Spontaneous Spread Research Articles

A Validated Preclinical Animal Model for Primary Bone Tumor Research.

Despite the introduction of 21st-century surgical and neoadjuvant treatment modalities, survival of patients with osteosarcoma (OS) has not improved in two decades. Advances will depend in part on the development of clinically relevant and reliable animal models. This report describes the engineering and validation of a humanized tissue-engineered bone organ (hTEBO) for preclinical research on primary bone tumors in order to minimize false-positive and false-negative results due to interspecies differences in current xenograft models. Pelvic bone and marrow fragments were harvested from patients during reaming of the acetabulum during hip arthroplasty. HTEBOs were engineered by embedding fragments in a fibrin matrix containing bone morphogenetic protein-7 (BMP-7) and implanted into NOD-scid mice. After 10 weeks of subcutaneous growth, one group of hTEBOs was harvested to analyze the degree of humanization. A second group was injected with human luciferase-labeled OS (Luc-SAOS-2) cells. Tumor growth was followed in vivo with bioluminescence imaging. After 5 weeks, the OS tumors were harvested and analyzed. They were also compared with tumors created via intratibial injection. After 10 weeks of in vivo growth, a new bone organ containing human bone matrix as well as viable and functional human hematopoietic cells developed. Five weeks after injection of Luc-SAOS-2 cells into this humanized bone microenvironment, spontaneous metastatic spread to the lung was evident. Relevant prognostic markers such as vascular endothelial growth factor (VEGF) and periostin were found to be positive in OS tumors grown within the humanized microenvironment but not in tumors created in murine tibial bones. Hypoxia-inducible transcription factor-2α (HIF-2α) was detected only in the humanized OS. We report an in vivo model that contains human bone matrix and marrow components in one organ. BMP-7 made it possible to maintain viable mesenchymal and hematopoietic stem cells and created a bone microenvironment mimicking human physiology. This novel platform enables preclinical research on primary bone tumors in order to test new treatment options.

Claustrum of the short-tailed fruit bat, Carollia perspicillata: Alignment of cellular orientation and functional connectivity.

The claustrum is a gray-matter structure that underlies neocortex and reciprocates connections with cortical and subcortical targets. In lower mammals, the claustrum is directly adjacent to neocortex, making the definition of claustral boundaries challenging. Latexin, an endogenous inhibitor of metallocarboxypeptidases, localizes to claustral cells, enabling a clear delineation of claustrum. Given its proportionately large claustrum, we hypothesized that the short-tailed fruit bat, Carollia perspicillata, can be a useful model for claustral structure-function relations. We used latexin immunohistochemistry to identify claustral boundaries and intrinsic structure and multielectrode recordings from brain slices to explore intrinsic excitatory connectivity of the claustrum. Carollia's claustrum contains cells whose intrinsic connectivity and alignment permit the generation of spontaneous, synchronous population events and mirror their pattern of spread in disinhibited brain slices over millimeters. Carollia shows cellular alignment and spontaneous population-activity spread along both horizontal and dorsoventral axes. Carollia claustrum possesses intrinsic excitatory connectivity sufficient to: 1) generate single, spontaneous, synchronized burst discharges, 2) support activity spread along axes where claustral cells are aligned, and 3), because of multiple axes for cell alignment, support activity spread along both rostrocaudal and dorsoventral axes. The smaller event sizes in bat claustrum compared with rat claustrum are consistent with events occurring in population subsets rather than the full claustral cell population. The overall size of claustrum, its pronounced vascularity, and its more complex intrinsic connectivity than rat suggest that the bat is an animal model for claustral structure and function that will permit unique access to claustrum's processing capabilities. J. Comp. Neurol. 525:1459-1474, 2017. © 2016 Wiley Periodicals, Inc.

