tbuckley/cabot-search huggingface dataset:
In Utero Transfer of Adeno-Associated Viral Vectors Produces Long-Term Factor IX Levels in a Cynomolgus Macaque Model
Authors: Citra N.Z. Mattar, Irene Gil-Farina, Cecilia Rosales, Nuryanti Johana, Yvonne Yi Wan Tan, Jenny McIntosh, Christine Kaeppel, Simon N. Waddington, Arijit Biswas, Mahesh Choolani, Manfred Schmidt, Amit C. Nathwani, Jerry K.Y. Chan
Journal: Molecular Therapy (2017)

The safe correction of an inherited bleeding disorder in utero prior to the onset of organ damage is highly desirable. Here, we report long-term transgene expression over more than 6 years without toxicity following a single intrauterine gene transfer (IUGT) at 0.9G using recombinant adeno-associated vector (AAV)-human factor IX (hFIX) in the non-human primate model we have previously described. Four of six treated animals monitored for around 74 months expressed hFIX at therapeutic levels (3.9%-120.0%). Long-term expression was 6-fold higher in males and with AAV8 compared to AAV5, mediated almost completely at this stage by random genome-wide hepatic proviral integrations, with no evidence of hotspots. Post-natal AAV challenge without immunosuppression was evaluated in two animals exhibiting chronic low transgene expression. The brief neutralizing immune reaction elicited had no adverse effect and, although expression was not improved at the dose administered, no clinical toxicity was observed. This long-term surveillance thus confirms the safety of late-gestation AAV-hFIX transfer and demonstrates that postnatal re-administration can be performed without immunosuppression, although it requires dose optimization for the desired expression. Nevertheless, eventual vector genotoxicity and the possibility of germline transmission will require lifelong monitoring and further evaluation of the reproductive function of treated animals.
Effect of perhexiline on myocardial protection during coronary artery surgery: a two-centre randomised double-blind placebo-controlled trial
Authors: Nigel E Drury, Neil J Howell, Ralf JM Weber, Melanie J Calvert, Michael E Lewis, Mark R Viant, Nick Freemantle, Michael P Frenneaux, Domenico Pagano
Journal: The Lancet (2013)
Whole genome SNP arrays using DNA derived from formalin-fixed, paraffin-embedded ovarian tumor tissue
Authors: Ian G. Campbell, Ella Thompson, Shane Herbert, Susan Forrest
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

