Publications by authors named "Suellen Greco"

15 Publications

  • Page 1 of 1

CC Chemokine Receptor 2-Targeting Copper Nanoparticles for Positron Emission Tomography-Guided Delivery of Gemcitabine for Pancreatic Ductal Adenocarcinoma.

ACS Nano 2021 01 6;15(1):1186-1198. Epub 2021 Jan 6.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with dire prognosis due to aggressive biology, lack of effective tools for diagnosis at an early stage, and limited treatment options. Detection of PDAC using conventional radiographic imaging is limited by the dense, hypovascular stromal component and relatively scarce neoplastic cells within the tumor microenvironment (TME). The CC motif chemokine 2 (CCL2) and its cognate receptor CCR2 (CCL2/CCR2) axis are critical in fostering and maintaining this kind of TME by recruiting immunosuppressive myeloid cells such as the tumor-associated macrophages, thereby presenting an opportunity to exploit this axis for both diagnostic and therapeutic purposes. We engineered CCR2-targeting ultrasmall copper nanoparticles (Cu@CuO) as nanovehicles not only for targeted positron emission tomography imaging by intrinsic radiolabeling with Cu but also for loading and delivery of the chemotherapy drug gemcitabine to PDAC. This Cu-radiolabeled nanovehicle allowed sensitive and accurate detection of PDAC malignancy in autochthonous genetically engineered mouse models. The ultrasmall Cu@CuO showed efficient renal clearance, favorable pharmacokinetics, and minimal toxicity. Systemic administration of gemcitabine-loaded Cu@CuO effectively suppressed the progression of PDAC tumors in a syngeneic xenograft mouse model and prolonged survival. These CCR2-targeted ultrasmall nanoparticles offer a promising image-guided therapeutic agent and show great potential for translation.
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http://dx.doi.org/10.1021/acsnano.0c08185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846978PMC
January 2021

Characterization of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-induced large-volume hyperthermia in deep and superficial targets in a porcine model.

Int J Hyperthermia 2020 ;37(1):1159-1173

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, Missouri, USA.

Purpose: To characterize temperature fields and tissue damage profiles of large-volume hyperthermia (HT) induced by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU) in deep and superficial targets in a porcine model.

Methods: Nineteen HT sessions were performed with a commercial MRgHIFU system (Sonalleve V2, Profound Medical Inc., Mississauga, ON, Canada) in hind leg muscles of eight pigs with temperature fields of cross-sectional diameter of 58-mm. Temperature statistics evaluated in the target region-of-interest (tROI) included accuracy, temporal variation, and uniformity. The impact of the number and location of imaging planes for feedback-based temperature control were investigated. Temperature fields were characterized by time-in-range (TIR, the duration each voxel stays within 40-45 °C) maps. Tissue damage was characterized by contrast-enhanced MRI, and macroscopic and histopathological analysis. The performance of the Sonalleve system was benchmarked against a commercial phantom.

Results: Across all HT sessions, the mean difference between the average temperature (T) and the desired temperature was -0.4 ± 0.5 °C; the standard deviation of temperature 1.2 ± 0.2 °C; the temporal variation of T for 30-min HT was 0.6 ± 0.2 °C, and the temperature uniformity was 1.5 ± 0.2 °C. A difference of 2.2-cm (in pig) and 1.5-cm (in phantom) in TIR dimensions was observed when applying feedback-based plane(s) at different locations. Histopathology showed 62.5% of examined HT sessions presenting myofiber degeneration/necrosis within the target volume.

Conclusion: Large-volume MRgHIFU-mediated HT was successfully implemented and characterized in a porcine model in deep and superficial targets with heating distributions modifiable by user-definable parameters.
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http://dx.doi.org/10.1080/02656736.2020.1825836DOI Listing
January 2020

A SARS-CoV-2 Infection Model in Mice Demonstrates Protection by Neutralizing Antibodies.