Abstract A09: Development of novel breast cancer brain-metastases-derived xenografts and cell lines

Abstract Symptomatic brain metastases develop in 10 to 16% of patients with metastatic breast cancer and the prognosis of these patients is dismal with a mortality rate of near 80% within 1 year of diagnosis. Understanding the mechanisms by which breast cancer cells adapt to the brain microenvironment is key to design therapies that could be used to prevent or treat brain metastases. To date, the field has relied almost exclusively on intracardiac (ic) injection of brain-homing cells derived from highly aggressive triple negative (TN) MDA-MB-231 and HER2+ BT474 (BT474BR) cell lines to study these interactions. Although these are well characterized models, these are far from representing the heterogeneity observed in breast tumors and their metastases. Purpose: The goal of this study was to develop and characterize novel human brain metastases patient-derived xenografts (BM-PDX) to study the biology of brain metastases and to serve as tools for testing novel therapeutic approaches. We have also developed a labeling method to tag these PDXs with traceable markers for in vivo studies. Experimental procedures: Metastatic tissue was removed from brain parenchyma during surgery (n=5) or from cerebral spinal fluid (CSF) via catheter (n=1) from consenting donors harboring TN (n=3) or HER2+ (n=3) metastatic breast cancer. Tissue was immediately implanted in the mammary fat pad of NOD/SCID/GAMMA female mice and tumor expanded as solid tumors (BM-PDX). Upon reaching a volume of >200 mm3, partitioned pieces were transplanted into new recipient mice and growth kinetics measured. In order to track metastatic spread using PDXs, we developed a protocol to label PDX-dissociated cells with GFP-luciferin followed by re-implantation in mice. Tumor sections before and after labeling were immunostained for hormone receptors (estrogen, progesterone and androgen receptors –ER, PR, AR), HER2, and the basal cell marker cytokeratin 5 (CK5). These were scored by a pathologist. Dissociated cells from an established BM-PDX were cultured under different conditions in vitro, to generate a BM-derived cell line. Gene expression profiling was performed in some PDX before and after GFP-luciferase labeling, and in derived cell lines. Dissociated cells from BM-PDXs (E22-1) were injected intracardially (n=5) to measure their ability to colonize the brain in an experimental model of brain metastasis. Summary: Three of 3 TN brain metastases were successfully established as transplantable PDXs, while 0 of 3 HER2+ tumors grew in mice. Immunohistochemical analyses demonstrated that BM-PDXs retain morphology and markers comparable to those of donor samples. Labeled tumors grew in the mammary fat pad without spontaneous metastatic spread as measured via in vivo imaging (IVIS). Intracardiac injection of dissociated cells from BM-PDX E22-1 resulted in micro or macrometastases in 5/5 (100%) injected mice, indicating that BM-PDXs remain capable of colonizing the organ of origin. Metastases developed in brain parenchyma, surrounding vessels, with associated microglia and astroglia activation, similar to what is observed in human brain metastases. BM-PDX dissociated cells were cultured under different conditions to derive BM-cell lines. Two cell lines have been derived from a TN BM-PDX (F2-6) after in vitro culture using brain-like media or primary cell media. RNAseq analyses to fully characterize the genetic makeup of BM-PDX and cell line derivatives are currently in progress. Conclusions: We have developed novel PDXs derived from breast cancer brain metastases, which retain their ability to colonize the brain when disseminated in circulation. These novel GFP-luciferase labeled xenografts and cell lines, represent unique tools to study brain metastasis biology and to test novel therapeutic treatments for brain metastasis in clinically relevant models. Citation Format: Colton Hanna, Britta M. Jacobsen, Carol A. Sartorius, Peter Kabos, Kevin Lillehei, David R. Ormond, Michael Graner, Virginia F. Borges, Diana M. Cittelly. Development of novel breast cancer brain-metastases-derived xenografts and cell lines. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A09.