1653 

The development of whole-genome sampling analysis (WGSA) is poised to revolutionise genome-wide studies of the genetic changes that occur in tumors, such as loss of heterozygosity (LOH) and copy number alterations. Apart from advantages of speed and high resolution, WGSA arrays require small quantities of DNA making them amenable to analysis of microdissected tumor tissue. WGSA has been shown to produce reliable results using high quality DNA derived from fresh tissues. However, it is not known if DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissue, which tends to yield degraded DNA, will be suitable for WGSA. The development of a protocol suitable for this tissue would dramatically expand the utility of WGSA since most tumor tissue resources available for research only exist as FFPE blocks. Therefore we performed WGSA on DNA derived from FFPE ovarian tumours and compared this to the data derived from matching fresh frozen tumour tissue to assess the suitability of archival tissue for WGSA. We performed WGSA using the Affymetrix GeneChip Human Mapping 10K Array Xba 131. DNA was extracted from FFPE tumour tissue microdissected using the MagneSil Genomic Fixed Tissue System (Promega). The recommended protocol for the assay was followed with the exception that additional PCR cycles were required to obtain sufficient DNA for some of the FFPE tissues. The data was analysed using GeneChip DNA Analysis Software and LOH and copy number was estimated with the Chromosome Copy Number Tool (Affymetrix). The average SNP call rate (rate of successful genotype identification) of the five fresh samples was 88.79% (range 78.72%-96.22%, median 92.72%). The average SNP call rate for the matching FFPE samples was only slightly lower at 81.76% (range 76.93%-93.17%, median 80.06%). The average concordance (rate of agreement between successful genotype calls) between the fresh and matching FFPE samples was 97.06% (range 92.70%-99.41%, median 97.52%). LOH profiles of the fresh and FFPE samples, as predicted by the Chromosome Copy Number Tool, were essentially identical across all chromosomes. Some clear regions of LOH were evident in just one of two matched samples that may be explained by tumour heterogeneity. Copy number data was less comparable. While trends of amplifications and deletions remained, the quantification of copy number changes appears overstated in the FFPE samples. In conclusion, we have shown that it is possible to achieve high-performance outcomes using FFPE-derived DNA in the Affymetrix GeneChip Human Mapping 10K Array Xba 131. The data generated shows a good level of concordance considering the general degradation of DNA derived from FFPE tissue. LOH assessment of matched samples indicate that the use of archival tissue for LOH and genotype applications may be achievable using this platform, however it may be less suitable for copy number applications.
Erratum: t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway
Authors: G Tonon, S Modi, L Wu, A Kubo, A B Coxon, T Komiya, K O'Neil, K Stover, A El-Naggar, J D Griffin, I R Kirsch, F J Kaye
Journal: Nature Genetics (2003)
Tumor-infiltrating lymphocyte-mediated pleuritis followed by marked shrinkage of metastatic kidney cancer of the chest wall during nivolumab treatment
Authors: T. Yanagihara, K. Tanaka, K. Ota, E. Kashiwagi, A. Takeuchi, K. Tatsugami, M. Eto, Y. Nakanishi, I. Okamoto
Journal: Annals of Oncology (2017)
Working in bigger groups of practices must not sacrifice core values, GP leader warns
Authors: Gareth Iacobucci
Journal: BMJ (2017)

GPs have a “window of opportunity” to transform the way they work but should not sacrifice the values of traditional general practice to do so, a senior GP leader has urged.

Michelle Drage, chief executive of Londonwide Local Medical Committees, which represents over 7000 GPs in the capital, urged GPs to take control of their own destiny and not be distracted by “all the noise” around new models of integrated care. Speaking to …
Stable Polycomb-dependent transgenerational inheritance of chromatin states in Drosophila
Authors: Filippo Ciabrelli, Federico Comoglio, Simon Fellous, Boyan Bonev, Maria Ninova, Quentin Szabo, Anne Xuéreb, Christophe Klopp, Alexei Aravin, Renato Paro, Frédéric Bantignies, Giacomo Cavalli
Journal: Nature Genetics (2017)
Abstract 360: IL-10-inhibits Pressure Overload-induced Homing, Proliferation And Differentiation Of Non-resident Fibroblast Progenitors And Improve Heart Function.
Authors: Suresh K Verma, Prasanna Krishnamurthy, David Barefield, Alexander R Mackie, Erin E Vaughan, Tatian Abramova, Veronica Ramirez, Sol Misener, Sakthivel Sadayappan, Gangjian Qin, Raj Kishore
Journal: Circulation Research (2013)