Cell 2020 08 10;182(3):744-753.e4. Epub 2020 Jun 10.

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA; The Andrew M. and Jane M. Bursky Center for Human Immunology & Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic with millions of human infections. One limitation to the evaluation of potential therapies and vaccines to inhibit SARS-CoV-2 infection and ameliorate disease is the lack of susceptible small animals in large numbers. Commercially available laboratory strains of mice are not readily infected by SARS-CoV-2 because of species-specific differences in their angiotensin-converting enzyme 2 (ACE2) receptors. Here, we transduced replication-defective adenoviruses encoding human ACE2 via intranasal administration into BALB/c mice and established receptor expression in lung tissues. hACE2-transduced mice were productively infected with SARS-CoV-2, and this resulted in high viral titers in the lung, lung pathology, and weight loss. Passive transfer of a neutralizing monoclonal antibody reduced viral burden in the lung and mitigated inflammation and weight loss. The development of an accessible mouse model of SARS-CoV-2 infection and pathogenesis will expedite the testing and deployment of therapeutics and vaccines.
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http://dx.doi.org/10.1016/j.cell.2020.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284254PMC
August 2020

Feasibility and safety assessment of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated mild hyperthermia in pelvic targets evaluated using an porcine model.

Int J Hyperthermia 2019 ;36(1):1147-1159

Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.

To evaluate the feasibility and assess safety parameters of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated hyperthermia (HT; heating to 40-45 °C) in various pelvic targets in a porcine model . Thirteen HT treatments were performed in six pigs with a commercial MRgHIFU system (Sonalleve V2, Profound Medical Inc., Mississauga, Canada) to muscle adjacent to the ventral/dorsal bladder wall and uterus to administer 42 °C (±1°) for 30 min (±5%) using an 18-mm target diameter and 100 W power. Feasibility was assessed using accuracy, uniformity, and MR-thermometry performance-based metrics. Safety parameters were assessed for tissues in the targets and beam-path by contrast-enhanced MRI, gross-pathology and histopathology. Across all HT sessions, the mean difference between average temperature (T) and the target temperature within the target region-of-interest (tROI, the cross-section of the heated volume at focal depth) was 0.51 ± 0.33 °C. Within the tROI, the temperature standard deviation averaged 1.55 ± 0.31 °C, the average 30-min T variation was 0.80 ± 0.17 °C, and the maximum difference between T and the 10th- or 90th-percentile temperature averaged 2.01 ± 0.44 °C. The average time to reach ≥41 °C and cool to ≤40 °C within the tROI at the beginning and end of treatment was 47.25 ± 27.47 s and 66.37 ± 62.68 s, respectively. Compared to unheated controls, no abnormally-perfused tissue or permanent damage was evident in the MR images, gross pathology or histological analysis. MRgHIFU-mediated HT is feasible and safety assessment is satisfactory for treating an array of clinically-mimicking pelvic geometries in a porcine model , implying the technique may have utility in treating pelvic targets in human patients.
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http://dx.doi.org/10.1080/02656736.2019.1685684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105895PMC
April 2020

Phylogenetic and functional analysis of ADAMTS13 identifies highly conserved domains essential for allosteric regulation.

Blood 2019 04 30;133(17):1899-1908. Epub 2019 Jan 30.

Department of Medicine and.