New localities of Heracleum mantegazzianum Sommier et Levier (Apiaceae) in Croatia and control measures taken

Background and Purpose: The species Heracleum mantegazzianum (Apiaceae) originates from the Western Greater Caucasus (Russia, Georgia), but today it is widely distributed in Europe due to deliberate introductions as ornamental plant and subsequent spontaneous spread. Therefore it is considered to be an invasive alien species. Its main negative impact concerns human health, as it produces phototoxic sap which causes skin burnings when exposed to UV light. In Croatia it was first recorded in 2009 near Žabnik (Međimurje County), but afterwards it has not been found on this locality again.Materials and Methods: Floristic research in the Zagorje area was carried out during July and August 2014, using GPS Receiver to determine investigated localities.Results: The species Heracleum mantegazzianum was recorded on 16th July 2014 in Gornja Šemnica (Radoboj, Krapina-Zagorje County), on two localities approximately 300 m apart. The localities were revisited on 1st August 2014. To control the spread of the species manual elimination of fructifying umbels was applied. On both localities floristic composition and general vegetation type were determined.Conclusion: Monitoring of recorded sites and adjacent areas, control measures, and possible eradication of all individuals of Heracleum mantegazzianum should be conducted in the following years in order to control and possibly eradicate this invasive alien species.

Abstract A5: Establishment of a novel spontaneous prostate cancer liver metastasis model

Abstract Introduction: It is well-documented that prostate cancer (PCa) preferentially spreads to bone, but the patterns of non-osseous metastases are less well-defined. With the increased options for treatment of late stage patients, metastatic spread to lung, lymph nodes and liver has become more prominent. Especially, men with visceral (especially hepatic) metastases have a particularly poor prognosis. To understand the determining factors of this metastatic pattern in PCa and to elucidate the mechanisms underlying metastatic outgrowth in the liver and other relevant organs, we set out to develop a patient-derived xenograft (PDX) model of metastasis. We used a multimodality imaging approach to identify and monitor metastatic outgrowth. Material & Methods: We established 3D cultures of the PC339 PDX model, originating from a TURP of a late stage patient. PCL339 3D cultures were transfected with M21 (firefly luciferase - GFP fused protein) and inoculated subcutaneously in NOD-SCID-gamma (NSG) mice. Mice with established PCL339-M21 tumors underwent tumorectomy (700-1000 mm3) to extent their life span and allow metastatic outgrowth. After tumorectomy, animals were imaged weekly using MRI, microCT and In Vivo Imaging System (IVIS) to monitor metastatic development. At sacrifice, liver and other luciferase-positive organs were stored for RNA isolation and qPCR and for immunohistochemistry. Additionally, the positive liver was cultured to retrieve the PCL339-M21-L subline. To investigate whether metastatic potential was improved, this subline was re-injected subcutaneously and the above described procedure was repeated. Positive organs, including lung, lymph node and bone, were cultured to retrieve the PCL339-M21-L-LN and PCL339-M21-ZL-LU sublines. Results: Subcutaneous PCL339-M21-L tumors spread more consistent (almost 100%) and faster to liver compared to PCL339-M21 tumors (30 days after tumorectomy). Luciferase-positive signals in liver were detected by IVIS as early as 7 days after tumorectomy. MRI showed the first visible lesions at 21 days while microCT imaging detected positive lesions only after 28 days. 3D reconstructed microCT images and MRI-detected lesions confirmed location of the signals as seen by IVIS. Similar to MRI images, macroscopic liver lesions could be clearly observed at 21 days. In all cases, additional (micro)metastatic spread to lymph nodes, lung and bone was seen by IVIS imaging. Positive signals from these micrometastases could be confirmed by qPCR and immunohistochemistry for androgen receptor, prostate specific antigen and luciferase or GFP. Conclusion: We have established a new reproducible and transplantable PCa liver metastasis model PCL339-M21-L that shows spontaneous spread to liver and other organs like lung and lymph nodes. We demonstrated the value of non-invasive multimodality imaging to localize and follow metastatic spread and outgrowth over time. This unique PCL339-M21-L model is a valuable asset to study the biological aspects of PCa liver metastasis and provide a new PDX model to test potential therapies aiming to block metastatic spread of PCa. Citation Format: Stefan J. Roobol, Johanneke A.A. van Zoggel, Corrina M.A. de Ridder, Sander A.H. Hoeben, Yin C.I.L. Versluis, Yanto R. Ridwan, Joost C. Haeck, Wytske M. van Weerden. Establishment of a novel spontaneous prostate cancer liver metastasis model. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A5.

