a Gram-negative opportunistic human pathogen that infects and multiplies in a broad range of phagocytic protozoan and mammalian phagocytes. Based on the observation that small regulatory RNAs (sRNAs) play an important role in controlling virulence-related genes in several pathogenic bacteria, we attempted to identify sRNAs expressed by L. pneumophila. We used computational prediction followed by experimental verification to identify and characterize sRNAs encoded in the L. pneumophila genome. A 50-mer probe microarray was constructed to test the expression of predicted sRNAs in bacteria grown under a variety of conditions. This strategy successfully identified 22 expressed RNAs, out of which 6 were confirmed by northern blot and RACE. One of the identified sRNAs is highly expressed in postexponential phase, and computational prediction of its secondary structure reveals a striking similarity to the structure of 6S RNA, a widely distributed prokaryotic sRNA, known to regulate the activity of 70-containing RNA polymerase. A 70-mer probe microarray was used to identify genes affected by L. pneumophila 6S RNA in stationary phase. The 6S RNA positively regulates expression of genes encoding type IVB secretion system effectors, stress response genes such as groES and recA, as well as many genes involved in acquisition of nutrients and genes with unknown or hypothetical functions. Deletion of 6S RNA significantly reduced L. pneumophila intracellular multiplication in both protistand mammalianhost cells, but had no detectable effect on growth in rich media.
Kurek K.C.,Harvard University |
Del Mare S.,Institute for Medical Research Israel Canada |
Salah Z.,Institute for Medical Research Israel Canada |
Abdeen S.,Institute for Medical Research Israel Canada |
And 14 more authors.
Cancer Research | Year: 2010
The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor that is deleted or attenuated in most human tumors. Wwox-deficient mice develop osteosarcoma (OS), an aggressive bone tumor with poor prognosis that often metastasizes to lung. On the basis of these observations, we examined the status of WWOX in human OS specimens and cell lines. In human OS clinical samples, WWOX expression was absent or reduced in 58% of tumors examined (P < 0.0001). Compared with the primary tumors, WWOX levels frequently increased in tumors resected following chemotherapy. In contrast, tumor metastases to lung often exhibited reduced WWOX levels relative to the primary tumor. In human OS cell lines having reduced WWOX expression, ectopic expression of WWOX inhibited proliferation and attenuated invasion in vitro, and suppressed tumorigenicity in nude mice. Expression of WWOX was associated with reduced RUNX2 expression in OS cell lines, whereas RUNX2 levels were elevated in femurs of Wwox-deficient mice. Furthermore, WWOX reconstitution in HOS cells was associated with downregulation of RUNX2 levels and RUNX2 target genes, consistent with the ability of WWOX to suppress RUNX2 transactivation activity. In clinical samples, RUNX2 was expressed in the majority of primary tumors and undetectable in most tumors resected following chemotherapy, whereas most metastases were RUNX2 positive. Our results deepen the evidence of a tumor suppressor role for WWOX in OS, furthering its prognostic and therapeutic significance in this disease. ©2010 AACR.
Reich L.,Institute for Medical Research Israel Canada |
Maidenbaum S.,Institute for Medical Research Israel Canada |
Amedi A.,Institute for Medical Research Israel Canada |
Amedi A.,Hebrew University of Jerusalem
Current Opinion in Neurology | Year: 2012
Purpose of review: The exciting view of our brain as highly flexible task-based and not sensory-based raises the chances for visual rehabilitation, long considered unachievable, given adequate training in teaching the brain how to see. Recent advances in rehabilitation approaches, both noninvasive, like sensory substitution devices (SSDs) which present visual information using sound or touch, and invasive, like visual prosthesis, may potentially be used to achieve this goal, each alone, and most preferably together. Recent findings: Visual impairments and said solutions are being used as a model for answering fundamental questions ranging from basic cognitive neuroscience, showing that several key visual brain areas are actually highly flexible, modality-independent and, as was recently shown, even visual experience-independent task machines, to technological and behavioral developments, allowing blind persons to 'see' using SSDs and other approaches. Summary: SSDs can be potentially used as a research tool for assessing the brain's functional organization; as an aid for the blind in daily visual tasks; to visually train the brain prior to invasive procedures, by taking advantage of the 'visual' cortex's flexibility and task specialization even in the absence of vision; and to augment postsurgery functional vision using a unique SSD-prostheses hybrid. Taken together the reviewed results suggest a brighter future for visual neuro-rehabilitation. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Sade-Feldman M.,Institute for Medical Research Israel Canada |
Kanterman J.,Institute for Medical Research Israel Canada |
Ish-Shalom E.,Institute for Medical Research Israel Canada |
Elnekave M.,Hebrew University of Jerusalem |
And 2 more authors.
Immunity | Year: 2013
Elevated concentrations of tumor necrosis factor-α (TNF-α) are detected in pathologies characterized by chronic inflammation. Whether TNF-α plays a role in manipulating the host's immune system toward generating an immunosuppressive milieu, typical of ongoing chronic inflammation, is unclear. Here we showed that TNF-α exhibited a dual function during chronic inflammation: arresting differentiation of immature myeloid-derived suppressor cells (MDSCs) primarily via the S100A8 and S100A9 inflammatory proteins and their corresponding receptor (RAGE) and augmenting MDSC suppressive activity. These functions led to in vivo T and NK cell dysfunction accompanied by T cell antigen receptor ζ chain downregulation. Furthermore, administration of etanercept (TNF-α antagonist) during early chronic inflammatory stages reduced MDSCs' suppressive activity and enhanced their maturation into dendritic cells and macrophages, resulting in the restoration of in vivo immune functions and recovery of ζ chain expression. Thus, TNF has a fundamental role in promoting an immunosuppressive environment generated during chronic inflammation. © 2013 Elsevier Inc.
