Publications by authors named "Roni Rayes"

20 Publications

  • Page 1 of 1

Role of neutrophil extracellular traps in radiation resistance of invasive bladder cancer.

Nat Commun 2021 05 13;12(1):2776. Epub 2021 May 13.

Urologic Oncology Research Division, McGill University Health Centre, Montreal, Canada.

Radiation therapy (RT) is used in the management of several cancers; however, tumor radioresistance remains a challenge. Polymorphonuclear neutrophils (PMNs) are recruited to the tumor immune microenvironment (TIME) post-RT and can facilitate tumor progression by forming neutrophil extracellular traps (NETs). Here, we demonstrate a role for NETs as players in tumor radioresistance. Using a syngeneic bladder cancer model, increased NET deposition is observed in the TIME of mice treated with RT and inhibition of NETs improves overall radiation response. In vitro, the protein HMGB1 promotes NET formation through a TLR4-dependent manner and in vivo, inhibition of both HMGB1 and NETs significantly delays tumor growth. Finally, NETs are observed in bladder tumors of patients who did not respond to RT and had persistent disease post-RT, wherein a high tumoral PMN-to-CD8 ratio is associated with worse overall survival. Together, these findings identify NETs as a potential therapeutic target to increase radiation efficacy.
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http://dx.doi.org/10.1038/s41467-021-23086-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119713PMC
May 2021

Development of patient-specific 3D models from histopathological samples for applications in radiation therapy.

Phys Med 2021 Jan 15;81:162-169. Epub 2021 Jan 15.

Medical Physics Unit, Department of Oncology, Faculty of Medicine, McGill University, Montréal, Québec, Canada; Research Institute of the McGill University Health Center, Montréal, Québec, Canada; Lady Davis Institute for Medical Research, Jewish General Hospital, Montréal, Québec, Canada.

The biological effects of ionizing radiation depend on the tissue, tumor type, radiation quality, and patient-specific factors. Inter-patient variation in cell/nucleus size may influence patient-specific dose response. However, this variability in dose response is not well investigated due to lack of available cell/nucleus size data. The aim of this study was to develop methods to derive cell/nucleus size distributions from digital images of 2D histopathological samples and use them to build digital 3D models for use in cellular dosimetry. Nineteen of sixty hematoxylin and eosin stained lung adenocarcinoma samples investigated passed exclusion criterion to be analyzed in the study. A difference of gaussians blob detection algorithm was used to identify nucleus centers and quantify cell spacing. Hematoxylin content was measured to determine nucleus radius. Pouring simulations were conducted to generate one-hundred 3D models containing volumes of equivalent cell spacing and nuclei radius to those in histopathological samples. The nuclei radius distributions of non-tumoral and cancerous regions appearing in the same slide were significantly different (p < 0.01) in all samples analyzed. The median nuclear-cytoplasmic ratio was 0.36 for non-tumoral cells and 0.50 for cancerous cells. The average cellular and nucleus packing densities in the 3D models generated were 65.9% (SD: 1.5%) and 13.3% (SD: 0.3%) respectively. Software to determine cell spacing and nuclei radius from histopathological samples was developed. 3D digital tissue models containing volumes with equivalent cell spacing, nucleus radius, and packing density to cancerous tissues were generated.
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http://dx.doi.org/10.1016/j.ejmp.2020.12.009DOI Listing
January 2021

Casting A Wide Net On Surgery: The Central Role of Neutrophil Extracellular Traps.

Ann Surg 2020 08;272(2):277-283

Division of Upper GI and Thoracic Surgery, McGill University Health Centre, Montral, QC, Canada.

: Since their discovery, neutrophil extracellular traps (NETs) have been implicated in a broad array of functions, both beneficial and detrimental to the host. Indeed, NETs have roles in infection, sepsis, wound healing, thrombotic disease, and cancer propagation, all of which are directly implicated in the care of surgical patients. Here we provide an updated review on the role of NETs in the perioperative period with specific emphasis on perioperative infections, wound healing, vascular complications, cancer propagation, as well as discussing ongoing, and future therapeutic targets. Surgeons will benefit from understanding the latest discoveries in neutrophil biology and how these novel functions affect the care of surgical patients. Furthermore, novel anti-NET therapies are being developed which may have profound effects on the care of surgical patients.
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http://dx.doi.org/10.1097/SLA.0000000000003586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373444PMC
August 2020

Targeting potential drivers of COVID-19: Neutrophil extracellular traps.