New localities of Heracleum mantegazzianum Sommier et Levier (Apiaceae) in Croatia and control measures taken

Background and Purpose: The species Heracleum mantegazzianum (Apiaceae) originates from the Western Greater Caucasus (Russia, Georgia), but today it is widely distributed in Europe due to deliberate introductions as ornamental plant and subsequent spontaneous spread. Therefore it is considered to be an invasive alien species. Its main negative impact concerns human health, as it produces phototoxic sap which causes skin burnings when exposed to UV light. In Croatia it was first recorded in 2009 near Žabnik (Međimurje County), but afterwards it has not been found on this locality again. Materials and Methods: Floristic research in the Zagorje area was carried out during July and August 2014, using GPS Receiver to determine investigated localities. Results: The species Heracleum mantegazzianum was recorded on 16th July 2014 in Gornja Semnica (Radoboj, Krapina-Zagorje County), on two localities approximately 300 m apart. The localities were revisited on 1st August 2014. To control the spread of the species manual elimination of fructifying umbels was applied. On both localities floristic composition and general vegetation type were determined. Conclusion: Monitoring of recorded sites and adjacent areas, control measures, and possible eradication of all individuals of Heracleum mantegazzianum should be conducted in the following years in order to control and possibly eradicate this invasive alien species.

An orthotopic xenograft model with survival hindlimb amputation allows investigation of the effect of tumor microenvironment on sarcoma metastasis.

Overall survival rates for pediatric high-grade sarcoma have improved greatly in the past few decades, but prevention and treatment of distant metastasis remain the most compelling problems facing these patients. Traditional preclinical mouse models have not proven adequate to study the biology and treatment of spontaneous distant sarcoma metastasis. To address this deficit, we developed an orthotopic implantation/amputation model in which patient-derived sarcoma xenografts are surgically implanted into mouse hindlimbs, allowed to grow, then subsequently amputated and the animals observed for development of metastases. NOD/SCID/IL-2Rγ-null mice were implanted with either histologically intact high grade sarcoma patient-derived xenografts or cell lines in the pretibial space and affected limbs were amputated after tumor growth. In contrast to subcutaneous flank tumors, we were able to consistently detect spontaneous distant spread of the tumors using our model. Metastases were seen in 27-90 % of animals, depending on the xenograft, and were repeatable and predictable. We also demonstrate the utility of this model for studying the biology of metastasis and present preliminary new insights suggesting the role of arginine metabolism and macrophage phenotype polarization in creating a tumor microenvironment that facilitates metastasis. Subcutaneous tumors express more arginase than inducible nitric oxide synthase and demonstrate significant macrophage infiltration, whereas orthotopic tumors express similar amounts of inducible nitric oxide synthase and arginase and have only a scant macrophage infiltrate. Thus, we present a model of spontaneous distant sarcoma metastasis that mimics the clinical situation and is amenable to studying the biology of the entire metastatic cascade.

The novel desmopressin analogue [V4Q5]dDAVP inhibits angiogenesis, tumour growth and metastases in vasopressin type 2 receptor-expressing breast cancer models.

Desmopressin (dDAVP) is a safe haemostatic agent with previously reported antitumour activity. It acts as a selective agonist for the V2 vasopressin membrane receptor (V2r) present on tumour cells and microvasculature. The purpose of this study was to evaluate the novel peptide derivative [V4Q5]dDAVP in V2r-expressing preclinical mouse models of breast cancer. We assessed antitumour effects of [V4Q5]dDAVP using human MCF-7 and MDA-MB-231 breast carcinoma cells, as well as the highly metastatic mouse F3II cell line. Effect on in vitro cancer cell growth was evaluated by cell proliferation and clonogenic assays. Cell cycle distribution was analysed by flow cytometry. In order to study the effect of intravenously administered [V4Q5]dDAVP on tumour growth and angiogenesis, breast cancer xenografts were generated in athymic mice. F3II cells were injected into syngeneic mice to evaluate the effect of [V4Q5]dDAVP on spontaneous and experimental metastatic spread. In vitro cytostatic effects of [V4Q5]dDAVP against breast cancer cells were greater than those of dDAVP, and associated with V2r-activated signal transduction and partial cell cycle arrest. In MDA-MB-231 xenografts, [V4Q5]dDAVP (0.3 μg/kg, thrice a week) reduced tumour growth and angiogenesis. Treatment of F3II mammary tumour-bearing immunocompetent mice resulted in complete inhibition of metastatic progression. [V4Q5]dDAVP also displayed greater antimetastatic efficacy than dDAVP on experimental lung colonisation by F3II cells. The novel analogue was well tolerated in preliminary acute toxicology studies, at doses ≥300-fold above that required for anti-angiogenic/antimetastatic effects. Our data establish the preclinical activity of [V4Q5]dDAVP in aggressive breast cancer, providing the rationale for further clinical trials.