Salpeter S.J.,Institute for Medical Research Israel Canada |
Khalaileh A.,Institute for Medical Research Israel Canada |
Weinberg-Corem N.,Institute for Medical Research Israel Canada |
Ziv O.,Institute for Medical Research Israel Canada |
And 2 more authors.
Diabetes | Year: 2013
The frequency of pancreatic β-cells replication declines dramatically with age, potentially contributing to the increased risk of type 2 diabetes in old age. Previous studies have shown the involvement of cell-Autonomous factors in this phenomenon, particularly the decline of polycomb genes and accumulation of p16/INK4A. Here, we demonstrate that a systemic factor found in the circulation of young mice is able to increase the proliferation rate of old pancreatic β-cells. Old mice parabiosed to young mice have increased β-cells replication compared with unjoined old mice or old mice parabiosed to old mice. In addition, we demonstrate that old β-cells transplanted into young recipients have increased replication rate compared with cells transplanted into old recipients; conversely, young β-cells transplanted into old mice decrease their replication rate compared with young cells transplanted into young recipients. The expression of p16/INK4A mRNA did not change in heterochronic parabiosis, suggesting the involvement of other pathways. We conclude that systemic factors contribute to the replicative decline of old pancreatic β-cells. © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
London N.,Institute for Medical Research Israel Canada |
Raveh B.,Institute for Medical Research Israel Canada |
Raveh B.,Tel Aviv University |
Schueler-Furman O.,Institute for Medical Research Israel Canada
Methods in Molecular Biology | Year: 2012
Peptide-protein interactions are prevalent in the living cell and form a key component of the overall protein-protein interaction network. These interactions are drawing increasing interest due to their part in signaling and regulation, and are thus attractive targets for computational structural modeling. Here we report an overview of current techniques for the high resolution modeling of peptide-protein complexes. We dissect this complicated challenge into several smaller subproblems, namely: modeling the receptor protein, predicting the peptide binding site, sampling an initial peptide backbone conformation and the final refinement of the peptide within the receptor binding site. For each of these conceptual stages, we present available tools, approaches, and their reported performance. We summarize with an illustrative example of this process, highlighting the success and current challenges still facing the automated blind modeling of peptide-protein interactions. We believe that the upcoming years will see considerable progress in our ability to create accurate models of peptide-protein interactions, with applications in binding-specificity prediction, rational design of peptide-mediated interactions and the usage of peptides as therapeutic agents. © 2011 Springer Science+Business Media,LLC.
Amit-Avraham I.,Institute for Medical Research Israel Canada |
Pozner G.,Institute for Medical Research Israel Canada |
Eshar S.,Institute for Medical Research Israel Canada |
Fastman Y.,Institute for Medical Research Israel Canada |
And 3 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2015
The virulence of Plasmodium falciparum, the causative agent of the deadliest form of human malaria, is attributed to its ability to evade human immunity through antigenic variation. These parasites alternate between expression ofvariable antigens, encoded by members of a multicopy gene family named var. Immune evasion through antigenic variation depends on tight regulation of var gene expression, ensuring that only a single var gene is expressed at a time while the rest of the family is maintained transcriptionally silent. Understanding how a single gene is chosen for activation is critical for understanding mutually exclusive expression but remains a mystery. Here, we show that antisense long noncoding RNAs (lncRNAs) initiating from var introns are associated with the single active var gene at the time in the cell cycle when the single var upstream promoter is active. We demonstrate that these antisense transcripts are incorporated into chromatin, and that expression of these antisense lncRNAs in trans triggers activation of a silent var gene in a sequence- and dose-dependent manner. On the other hand, interference with these lncRNAs using complement peptide nucleic acid molecules down-regulated the active var gene, erased the epigenetic memory, and induced expression switching. Altogether, our data provide evidence that these antisense lncRNAs play a key role in regulating var gene activation and mutually exclusive expression.
Betser-Cohen G.,Institute for Medical Research Israel Canada |
Mizrahi S.,Institute for Medical Research Israel Canada |
Elboim M.,Institute for Medical Research Israel Canada |
Alsheich-Bartok O.,Institute for Medical Research Israel Canada |
Mandelboim O.,Institute for Medical Research Israel Canada
Journal of Immunology | Year: 2010
The killing activity of NK cells is carried out by several activating NK receptors, which includes NKp46, NKp44, NKp30, NKp80, NKG2D, and 2B4. The ligands of these receptors are either self-derived, pathogen-derived, stress-induced ligands or tumor ligands. Importantly, none of these killer ligands are expressed on NK cells and thus self-killing of NK cells is prevented. A notable exception with this regard, is the ligand of the 2B4 receptor. This unusual receptor can exert both activating and inhibiting signals; however, in human NK cells, it serves mainly as an activating receptor. The ligand of 2B4 is CD48 and in contrast to the ligands of all the other NK activating receptors, CD48 is also present on NK cells. Thus, NK cells might be at risk for self-killing that is mediated via the 2B4-CD48 interaction. In this study, we identify a novel mechanism that prevents this self-killing as we show that the association of the MHC class I proteins with the 2B4 receptor, both present on NK cells, results in the attenuation of the 2B4-mediated self-killing of NK cells. Copyright © 2010 by The American Association of Immunologists, Inc.