J Exp Med 2020 06;217(6)

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY.

Coronavirus disease 2019 (COVID-19) is a novel, viral-induced respiratory disease that in ∼10-15% of patients progresses to acute respiratory distress syndrome (ARDS) triggered by a cytokine storm. In this Perspective, autopsy results and literature are presented supporting the hypothesis that a little known yet powerful function of neutrophils-the ability to form neutrophil extracellular traps (NETs)-may contribute to organ damage and mortality in COVID-19. We show lung infiltration of neutrophils in an autopsy specimen from a patient who succumbed to COVID-19. We discuss prior reports linking aberrant NET formation to pulmonary diseases, thrombosis, mucous secretions in the airways, and cytokine production. If our hypothesis is correct, targeting NETs directly and/or indirectly with existing drugs may reduce the clinical severity of COVID-19.
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http://dx.doi.org/10.1084/jem.20200652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161085PMC
June 2020

Neutrophil Extracellular Trap-Associated CEACAM1 as a Putative Therapeutic Target to Prevent Metastatic Progression of Colon Carcinoma.

J Immunol 2020 04 13;204(8):2285-2294. Epub 2020 Mar 13.

Cancer Research Program and the LD MacLean Surgical Research Laboratories, Department of Surgery, Research Institute of the McGill University Health Center, Montreal, Quebec H4A 3J1, Canada;

Neutrophils promote tumor growth and metastasis at multiple stages of cancer progression. One mechanism through which this occurs is via release of neutrophil extracellular traps (NETs). We have previously shown that NETs trap tumor cells in both the liver and the lung, increasing their adhesion and metastasis following postoperative complications. Multiple studies have since shown that NETs play a role in tumor progression and metastasis. NETs are composed of nuclear DNA-derived web-like structures decorated with neutrophil-derived proteins. However, it is unknown which, if any, of these NET-affiliated proteins is responsible for inducing the metastatic phenotype. In this study, we identify the NET-associated carcinoembryonic Ag cell adhesion molecule 1 (CEACAM1) as an essential element for this interaction. Indeed, blocking CEACAM1 on NETs, or knocking it out in a murine model, leads to a significant decrease in colon carcinoma cell adhesion, migration and metastasis. Thus, this work identifies NET-associated CEACAM1 as a putative therapeutic target to prevent the metastatic progression of colon carcinoma.
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http://dx.doi.org/10.4049/jimmunol.1900240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534954PMC
April 2020

C3a elicits unique migratory responses in immature low-density neutrophils.

Oncogene 2020 03 4;39(12):2612-2623. Epub 2020 Feb 4.

Goodman Cancer Research Centre, McGill University, Montréal, QC, H3A 1A3, Canada.

Neutrophils represent the immune system's first line of defense and are rapidly recruited into inflamed tissue. In cancer associated inflammation, phenotypic heterogeneity has been ascribed to this cell type, whereby neutrophils can manifest anti- or pro-metastatic functions depending on the cellular/micro-environmental context. Here, we demonstrate that pro-metastatic immature low-density neutrophils (iLDNs) more efficiently accumulate in the livers of mice bearing metastatic lesions compared with anti-metastatic mature high-density neutrophils (HDNs). Transcriptomic analyses reveal enrichment of a migration signature in iLDNs relative to HDNs. We find that conditioned media derived from liver-metastatic breast cancer cells, but not lung-metastatic variants, specifically induces chemotaxis of iLDNs and not HDNs. Chemotactic responses are due to increased surface expression of C3aR in iLDNs relative to HDNs. In addition, we detect elevated secretion of cancer-cell derived C3a from liver-metastatic versus lung-metastatic breast cancer cells. Perturbation of C3a/C3aR signaling axis with either a small molecule inhibitor, SB290157, or reducing the levels of secreted C3a from liver-metastatic breast cancer cells by short hairpin RNAs, can abrogate the chemotactic response of iLDNs both in vitro and in vivo, respectively. Together, these data reveal novel mechanisms through which iLDNs prefentially accumulate in liver tissue harboring metastases in response to tumor-derived C3a secreted from the liver-aggressive 4T1 breast cancer cells.
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http://dx.doi.org/10.1038/s41388-020-1169-8DOI Listing
March 2020

Primary tumors induce neutrophil extracellular traps with targetable metastasis promoting effects.