Diffusion of Enhanced Recovery principles in gynecologic oncology surgery: Is active implementation still necessary?

ObjectiveSpontaneous diffusion of the evidence-based Enhanced Recovery After Surgery (ERAS) program from an early adopter department (colorectal surgery) to other closely related departments (gynecologic surgery) within the same hospital could be expected. Given this diffusion hypothesis, this quality improvement study examines the value of active implementation of ERAS in addition to spontaneous diffusion. MethodsA nonrandomized, pre-post intervention study was conducted at a tertiary referral hospital. Prospective data of consecutive patients who underwent abdominal surgery between March, 2010 and March, 2011 for gynecologic malignancies were collected and compared with those of a historical cohort of patients treated before the structured implementation of ERAS by an expert team. Outcomes were length of hospital stay, length of functional recovery, and compliance to protocol care elements. ResultsSeventy-seven patients treated after structured implementation of ERAS were compared with 38 patients included in the historical cohort. Most women had surgery for ovarian or endometrial cancer (48% and 37% respectively). Postoperative care mostly lacked ERAS elements and needed to be actively implemented. With structured implementation, a reduced time to functional recovery (median 3 versus 6days, p<0.001) and a shorter length of hospital stay (5 versus 7days, p<0.001) were achieved. ConclusionsAfter several years of practicing ERAS in colorectal surgery, spontaneous spread of ERAS principles to gynecologic oncology surgery occurred partially. The results of this study underscore the need for a structured and supported pro-active process to implement the ERAS program in a complete and successful way.

Aberrant Presentation of HPA-Reactive Carbohydrates Implies Selectin-Independent Metastasis Formation in Human Prostate Cancer

To investigate the impact of prostate cancer cell surface glycosylation as part of the tumor cell-endothelial cell interaction in prostate cancer metastasis. Glycosyltransferase expression was profiled in metastasis-derived prostate cancer cell lines and compared with primary epithelium. Prostate cancer cells were examined for HPA- and selectin-binding and adhesion to endothelium. Spontaneous metastasis xenograft models were established to test the lectin HPA-binding sites as a marker of metastatic competence and to evaluate E-selectin-binding sites in vivo. The importance of selectins for metastasis formation was analyzed using Sele(-/-)/Selp(-/-) mice. The clinical relevance of HPA- and E-selectin-binding sites in prostate cancer was determined. Glycosyltransferases involved in the synthesis of common HPA-binding sites are downregulated in prostate cancer cells. An absence of HPA-reactive carbohydrates specifically indicates spontaneous metastatic spread of prostate cancer xenografts in vivo and a poor prognosis of patients with prostate cancer. HPA-binding sites decrease in lymph node metastases compared with corresponding primary tumors. Common selectin ligands are absent on prostate cancer cells, which do not adhere to recombinant selectins or endothelium under shear stress in vitro. Spontaneous metastasis formation is largely independent of selectins in vivo. E-selectin-binding sites are detectable in only 2% of patients with prostate cancer without prognostic significance. Prostate cancer is characterized by an inverse functional and prognostic importance of HPA-binding sites compared with other adenocarcinomas. Accordingly, this study surprisingly shows that the selectin-selectin ligand axis, which is essential for extravasation and thus metastasis formation in several malignancies, can be circumvented in prostate cancer.