The metalloprotease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats member 13) prevents microvascular thrombosis by cleaving von Willebrand factor (VWF) within platelet-rich thrombi, and cleavage depends on allosteric activation of ADAMTS13 by the substrate VWF. Human ADAMTS13 has a short propeptide, metalloprotease (M), disintegrin-like (D), thrombospondin-1 (T), Cys-rich (C), and spacer (S) domains (proximal domains), followed by 7 T and 2 CUB (complement components C1r and C1s, sea urchin protein Uegf, and bone morphogenetic protein-1) domains (distal domains). Distal domains inhibit the catalytic proximal domains; binding of distal T8-CUB domains to the VWF D4 domain relieves autoinhibition and promotes cleavage of the nearby VWF A2 domain. However, the role of specific ADAMTS13 distal domains in this allosteric mechanism is not established. Assays of plasma ADAMTS13 from 20 placental mammals, birds, and amphibians show that allosteric regulation is broadly conserved, and phylogenetic analysis of 264 vertebrates shows the long propeptide, T3, T4, T6, and T6a domains have been deleted several times in placental mammals, birds, and fish. Notably, pigeon ADAMTS13 has only 3 distal T domains but was activated normally by human VWF D4 and cleaved VWF multimers, preferentially under fluid shear stress. Human ADAMTS13 constructed to resemble pigeon ADAMTS13 retained normal allosteric regulation and shear-dependent cleavage of VWF. Thus, the T3-T6 domains of human ADAMTS13 are dispensable. Conversely, deletion of T7 or T8 abolished allosteric activation. For most species, some sequence changes in the VWF substrate can markedly increase the rate of cleavage, suggesting that ADAMTS13 and VWF have not evolved to be optimal enzyme-substrate pairs. These properties may reflect evolutionary pressure to balance the risk for VWF-dependent bleeding and thrombosis.
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http://dx.doi.org/10.1182/blood-2018-11-886275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484387PMC
April 2019

Maternal obesogenic diet induces endometrial hyperplasia, an early hallmark of endometrial cancer, in a diethylstilbestrol mouse model.

PLoS One 2018 18;13(5):e0186390. Epub 2018 May 18.

Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, United States of America.

Thirty-eight percent of US adult women are obese, meaning that more children are now born of overweight and obese mothers, leading to an increase in predisposition to several adult onset diseases. To explore this phenomenon, we developed a maternal obesity animal model by feeding mice a diet composed of high fat/ high sugar (HF/HS) and assessed both maternal diet and offspring diet on the development of endometrial cancer (ECa). We show that maternal diet by itself did not lead to ECa initiation in wildtype offspring of the C57Bl/6J mouse strain. While offspring fed a HF/HS post-weaning diet resulted in poor metabolic health and decreased uterine weight (regardless of maternal diet), it did not lead to ECa. We also investigated the effects of the maternal obesogenic diet on ECa development in a Diethylstilbestrol (DES) carcinogenesis mouse model. All mice injected with DES had reproductive tract lesions including decreased number of glands, condensed and hyalinized endometrial stroma, and fibrosis and increased collagen deposition that in some mice extended into the myometrium resulting in extensive disruption and loss of the inner and outer muscular layers. Fifty percent of DES mice that were exposed to maternal HF/HS diet developed several features indicative of the initial stages of carcinogenesis including focal glandular and atypical endometrial hyperplasia versus 0% of their Chow counterparts. There was an increase in phospho-Akt expression in DES mice exposed to maternal HF/HS diet, a regulator of persistent proliferation in the endometrium, and no difference in total Akt, phospho-PTEN and total PTEN expression. In summary, maternal HF/HS diet exposure induces endometrial hyperplasia and other precancerous phenotypes in mice treated with DES. This study suggests that maternal obesity alone is not sufficient for the development of ECa, but has an additive effect in the presence of a secondary insult such as DES.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0186390PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5959064PMC
July 2018

Identification and taxonomic characterization of Bordetella pseudohinzii sp. nov. isolated from laboratory-raised mice.

Int J Syst Evol Microbiol 2016 Dec 4;66(12):5452-5459. Epub 2016 Oct 4.

Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA, USA.