JCI Insight 2019 07 25;5. Epub 2019 Jul 25.

Cancer Research Program and the LD MacLean Surgical Research Laboratories, Department of Surgery, McGill University Health Center (MUHC), Montreal, Québec, Canada.

Targeting the dynamic tumor immune microenvironment (TIME) can provide effective therapeutic strategies for cancer. Neutrophils are the predominant leukocyte population in mice and humans, and mounting evidence implicates these cells during tumor growth and metastasis. Neutrophil extracellular traps (NETs) are networks of extracellular neutrophil DNA fibers that are capable of binding tumor cells to support metastatic progression. Here we demonstrate for the first time that circulating NET levels are elevated in advanced esophageal, gastric and lung cancer patients compared to healthy controls. Using pre-clinical murine models of lung and colon cancer in combination with intravital video microscopy, we show that NETs functionally regulate disease progression and that blocking NETosis through multiple strategies significantly inhibits spontaneous metastasis to the lung and liver. Further, we visualize how inhibiting tumor-induced NETs decreases cancer cell adhesion to liver sinusoids following intrasplenic injection - a mechanism previously thought to be driven primarily by exogenous stimuli. Thus, in addition to neutrophil abundance, the functional contribution of NETosis within the TIME has critical translational relevance and represents a promising target to impede metastatic dissemination.
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http://dx.doi.org/10.1172/jci.insight.128008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777835PMC
July 2019

Collagen IV-conveyed signals can regulate chemokine production and promote liver metastasis.

Oncogene 2018 07 13;37(28):3790-3805. Epub 2018 Apr 13.

Department of Surgery, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.

Liver metastases remain a major cause of death from gastrointestinal tract cancers as well as from other malignancies such as breast and lung carcinomas and melanoma. Understanding the underlying biology is essential for the design of effective targeted therapies. We previously reported that collagen IV α1/α2 overexpression in non-metastatic lung carcinoma (M27) cells increased their metastatic ability, specifically to the liver and documented high collagen IV levels in surgical resections of liver metastases from diverse tumor types. Here, we aimed to elucidate the functional relevance of collagen IV to metastatic outgrowth in the liver. Gene expression profiling revealed in M27cells significant increases in the expression of chemokines CCL5 (5.7-fold) and CCL7 (2.6-fold) relative to wild-type cells, and this was validated by qPCR and western blotting. Similarly, in human colon carcinoma KM12C and KM12SM cells with divergent liver-colonizing potentials, CCL7 and CCL5 production correlated with type IV collagen expression and the metastatic phenotype. CCL7 silencing by short hairpin RNA (shRNA) reduced experimental liver metastasis in both cell types, whereas CCL5 silencing reduced metastasis of M27 cells, implicating these cytokines in metastatic expansion in the liver. Subsequent functional analyses implicated both MEK/ERK and PI3K signaling upstream of CCL7 upregulation and identified CCL7 (but not CCL5) as a critical migration/invasion factor, acting via the chemokine receptor CCR3. Chemokine CCL5 was identified as a regulator of the T-cell immune response in the liver. Loss of CCL7 in KM12SM cells was also associated with altered E-cadherin and reduced vimentin and Snail expression, implicating it in epithelial-to-mesenchymal transition in these cells. Moreover, in clinical specimens of colon cancer liver metastases analyzed by immunohistochemistry, CCL5 and CCL7 levels paralleled those of collagen IV. The results identify the chemokines CCL5 and CCL7 as type IV collagen-regulated genes that promote liver metastasis by distinct and complementary mechanisms.
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http://dx.doi.org/10.1038/s41388-018-0242-zDOI Listing
July 2018

Loss of neutrophil polarization in colon carcinoma liver metastases of mice with an inducible, liver-specific IGF-I deficiency.

Oncotarget 2018 Mar 28;9(21):15691-15704. Epub 2018 Feb 28.

Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada.