Genetic Ablation of the Tetraspanin CD151 Reduces Spontaneous Metastatic Spread of Prostate Cancer in the TRAMP Model

Tetraspanins are integral membrane proteins that associate with motility-related molecules such as integrins. Experimental studies have indicated that they may be important regulators of tumor invasion and metastasis, and high expression of the tetraspanin CD151 has been linked to poor prognosis in a number of cancers. Here, we show for the first time that genetic ablation of CD151 inhibits spontaneous metastasis in a transgenic mouse model of de novo tumorigenesis. To evaluate the effects of CD151 on de novo prostate cancer initiation and metastasis, a Cd151(-/-) (KO) murine model was crossed with the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Mice were analyzed for initiation of prostate tumor by palpation and primary tumors were analyzed by immunohistochemistry. Liver and lungs were examined for incidence and size of spontaneous metastatic lesions by histopathology. Knocking-out Cd151 had no significant effect on prostate cancer initiation or on expression of markers of proliferation, apoptosis, or angiogenesis in primary tumors. However, it did significantly decrease metastasis in a site-specific fashion, notably to the lungs but not the liver. Thus, CD151 acts principally as promoter of metastasis in this model. Prostate cancer is the second highest cause of cancer-related deaths in men in most Western countries, with the majority of deaths attributed to late-stage metastatic disease. CD151 may prove to be a valuable prognostic marker for treatment stratification and is a possible antimetastatic target.

Giant solitary hydatid cyst of spleen—A case report

INTRODUCTIONPrimary hydatid disease of the spleen is very rare and even rarer to cause (any complication … pancreatitis.). Usually, splenic hydatid cysts are secondary, either resulting from spontaneous spread of cysts or occurring after operations involving hydatidosis in other regions. Here, we report a case of a primary isolated splenic hydatid cyst treated with a classical surgical approach. This case report and literature review describes the management of hydatid splenic invasion. PRESENTATION OF CASEWe report the case of a 28-year-old female who presented with left hypochondriac non tender swelling/(mass). Abdominal ultrasonography and computed tomography (CT) revealed a cyst located in the spleen. The diagnosis was confirmed by a serological test. Surgical treatment involved a radical en bloc splenic resection (together with resection of the diaphragm and subcutaneous tissue.) The postoperative course was uneventful with three weeks of albendazole treatment. CT follow-up at six months demonstrated the absence of recurrence. Histopathologic examination revealed a hydatid cyst. DISCUSSIONComplete aggressive surgical en bloc resection resection is the gold standard treatment of patients with hydatid cysts with the aim to remove all parasitic and pericystic tissues. CONCLUSIONThe infrequency with which it is encountered makes splenic hydatid disease a formidable early diagnostic challenge especially in nonendemic areas. Hydatid disease should be considered in the differential diagnosis of all cystic masses in the spleen/(abdomen), especially in the geographical regions where the disease is endemic.

Insights in the chestnut genetic diversity in Canton Ticino (Southern Switzerland)

AbstractCastanea sativa Miller displays a high variability of morphological and ecological traits, vegetative and reproductive habits, nut morphology, wood characteristics, adaptability, and resistance to biotic and abiotic stresses. The present range of distribution of the species has been strongly influenced by human migrations and it is thought that Romans played a crucial role in the spread of the cultivation in Europe, although in some areas there is also evidence of local domestication and spontaneous spread of the tree after the last glacial period. In Switzerland chestnut stands are found mostly in the South (Canton Ticino), a region where the debate about the origin of the local germplasm, whether derived from the survival or spontaneous migration of C. sativa on the territory or due to the introduction of the tree during the Roman colonisation, is still open. This study aims contributing to depict the chestnut genetic situation of the species in Canton Ticino as a contribution to the debate about the native character of the species. The study area is located in Switzerland, on the southern slopes of the Alps, where 3 C. sativa populations were sampled and analysed at 9 SSR loci. Populations showed a high degree of diversity, as it is observed in most natural population of tree species: all nine SSR loci were polymorphic (no fixed alleles were detected), and genetic diversity, measured by expected heterozygosity, was high ranging in the populations between 0.647 and 0.721, on average. Results suggest that three homogeneous gene pools contributed to the formation of the 3 populations sampled. The genetic germplasm structuring of the analysed chestnut stands is very mild as confirmed by the relatively low level of genetic differentiation and divergence observed among sites.