Background: Recently we have shown that IL-10, an anti-inflammatory cytokine, markedly inhibited the pressure overload-induced cardiac fibrosis, however, antifibrotic mechanisms of IL-10 are largely unknown. In most of organs, including heart, extracellular matrix (ECM) remodeling is primarily mediated by excessive proliferation of activated fibroblasts and myofibroblasts. Here we hypothesized that IL-10 inhibits stress-induced homing, proliferation and differentiation of nonresident bone marrow-derived fibroblast progenitor cells and therefore, attenuates cardiac remodeling and improves of heart function. Methods and Results: Cardiac hypertrophy was induced in Wild-type (WT) and IL-10-knockout (KO) mice by transverse aortic constriction (TAC). TAC-induced left ventricular (LV) dysfunction and fibrosis were further exaggerated in KO mice compared to WT. TAC significantly increased TGF-β, collagen Iα and IIIα genes expression. Systemic recombinant mouse IL-10 administration markedly improved LV function, inhibited TAC-induced cardiac fibrosis and fibrosis associated genes expression. To identify the role of fibroblast progenitor cells (FPCs), we measured the mobilization of FPCs (Prominin1 positive cells) from bone marrow to heart by FACs. Exacerbated mobilization of FPCs in peripheral blood and heart in IL-10 KO mice were found 3 and 7 days after aortic constriction. Bone marrow transplantation experiments were performed where WT-GFP positive marrow was transplanted in BM depleted IL-10 KO mice. TAC-induced mobilization was significantly reduced in WT-transplanted marrow as compare to TAC-IL-10 KO mice. To identify the role IL-10 on TGFβ-induced endothelial cells trans-differentiation to myofibroblasts, we treated aortic endothelial cells with IL-10 and TGFβ2 for 96 hrs. Both Immunocytochemistry and Western blot analysis results suggested that TGF-β2-induced EndMT was significantly inhibited by IL-10 treatment. To understand the mechanisms, we found that TGF-β2-induced Notch1 signaling was reduced by IL-10. Conclusion: Taken together our observations suggest that the anti-fibrotic effects of IL-10 treatment are mediated by reduced proliferation and differentiation of non-resident myofibroblasts.
P04.14 Changes of motor deactivation regions in patients with intracranial tumors
Authors: S. Lee
Journal: Neuro-Oncology (2017)

Objective: There is a rich literature confirming the default mode network found compatible with task-induced deactivation regions in normal subjects, but few investigations of alterations of the motor deactivation in patients with intracranial lesions. Therefore, we hypothesized that an intracranial lesion results in abnormal changes in a task-induced deactivation region compared with default mode network, and these changes are associated with specific attributes of allocated regions. Patients and methods: Blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) during a motor task were obtained from 27 intracranial lesion patients (mean age, 57.3 years; range 15~78 years) who had various kinds of brain tumors. The BOLD fMRI data for each patient were evaluated to obtain activation or deactivation regions. The distinctive deactivation regions from intracranial lesion patients were evaluated by comparing to the literature reports. Results: There were additionally deactivated regions according to intracranial lesions: fusiform gyrus in cavernous hemangioma; lateral occipital gyrus in meningioma; crus cerebri in hemangiopericytoma; globus pallidus, lateral occipital gyrus, caudate nucleus, fusiform gyrus, lingual gyrus, claustrum, substantia nigra, subthalamic nucleus in GBM; fusiform gyrus in metastatic brain tumors. Conclusion: There is increasing interest in human brain function using fMRI. The authors report the brain function migrations and changes that occur in patients with intracranial lesions.
Requirement for Ca 2+/calmodulin-dependent kinase II in the transition from pressure overload-induced cardiac hypertrophy to heart failure in mice (Journal of Clinical Investigation (2009) 119, 5, (1230-1240) doi: 10.1172/JCI38022)
Authors: Haiyun Ling, Tong Zhang, Laetitia Pereira, Christopher Kable Means, Hongqiang Cheng, Yusu Gu, Nancy D. Dalton, Kirk L. Peterson, Ju Chen, Donald Bers, Joan Heller Brown
Journal: Journal of Clinical Investigation (2012)
P10.13 Outcomes in older patients referred with low grade glioma
Authors: S. Irvine, N. Catania
Journal: Neuro-Oncology (2017)