The growth of cancer metastases in the liver depends on a permissive interaction with the hepatic microenvironment and neutrophils can contribute to this interaction, either positively or negatively, depending on their phenotype. Here we investigated the role of IGF-I in the control of the tumor microenvironment in the liver, using mice with a conditional, liver-specific, IGF-I deficiency (iLID) induced by a single tamoxifen injection. In mice that had a sustained (3 weeks) IGF-I deficiency prior to the intrasplenic/portal inoculation of colon carcinoma MC-38 cells, we observed an increase in neutrophil accumulation in the liver relative to controls. However, unlike controls, these neutrophils did not acquire the (anti-inflammatory) tumor-promoting phenotype, as evidenced by retention of high ICAM-1 expression and nitric oxide production and low CXCR4, CCL5, and VEGF expression and arginase production, all characteristic of the (pro-inflammatory) phenotype. This coincided with an increase in apoptotic tumor cells and reduced metastasis. Neutrophils isolated from these mice also had reduced IGF-IR expression levels. These changes were not observed in iLID mice with a short-term (2 days) IGF-I depletion, despite a 70% reduction in their circulating IGF-I levels, indicating that a sustained IGF-I deficiency was necessary to alter the neutrophil phenotype. Similar results were obtained with the highly metastatic Lewis lung carcinoma subline H-59 cells and in mice injected with an IGF-Trap that blocks IGF-IR signaling by reducing ligand bioavailability. Our results implicate the IGF axis in neutrophil polarization and the induction of a pro-metastatic microenvironment in the liver.
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http://dx.doi.org/10.18632/oncotarget.24593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884657PMC
March 2018

International consensus guidelines for scoring the histopathological growth patterns of liver metastasis.

Br J Cancer 2017 Nov 5;117(10):1427-1441. Epub 2017 Oct 5.

Departments of Surgery, Oncology and Medicine, McGill University and the McGill University Health Center Research Institute, Cancer Research Program, Montreal, QC, Canada.

Background: Liver metastases present with distinct histopathological growth patterns (HGPs), including the desmoplastic, pushing and replacement HGPs and two rarer HGPs. The HGPs are defined owing to the distinct interface between the cancer cells and the adjacent normal liver parenchyma that is present in each pattern and can be scored from standard haematoxylin-and-eosin-stained (H&E) tissue sections. The current study provides consensus guidelines for scoring these HGPs.

Methods: Guidelines for defining the HGPs were established by a large international team. To assess the validity of these guidelines, 12 independent observers scored a set of 159 liver metastases and interobserver variability was measured. In an independent cohort of 374 patients with colorectal liver metastases (CRCLM), the impact of HGPs on overall survival after hepatectomy was determined.

Results: Good-to-excellent correlations (intraclass correlation coefficient >0.5) with the gold standard were obtained for the assessment of the replacement HGP and desmoplastic HGP. Overall survival was significantly superior in the desmoplastic HGP subgroup compared with the replacement or pushing HGP subgroup (P=0.006).

Conclusions: The current guidelines allow for reproducible determination of liver metastasis HGPs. As HGPs impact overall survival after surgery for CRCLM, they may serve as a novel biomarker for individualised therapies.
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http://dx.doi.org/10.1038/bjc.2017.334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680474PMC
November 2017

The type I insulin-like growth factor regulates the liver stromal response to metastatic colon carcinoma cells.

Oncotarget 2017 Aug 12;8(32):52281-52293. Epub 2016 Oct 12.

Departments of Surgery, McGill University and the McGill University Health Centre, Montréal, QC, Canada.

Hepatic stellate cells (HSC) play a major role in initiating the liver fibrogenic (wounding) response of the liver and can also orchestrate a pro-metastatic microenvironment in the liver in response to invading cancer cells. Here we explored the role of the hepatic stellate cells in colon carcinoma liver metastasis with emphasis on the contribution of the insulin-like growth factor (IGF) axis to their activation and function. To this end, we used mice with a Tamoxifen inducible liver IGF-I deficiency. We found that in mice with a sustained IGF-I deficiency, recruitment and activation of HSC into tumor-infiltrated areas of the liver were markedly diminished, resulting in decreased collagen deposition and reduced tumor expansion. In addition, IGF-I could rescue HSC from apoptosis induced by pro-inflammatory factors such as TNF-α known to be upregulated in the early stages of liver metastasis. Moreover, in surgical specimens, activated IGF-IR was observed on HSC-like stromal cells surrounding colorectal carcinoma liver metastases. Finally, IGF-targeting using an IGF-Trap caused a significant reduction in HSC activation in response to metastatic colon cancer cells. Therefore, our data identify IGF as a survival factor for HSC and thereby, a promoter of the pro-metastatic microenvironment in the liver. IGF-targeting could therefore provide a strategy for curtailing the pro-metastatic host response of the liver during the early stages of liver metastasis.
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http://dx.doi.org/10.18632/oncotarget.12595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581028PMC
August 2017