Spontaneous emergence, imitation and spread of alternative foraging techniques among groups of vervet monkeys.

Animal social learning has become a subject of broad interest, but demonstrations of bodily imitation in animals remain rare. Based on Voelkl and Huber's study of imitation by marmosets, we tested four groups of semi-captive vervet monkeys presented with food in modified film canisters (“aethipops’). One individual was trained to take the tops off canisters in each group and demonstrated five openings to them. In three groups these models used their mouth to remove the lid, but in one of the groups the model also spontaneously pulled ropes on a canister to open it. In the last group the model preferred to remove the lid with her hands. Following these spontaneous differentiations of foraging techniques in the models, we observed the techniques used by the other group members to open the canisters. We found that mouth opening was the most common technique overall, but the rope and hands methods were used significantly more in groups they were demonstrated in than in groups where they were not. Our results show bodily matching that is conventionally described as imitation. We discuss the relevance of these findings to discoveries about mirror neurons, and implications of the identity of the model for social transmission.

The IGR-CaP1 Xenograft Model Recapitulates Mixed Osteolytic/Blastic Bone Lesions Observed in Metastatic Prostate Cancer

Bone metastases have a devastating impact on quality of life and bone pain in patients with prostate cancer and decrease survival. Animal models are important tools in investigating the pathogenesis of the disease and in developing treatment strategies for bone metastases, but few animal models recapitulate spontaneous clinical bone metastatic spread. In the present study, IGR-CaP1, a new cell line derived from primary prostate cancer, was stably transduced with a luciferase-expressing viral vector to monitor tumor growth in mice using bioluminescence imaging. The IGR-CaP1 tumors grew when subcutaneously injected or when orthotopically implanted, reconstituted the prostate adenocarcinoma with glandular acini-like structures, and could disseminate to the liver and lung. Bone lesions were detected using bioluminescence imaging after direct intratibial or intracardiac injections. Anatomic bone structure assessed using high-resolution computed tomographic scans showed both lytic and osteoblastic lesions. Technetium Tc 99m methylene diphosphonate micro single-photon emission computed tomography confirmed the mixed nature of the lesions and the intensive bone remodeling. We also identified an expression signature for responsiveness of IGR-CaP1 cells to the bone microenvironment, namely expression of CXCR4, MMP-9, Runx2, osteopontin, osteoprotegerin, ADAMTS14, FGFBP2, and HBB. The IGR-CaP1 cell line is a unique model derived from a primary tumor, which can reconstitute human prostate adenocarcinoma in animals and generate experimental bone metastases, providing a novel means for understanding the mechanisms of bone metastasis progression and allowing preclinical testing of new therapies.

ESTUDIO DE LA VULNERABILIDAD DE LAS REDES DE TRANSPORTE DESDE UNA PERSPECTIVA GEOGRÁFICA

In the planning and management of transport networks often referred to the vulnerability of the same. The economic, social and territorial damage on these occurrences networks by natural or human, whether spontaneous or deliberate spread over the territory or territories affected with varying degrees of incidence. From a geographic view the case studies are presented with a Geographic Information System relating to the assessment of the vulnerability of two networks of transport, the road of the island of Mallorca and Madrid Metro, by analyzing the variation in the accessibility of the points of origin and destination of such networks and their impact on the territory comprising.

Assessing invasion process through pathway and vector analysis: case of saltcedar (Tamarix spp.)