Bordetella hinzii is known to cause respiratory disease in poultry and has been associated with a variety of infections in immunocompromised humans. In addition, there are several reports of B. hinzii infections in laboratory-raised mice. Here we sequenced and analysed the complete genome sequences of multiple B. hinzii-like isolates, obtained from vendor-supplied C57BL/6 mice in animal research facilities on different continents, and we determined their taxonomic relationship to other Bordetella species. The whole-genome based and 16S rRNA gene based phylogenies each identified two separate clades in B. hinzii, one was composed of strains isolated from poultry, humans and a rabbit whereas the other clade was restricted to isolates from mice. Distinctly different estimated DNA-DNA hybridization values, average nucleotide identity scores, gene content, metabolic profiles and host specificity all provide compelling evidence for delineation of the two species, B. hinzii - from poultry, humans and rabbit - and Bordetella pseudohinzii sp. nov. type strain 8-296-03T (=NRRL B-59942T=NCTC 13808T) that infect mice.
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http://dx.doi.org/10.1099/ijsem.0.001540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244500PMC
December 2016

Intrawound vancomycin powder eradicates surgical wound contamination: an in vivo rabbit study.

J Bone Joint Surg Am 2014 Jan;96(1):46-51

Departments of Orthopaedic Surgery (L.P.Z., T.C., M.P.K., and K.D.R.) and Comparative Medicine (M.T. and S.G.), Washington University in St. Louis, One Barnes-Jewish Hospital Plaza, Suite 11300 WP, CB 8233, St. Louis, MO 63110. E-mail address for L.P. Zeb.

Background: Surgical site infection remains a complication of spine surgery despite routine use of prophylactic antibiotics. Retrospective clinical studies of intrawound vancomycin use have documented a decreased prevalence of surgical site infection after spine surgery. The purpose of the present study was to assess the efficacy of intrawound vancomycin powder in terms of eradicating a known bacterial surgical site contamination in a rabbit spine surgery model.

Methods: Twenty New Zealand White rabbits underwent lumbar partial laminectomy and wire implantation. The surgical sites were inoculated, prior to closure, by injecting 100 μL of cefazolin-sensitive and vancomycin-sensitive Staphylococcus aureus (S. aureus) (1 × 10⁸ colony-forming units [CFU]/mL) into the wound. Preoperative cefazolin was administered to all rabbits, and vancomycin powder (100 mg) was placed into the wound of ten rabbits prior to closure. The rabbits were killed on postoperative day four, and tissue and wire samples were obtained for bacteriologic assessment. An independent samples t test was used to assess mean group differences, and a Fisher exact test was used to assess differences in categorical variables.

Results: The vancomycin-treated and the control rabbits were similar in weight (mean [and standard deviation], 4.1 ± 0.5 kg and 4.0 ± 0.4 kg, respectively; p = 0.60) and sex distribution and had similar durations of surgery (21.7 ± 7.7 minutes and 16.9 ± 6.7 minutes; p = 0.15). The bacterial cultures of the surgical site tissues were negative for all ten vancomycin-treated rabbits and positive for all ten control rabbits (p < 0.0001). Bacterial growth occurred in thirty-nine of forty samples from the control group but in zero of forty samples from the vancomycin group (p < 0.0001). All blood and liver samples were sterile. No rabbit had evidence of sepsis or vancomycin toxicity. Gross examination of the surgical sites showed no differences between the groups.

Conclusions: In a rabbit spine-infection model, intrawound vancomycin powder in combination with preoperative cefazolin eliminated S. aureus surgical site contamination. All rabbits that were managed with only prophylactic cefazolin had persistent S. aureus contamination.

Clinical Relevance: This animal study supports the findings in prior clinical reports that intrawound vancomycin powder helps reduce the risk of surgical site infections.
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http://dx.doi.org/10.2106/JBJS.L.01257DOI Listing
January 2014

Metabotropic glutamate receptor 5 antagonism with fenobam: examination of analgesic tolerance and side effect profile in mice.

Anesthesiology 2011 Dec;115(6):1239-50

Medical Scientist Training Program, Department of Anesthesiology, Washington University Pain Center, Program in Neuroscience, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

Background: The metabotropic glutamate receptor 5 noncompetitive antagonist fenobam is analgesic in rodents. Future development of fenobam as an analgesic in humans will require a favorable long-term treatment profile and a lack of significant deleterious side effects. This study aimed to determine whether tolerance to fenobam's analgesic effects developed over 14 days and to assess for side effects in mice.