The concerted movement of the switch region of Troponin I in cardiac muscle thin filaments as tracked by conventional and pulsed (DEER) EPR.

J Struct Biol 2017 12 31;200(3):376-387. Epub 2017 Aug 31.

Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, New South Wales 2109, Australia. Electronic address:

The absence of a crystal structure of the calcium free state of the cardiac isoform of the troponin complex has hindered our understanding of how the simple binding of Ca triggers conformational changes in troponin which are then propagated to enable muscle contraction. Here we have used continuous wave (CW) and Double Electron-Electron Resonance (DEER) pulsed EPR spectroscopy to measure distances between TnI and TnC to track the movement of the functionally important regulatory 'switch' region of cardiac Tn. Spin labels were placed on the switch region of Troponin I and distances measured to Troponin C. Under conditions of high Ca, the interspin distances for one set (TnI151/TnC84) were 'short' (9-10Å) with narrow distance distribution widths (3-8Å) indicating the close interaction of the switch region with the N-lobe of TnC. Additional spin populations representative of longer interspin distances were detected by DEER. These longer distance populations, which were ∼16-19Å longer than the short distance populations, possessed notably broader distance distribution widths (14-29Å). Upon Ca removal, the interspin population shifted toward the longer distances, indicating the release of the switch region from TnC and an overall increase in disorder for this region. Together, our results suggest that under conditions of low Ca, the close proximity of the TnI switch region to TnC in the cardiac isoform is necessary for promoting the interaction between the regulatory switch helix with the N-lobe of cardiac Troponin C, which, unlike the skeletal isoform, is largely in a closed conformation.
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http://dx.doi.org/10.1016/j.jsb.2017.08.007DOI Listing
December 2017

Thermal scribing to prototype plastic microfluidic devices, applied to study the formation of neutrophil extracellular traps.

Lab Chip 2017 05;17(11):2003-2012

Department of Chemical Engineering, McGill University, Montreal, Canada.

Innovation in microfluidics-based biological research has been aided by the growing accessibility of versatile microscale fabrication techniques, particularly in rapid prototyping of elastomeric polydimethylsiloxane (PDMS) based devices. However, the use of PDMS presents considerable and often unexpected limitations, particularly in interpreting and validating biological data. To rapidly prototype microfluidic culture systems in conventional plastics commonly used in cell culture, we developed 'thermal scribing', a one-step micromachining technique in which thermoplastics are locally patterned by a heated tip, moving in user-controlled patterns. To demonstrate and study the thermal scribing process, we modified an inexpensive desktop hobby craft cutter with a soldering iron to scribe micropatterns on polystyrene substrates. The thermal scribing technique is useful for creating a variety of channel profiles and geometries, which cannot be readily achieved using other microfabrication approaches. The entire fabrication process, including post-processing operations needed to fabricate devices, can be completed within a few hours without the need for skilled engineering expertise or expensive equipment. We apply this technique to demonstrate that induction of functional neutrophil extracellular traps (NETs) can be significantly enhanced over previous studies, when experiments are conducted in microfluidic channels prototyped in an appropriate material. These results ultimately inform the design of neutrophil culture systems and suggest that the inherent ability of neutrophils to form NETs may have been significantly under-reported.
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http://dx.doi.org/10.1039/c7lc00356kDOI Listing
May 2017

Neutrophil extracellular traps sequester circulating tumor cells via β1-integrin mediated interactions.

Int J Cancer 2017 05 2;140(10):2321-2330. Epub 2017 Mar 2.

Department of Surgery, LD MacLean Surgical Research Laboratories, Montreal, QC, Canada.