Biological invasions are one of the most pervasive environmental threats to native ecosystems worldwide. The spontaneous spread of saltcedar is a particular threat to biodiversity conservation in arid and semiarid environments. In Argentina, three species belonging to this genus have been recognized as invaders. The aim of the present study was to identify main dispersal vectors and pathways to refine risk analysis and increase our ability to predict new areas at risk of Tamarix establishment. We surveyed and categorized 223 populations, 39% as invasive, 26% as established, 21% as contained and 14% as detected in nature. Dispersion of saltcedar was found to be associated with watercourses and human-driven disturbances; in addition roads were found to be relevant for the introduction of propagules in new environments. Considering the potential impact of saltcedar invasion and that it is an easily wind-dispersed invasive, it is necessary to implement strategies to monitor dispersal pathways and take actions to eliminate invasion foci, particularly in vulnerable and highconservation value areas.

Spreading of complex regional pain syndrome: not a random process

Complex regional pain syndrome (CRPS) generally remains restricted to one limb but occasionally may spread to other limbs. Knowledge of the spreading pattern of CRPS may lead to hypotheses about underlying mechanisms but to date little is known about this process. The objective is to study patterns of spread of CRPS from a first to a second limb and the factors associated with this process. One hundred and eighty-five CRPS patients were retrospectively evaluated. Cox’s proportional hazards model was used to evaluate factors that influenced spread of CRPS symptoms. Eighty-nine patients exhibited CRPS in multiple limbs. In 72 patients spread from a first to a second limb occurred showing a contralateral pattern in 49%, ipsilateral pattern in 30% and diagonal pattern in 14%. A trauma preceded the onset in the second limb in 37, 44 and 91%, respectively. The hazard of spread of CRPS increased with the number of limbs affected. Compared to patients with CRPS in one limb, patients with CRPS in multiple limbs were on average 7 years younger and more often had movement disorders. In patients with CRPS in multiple limbs, spontaneous spread of symptoms generally follows a contralateral or ipsilateral pattern whereas diagonal spread is rare and generally preceded by a new trauma. Spread is associated with a younger age at onset and a more severely affected phenotype. We argue that processes in the spinal cord as well as supraspinal changes are responsible for spontaneous spread in CRPS.

Laparoscopic management of an isolated primary omental hydatid cyst: A case report and literature review

Primary isolated omental hydatid cysts are extremely rare. Usually, omental hydatid cysts are secondary, either resulting from spontaneous spread of cysts or occurring after operations involving hydatidosis in other regions. Here, we report a case of a primary isolated omental hydatid cyst treated with a laparoscopic approach.We report a 16-year-old female who admitted to hospital with right upper quadrant pain. Abdominal ultrasonography and computed tomography (CT) revealed a cyst located between the liver and right kidney. The cyst was enucleated from the omentum and removed with a laparoscopic approach. Histopathologic examination revealed a hydatid cyst. There was no recurrence during 3 years of follow-up. Primary isolated omental hydatid disease should be considered in patients in endemic regions with intra-abdominal cysts. Laparoscopic surgery seems to be effective and safe for hydatid cysts in accessible locations.

Establishment of Tamarix ramosissima under different conditions of salinity and water availability: Implications for its management as an invasive species

The spontaneous spread of Tamarix represents a threat for biodiversity conservation. Tamarix ramosissima has been identified as an invader of arid and semi-arid environments in Argentina. The effects of salinity and water availability on vegetative reproduction and germination were evaluated in this study in order to determine ecological conditions that are appropriate for the species, and to identify areas of potential invasion in Argentina. Seeds and cuttings were grown in different concentrations of NaCl and PEG-6000 and under of soil saturation conditions. Percentages of seed germination and establishment and survival of cuttings were measured. The tolerance limits for germination reached values of −0.4 MPa (PEG-6000) and −0.8 MPa (NaCl). Cutting survival was significantly reduced at concentrations above 8.8 g/lt NaCl (−0.6 MPa) and under saturated soil conditions. Any cuttings survived under drought conditions. We concluded that soils with an EC less than 15 dS/m were adequate for germination, whereas cuttings tolerated values below 6 dS/m. Consequently, temperate, semi-arid and arid zones of Argentina are under risk of invasion by T. ramosissima even though the species is not resistant to local conditions of extreme drought or prolonged flooding.