Methods: Mouse models of pain, locomotor behavior, and coordination were used. Fenobam or vehicle (n = 8 or 11 per group) was administered for 14 days, and analgesic tolerance to fenobam was assessed using the formalin test. Histopathologic examination, hematology, and clinical chemistry analysis after 14-day fenobam administration were also assessed (n = 12 or 9). The effects of fenobam on locomotor activity were assessed in the open field and elevated zero maze (n = 8 or 7). Coordination was assessed using ledge crossing and vertical pole descent tasks (n = 11 or 10).

Results: Tolerance to fenobam's analgesic effect did not develop after 14 days. Chronic fenobam administration resulted in statistically significantly less weight gain compared with vehicle control subjects, but did not cause any physiologically or statistically significant hematologic abnormalities, altered organ function, or abnormal histopathology of the liver, brain, or testes. Fenobam administration resulted in a metabotropic glutamate receptor 5-dependent increase in exploratory behavior but does not impair motor coordination at analgesic doses.

Conclusions: Analgesic tolerance to repeat fenobam dosing does not develop. Chronic dosing of up to 14 days is well tolerated. Fenobam represents a promising candidate for the treatment of human pain conditions.
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http://dx.doi.org/10.1097/ALN.0b013e318238c051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226928PMC
December 2011

Laparoscopic fixation of biologic mesh at the hiatus with fibrin or polyethylene glycol sealant in a porcine model.

Surg Endosc 2011 Oct 19;25(10):3405-13. Epub 2011 May 19.

Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.

Background: The objective of this study was to determine the acute and chronic fixation strengths achieved by fibrin or polyethylene glycol (PEG) sealants to secure biologic mesh at the esophageal hiatus in a porcine model.

Methods: For this study, 32 female domestic pigs were divided into four groups of 8 each. The four groups respectively received acute fibrin sealant, acute PEG sealant, chronic fibrin sealant, and chronic PEG sealant. Laparoscopically, a 5.5 × 8.5-cm piece of Biodesign Surgisis Hiatal Hernia Graft (porcine small intestine submucosa) was oriented with the U-shaped cutout around the gastroesophageal junction and the short axis in the craniocaudal direction to simulate hiatal reinforcement with a biologic mesh. The mesh then was secured with 2 ml of either fibrin sealant or PEG sealant. The pigs in the acute groups were maintained alive for 2 h to allow for complete polymerization of the sealants, and the pigs in the chronic group were maintained alive for 14 days. After the pigs were euthanized, specimens of the mesh-tissue interface were subjected to lap shear testing to determine fixation strength, and hematoxylin and eosin (H&E) stained slides were evaluated for evidence of remodeling.

Results: No significant differences were observed between the acute and chronic fixation strengths or the remodeling characteristics of the two sealants. However, fixation strength increased significantly over time for both types of sealant. Evidence of remodeling also was significantly more pronounced in the chronic specimens than in the acute specimens.

Conclusions: This study demonstrated the feasibility of using fibrin or PEG sealants to secure biologic mesh at the hiatus in a porcine model.
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http://dx.doi.org/10.1007/s00464-011-1741-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3826827PMC
October 2011

Histologic and biomechanical evaluation of crosslinked and non-crosslinked biologic meshes in a porcine model of ventral incisional hernia repair.

J Am Coll Surg 2011 May 23;212(5):880-8. Epub 2011 Mar 23.

Department of Surgery, Section of Minimally Invasive Surgery, Washington University School of Medicine, St Louis, MO, USA.

Background: The objective of this study was to evaluate the biomechanical characteristics and histologic remodeling of crosslinked (Peri-Guard, Permacol) and non-crosslinked (AlloDerm, Veritas) biologic meshes over a 12 month period using a porcine model of incisional hernia repair.