Despite advances in cancer treatment, metastasis remains today the main cause of cancer death. Local control through complete surgical resection of the primary tumor continues to be a key principle in cancer treatment. However, surgical interventions themselves lead to adverse oncologic outcomes and are associated with significantly increased rates of metastasis. Neutrophils through release of neutrophil extracellular traps (NETs) in response to infections were shown to be able to capture circulating cancer cells, and in doing so, support the development of metastatic disease. To be able to intervene on this process, understanding the exact molecular nature of these mechanisms is crucial. We therefore hypothesize and demonstrate that β1-integrin is an important factor mediating the interactions between circulating tumor cells and NETs. We show that β1-integrin expression on both cancer cells and NETs is important for the adhesion of circulating tumor cells to NETs both in vitro and in vivo. Using a murine model of intra-abdominal sepsis to mimic the postoperative inflammatory environment, we show that β1-integrin expression is upregulated in the context of inflammation in vivo. Ultimately, we show that this increased early cancer cell adhesion to NETs in vivo and this effect is abrogated when mice are administered DNAse 1. Our data therefore sheds light on the first molecular mechanism by which NETs can trap circulating tumor cells (CTCs), broadening our understanding of this process.
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http://dx.doi.org/10.1002/ijc.30635DOI Listing
May 2017

The IGF-Trap: Novel Inhibitor of Carcinoma Growth and Metastasis.

Mol Cancer Ther 2015 Apr 11;14(4):982-93. Epub 2015 Feb 11.

Department of Surgery, McGill University Health Centre, McGill University, Montreal, Québec, Canada. Department of Medicine, McGill University Health Centre, McGill University, Montreal, Québec, Canada. Department of Oncology, McGill University Health Centre, McGill University, Montreal, Québec, Canada.

The IGFI receptor promotes malignant progression and has been recognized as a target for cancer therapy. Clinical trials with anti-IGFIR antibodies provided evidence of therapeutic efficacy but exposed limitations due in part to effects on, and the compensatory function of, the insulin receptor system. Here, we report on the production, characterization, and biologic activity of a novel, IGF-targeting protein (the IGF-Trap) comprising a soluble form of hIGFIR and the Fc portion of hIgG1. The IGF-Trap has a high affinity for hIGFI and hIGFII but low affinity for insulin, as revealed by surface plasmon resonance. It efficiently blocked IGFIR signaling in several carcinoma cell types and inhibited tumor cell proliferation, migration, and invasion in vitro. In vivo, the IGF-Trap showed favorable pharmacokinetic properties and could suppress the growth of established breast carcinoma tumors when administered therapeutically into tumor-bearing mice, improving disease-free survival. Moreover, IGF-Trap treatment markedly reduced experimental liver metastasis of colon and lung carcinoma cells, increasing tumor cell apoptosis and reducing angiogenesis. Finally, when compared with an anti-IGFIR antibody or IGF-binding protein-1 that were used at similar or higher concentrations, the IGF-Trap showed superior therapeutic efficacy to both inhibitors. Taken together, we have developed a targeted therapeutic molecule with highly potent anticancer effects that could address limitations of current IGFIR-targeting agents.
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http://dx.doi.org/10.1158/1535-7163.MCT-14-0751DOI Listing
April 2015

Dynamics of tropomyosin in muscle fibers as monitored by saturation transfer EPR of bi-functional probe.

PLoS One 2011 20;6(6):e21277. Epub 2011 Jun 20.

Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.

The dynamics of four regions of tropomyosin was assessed using saturation transfer electron paramagnetic resonance in the muscle fiber. In order to fully immobilize the spin probe on the surface of tropomyosin, a bi-functional spin label was attached to i,i+4 positions via cysteine mutagenesis. The dynamics of bi-functionally labeled tropomyosin mutants decreased by three orders of magnitude when reconstituted into "ghost muscle fibers". The rates of motion varied along the length of tropomyosin with the C-terminus position 268/272 being one order of magnitude slower then N-terminal domain or the center of the molecule. Introduction of troponin decreases the dynamics of all four sites in the muscle fiber, but there was no significant effect upon addition of calcium or myosin subfragment-1.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0021277PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3118794PMC
October 2011

Distribution of killer cell immunoglobulin-like receptor (KIR) genotypes in patients with familial Mediterranean fever.

Genet Test Mol Biomarkers 2009 Feb;13(1):91-5

Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon.