Study Design: Bilateral incisional hernias were created in 48 Yucatan minipigs and repaired after 21 days using an underlay technique. Samples were harvested at 1, 6, and 12 months and analyzed for biomechanical and histologic properties. The same biomechanical tests were conducted with de novo (time 0) meshes as well as samples of native abdominal wall. Statistical significance (p < 0.05) was determined using 1-way analysis of variance with a Fisher's least significant difference post-test.

Results: All repair sites demonstrated similar tensile strengths at 1, 6, and 12 months and no significant differences were observed between mesh materials (p > 0.05 in all cases). The strength of the native porcine abdominal wall was not augmented by the presence of the mesh at any of the time points, regardless of de novo tensile strength of the mesh. Histologically, non-crosslinked materials showed earlier cell infiltration (p < 0.01), extracellular matrix deposition (p < 0.02), scaffold degradation (p < 0.05), and neovascularization (p < 0.02) compared with crosslinked materials. However, by 12 months, crosslinked materials showed similar results compared with the non-crosslinked materials for many of the features evaluated.

Conclusions: The tensile strengths of sites repaired with biologic mesh were not impacted by very high de novo tensile strength/stiffness or mesh-specific variables such as crosslinking. Although crosslinking distinguishes biologic meshes in the short-term for histologic features, such as cellular infiltration and neovascularization, many differences diminish during longer periods of time. Characteristics other than crosslinking, such as tissue type and processing conditions, are likely responsible for these differences.
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http://dx.doi.org/10.1016/j.jamcollsurg.2011.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3782991PMC
May 2011

Biomechanical and histologic evaluation of fenestrated and nonfenestrated biologic mesh in a porcine model of ventral hernia repair.

J Am Coll Surg 2011 Mar;212(3):327-39

Department of Surgery, Washington University, St Louis, MO, USA.

Background: The purpose of this study was to compare tissue incorporation and adhesion characteristics of a novel fenestrated versus nonfenestrated crosslinked porcine dermal matrix (CPDM) (Bard CollaMend) in a porcine model of ventral hernia repair.

Study Design: Bilateral abdominal wall defects were created in 24 Yucatan minipigs, resulting in 48 defects, which were allowed to mature for 21 days. Twelve defects were repaired with fenestrated CPDM using a preperitoneal technique, 12 with fenestrated CPDM using an intraperitoneal technique, 12 with nonfenestrated CPDM using a preperitoneal technique, and 12 with nonfenestrated CPDM using an intraperitoneal technique. Half of the animals in the intraperitoneal group were euthanized after 1 month, and the other half after 3 months. Similarly, half of the animals in the preperitoneal group were euthanized after 1 month, and the other half after 6 months. Biomechanical testing and histologic evaluation were performed.

Results: Intraperitoneal placement of the CPDM products resulted in significantly greater adhesed area compared with preperitoneal placement (p < 0.05). Tissue ingrowth into preperitoneal fenestrated and nonfenestrated CPDM resulted in significantly greater incorporation strengths after 6 months compared with 1 month (p = 0.03 and p < 0.0001). Histologic analysis showed significantly greater cellular infiltration, extracellular matrix deposition, and neovascularization, with less fibrous encapsulation through the center of the fenestrations compared with all other sites evaluated, including nonfenestrated grafts.

Conclusions: Histologic findings revealed increased tissue incorporation at fenestration sites compared with nonfenestrated grafts regardless of implant location or time in vivo. However, preperitoneal placement resulted in greater incorporation strength, less adhesed area, and lower adhesion scores compared with intraperitoneal placement for both fenestrated and nonfenestrated CPDM.
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http://dx.doi.org/10.1016/j.jamcollsurg.2010.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3783002PMC
March 2011

Indolyl-quinuclidinols inhibit ENOX activity and endothelial cell morphogenesis while enhancing radiation-mediated control of tumor vasculature.

FASEB J 2009 Sep 24;23(9):2986-95. Epub 2009 Apr 24.