Genotypic profiles of the natural killer cell immunoglobulin-like receptors (KIR) have been reported to vary among different ethnic groups and variable clinical entities. This study represents the first report on its distribution among patients with familial Mediterranean fever (FMF). We studied 56 unrelated Lebanese FMF patients, had their DNA typed using sequence-specific primer (SSP) technique for the presence of 16 KIR gene and pseudogene loci, and compared them to the general Lebanese population. The AA1 genotype was the most frequent in both the FMF and control groups. Six new KIR profiles were identified. The FMF group showed a higher prevalence of KIR 3DP1*003 (p<0.05) and an increase in the BB genotype compared with controls. The results lead to an interesting future research question of whether or not KIR genotype is involved in the predisposition to or pathogenesis of FMF. This is the first report that describes the KIR genotypic profile in this important clinical disease.
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http://dx.doi.org/10.1089/gtmb.2008.0081DOI Listing
February 2009

Natural killer cell immunoglobulin-like receptors (KIR) genotypes in two arab populations: will KIR become a genetic landmark between nations?

Mol Biol Rep 2008 Jun 26;35(2):225-9. Epub 2007 Mar 26.

Department of Pathology & Laboratory Medicine, American University of Beirut Medical Center (AUBMC), P.O. BOX 11-0236, Riad El Solh 1107 2020, Beirut, Lebanon.

Genotypic profiles of the Natural killer cell Immunoglobulin-like Receptors (KIR) have been reported to vary among different ethnic groups and this study represents a comparative report on its distribution between two Arabic populations in the Middle East: Lebanese and Palestinians. Our compared population samples included 120 unrelated healthy Lebanese (as per Mahfouz et al.) and a Palestinian population of 105 individuals (as per Norman et al.). All had their DNA typed using Sequence Specific Primer (SSP) technique for the presence of the different KIR loci. Similar to most published data, we observed that the two framework genes 2DL4 and 3DL2 are present in 100% of individuals from both communities, while 2DL2, 2DL3, 2DS1, 2DS2, 2DS3, 2DS5, 3DL1, and 3DS1 were very similar in frequency. However, significant differences were noted in the frequencies of 2DL1 and 2DS4. This report is comparing KIR genotyping distribution in two Arab populations that sheds additional light on the importance of this gene in delineating a possible geographic genetic demarcation among different ethnicities or even different communities among the same or close ethnic groups.
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http://dx.doi.org/10.1007/s11033-007-9074-6DOI Listing
June 2008

Prevalence of factor V Leiden, prothrombin and methylene tetrahydrofolate reductase mutations in women with adverse pregnancy outcomes in Lebanon.

Am J Obstet Gynecol 2006 Oct;195(4):1114-8

Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Lebanon.

Objective: The purpose of this study was to determine the prevalence of factor V Leiden, prothrombin, and methylene tetrahydrofolate reductase gene mutations in women with adverse pregnancy outcome compared with women who had uneventful pregnancies.

Study Design: Between 2003 and 2005, pregnant women with > or = 1 unexplained second trimester abortion, > or = 1 intrauterine fetal death, severe preeclampsia, or severe intrauterine growth restriction (study subjects) were compared with control subjects (uneventful pregnancy) for the frequency of the mutations.

Results: The cases of 91 patients in each arm were analyzed. Obstetric complications were second trimester abortions (16.5%), intrauterine fetal death (53.8%), preeclampsia (8.8%), and severe intrauterine growth restriction (20.9%). Study subjects were more likely to be older and multiparous compared with control subjects. The 2 groups showed no difference in the incidence of smoking or family history of thrombosis, but study subjects were more likely to have a positive family history of obstetric complications. The prevalence of factor V Leiden (12.1% vs 18.7%; P = .304), prothrombin (7.7% vs 5.5%; P = .765), methylene tetrahydrofolate reductase gene mutations (53.8% vs 65.9%; P = .130), and > 1 mutation (11.0% vs 17.6%; P = .290) was not significantly different between study subjects and control subjects.

Conclusion: Factor V Leiden, prothrombin, and methylene tetrahydrofolate reductase gene mutations did not seem to play a significant role in adverse pregnancy outcome in our population.
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http://dx.doi.org/10.1016/j.ajog.2006.06.082DOI Listing
October 2006
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