Department of Radiation Oncology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

There is a need for novel strategies that target tumor vasculature, specifically those that synergize with cytotoxic therapy, in order to overcome resistance that can develop with current therapeutics. A chemistry-driven drug discovery screen was employed to identify novel compounds that inhibit endothelial cell tubule formation. Cell-based phenotypic screening revealed that noncytotoxic concentrations of (Z)-(+/-)-2-(1-benzenesulfonylindol-3-ylmethylene)-1-azabicyclo[2. 2.2]octan-3-ol (analog I) and (Z)-(+/-)-2-(1-benzylindol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol (analog II) inhibited endothelial cell migration and the ability to form capillary-like structures in Matrigel by > or =70%. The ability to undergo neoangiogenesis, as measured in a window-chamber model, was also inhibited by 70%. Screening of biochemical pathways revealed that analog II inhibited the enzyme ENOX1 (EC(50) = 10 microM). Retroviral-mediated shRNA suppression of endothelial ENOX1 expression inhibited cell migration and tubule formation, recapitulating the effects observed with the small-molecule analogs. Genetic or chemical suppression of ENOX1 significantly increased radiation-mediated Caspase3-activated apoptosis, coincident with suppression of p70S6K1 phosphorylation. Administration of analog II prior to fractionated X-irradiation significantly diminished the number and density of tumor microvessels, as well as delayed syngeneic and xenograft tumor growth compared to results obtained with radiation alone. Analysis of necropsies suggests that the analog was well tolerated. These results suggest that targeting ENOX1 activity represents a novel therapeutic strategy for enhancing the radiation response of tumors.
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http://dx.doi.org/10.1096/fj.09-130005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2796904PMC
September 2009

Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii.

Immunity 2008 Aug;29(2):306-17

Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA.

The enteric pathogen Toxoplasma gondii is controlled by a vigorous innate T helper 1 (Th1) cell response in the murine model. We demonstrated that after oral infection, the parasite rapidly recruited inflammatory monocytes [Gr1(+) (Ly6C(+), Ly6G(-)) F4/80(+)CD11b(+)CD11c(-)], which established a vital defensive perimeter within the villi of the ileum in the small intestine. Mice deficient of the chemokine receptor CCR2 or the ligand CCL2 failed to recruit Gr1(+) inflammatory monocytes, whereas dendritic cells and resident tissue macrophages remained unaltered. The selective lack of Gr1(+) inflammatory monocytes resulted in an inability of mice to control replication of the parasite, high influx of neutrophils, extensive intestinal necrosis, and rapid death. Adoptive transfer of sorted Gr1(+) inflammatory monocytes demonstrated their ability to home to the ileum in infected animals and protect Ccr2(-/-) mice, which were otherwise highly susceptible to oral toxoplasmosis. Collectively, these findings illustrate the critical importance of inflammatory monocytes as a first line of defense in controlling intestinal pathogens.
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http://dx.doi.org/10.1016/j.immuni.2008.05.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2605393PMC
August 2008

In vivo developmental stages in murine natural killer cell maturation.

Nat Immunol 2002 Jun 13;3(6):523-8. Epub 2002 May 13.

Howard Hughes Medical Institute and Rheumatology Division, Department of Internal Medicine, Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO 63110, USA.

Natural killer (NK) cells develop in the bone marrow, but their in vivo stages of maturation, expansion and acquisition of receptors that guide target cell specificity are not well defined. We describe here such stages of development. We also show that developing NK cells actively proliferate at a phenotypically distinguishable immature stage after they have acquired expression of Ly49 and CD94-NKG2 receptors. These studies provide a developmental framework for NK cell maturation in vivo and suggest the possible involvement of the Ly49 and CD94-NKG2 receptors themselves in modulating expansion of NK cell populations with a given NK cell receptor repertoire.
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http://dx.doi.org/10.1038/ni796DOI Listing
June 2002