OBJECTIVES: To investigate the progression-free (PFS) and overall survival (OS) in patients ≥60 years old referred with a presumed diagnosis of low grade glioma (LGG). DESIGN: Neuro-oncology MDT outcomes from a single institution between 1/1/2009 and 31/12/2013 (n=7158) were retrospectively reviewed. Patients ≥ 60 years old referred with a presumed diagnosis of LGG were identified for further analysis (n=59). Where patients were still alive, overall survival was calculated up to 1/11/2016. Low grade lesions were defined as WHO grade I or II. METHODS: Data was collected from notes, electronic and summary care records for analysis to find index operation type, histology, radiological follow-up, MDT discussion, adjuvant treatments, any re- operations and dates of death. PFS and OS were calculated from this information. Results: Of 59 patients referred with presumed low grade lesions, 40 had a LGG confirmed at biopsy; 9 had a high or intermediate grade tumour identified at biopsy; 7 patients did not have a biopsy and 3 patients had an alternative diagnosis made at biopsy. Median PFS for patients with confirmed LGG was 27.2 months (range 0.1-172.8) and median OS was 36.5 months (range 0.1-222.3). 5-year survival rate in this group was 40.0% (95% CI 23.8-56.2%). In patients with intermediate and high grade tumours, median OS was 12.5 months (range 2.8-52.3) and 5-year survival rate was 11.1% (95% CI 0.5-49.3%). Conclusions: This study suggests that survival rates in older patients with LGG are significantly lower than in younger age groups, and supports the possibility of a different and more aggressive pathology.
P04.04 Optic Radiation Diffusion Tensor Imaging Tractography: a New and Simple Method for the Accurate Detection of Meyer’s Loop
Authors: G. A. Bertani, E. Scola
Journal: Neuro-Oncology (2017)

The optic radiation is a white matter bundle which carries the visual information from the lateral geniculate nucleus to the visual cortex, and it is characterised by a very complex anatomy. It runs together with other large white matter tracts in the deep of the temporal and parietal lobes and its anterior component, which forms the Meyer’s Loop, makes a sharp bend around the tip of the temporal horn of the lateral ventricle. Therefore, both with anatomical dissection and advanced magnetic resonance imaging techniques, like tractography, its exact anatomy is still challenging to define. During neurosurgical procedures it is extremely important for the surgeon to avoid damage of this structure in order to preserve the visual function of the patient. Diffusion tensor imaging tractography is a valid help for the neurosurgeon, but with the standard tracking procedure it is not easy to accurately identify the position of Meyer’s Loop. In this view, we developed a new tracking technique and evaluated its feasibility and anatomical accuracy in detecting Meyer’s Loop position. We made a DTI study of twenty-six patients undergoing resection of a temporal, occipital or temporo-parieto-occipital lesion; then, we reconstructed the optic radiations of each patient with the method developed by our team and with the most used tracking technique, measuring several parameters to define the anatomy of Meyer’s Loop and optic radiation. Finally, we compared our results with anatomy and other tractographic studies. Our study shows that our method allows a more accurate definition of Meyer’s Loop position, even with a commonly employed tracking software; moreover, it is easy to perform and repeatable. Lastly, it allowed us to perform a safer resection, avoiding injuries to the bundles and preserving the visual function of the patient. Therefore, it is of marked relevance to all neuroscientists interested in the evaluation and anatomical definition of the optic radiations, particularly to neurosurgeons approaching a lesion in the temporo-parieto-occipital junction.
Multiple Myeloma
Authors: Robert A. Kyle, S. Vincent Rajkumar
Journal: New England Journal of Medicine (2004)

Multiple myeloma, a plasma-cell neoplasm characterized by skeletal destruction, renal failure, anemia, and hypercalcemia, remains incurable. However, recent advances in its treatment, in particular, the use of thalidomide and such new drugs as bortezomib and CC-5013, are promising. This article discusses current therapy for multiple myeloma.
P06.04 By reversing tumor hypoxia, omx, an ind-stage drug candidate, promotes anti-tumor response and increases survival in the gl261 intracranial glioblastoma model
Authors: N. Le Moan, P. Leung
Journal: Neuro-Oncology (2017)

Intratumoral hypoxia is a common feature in solid tumors such as glioblastoma (GB). Hypoxic tumor cells develop aggressive phenotypes and resistance to chemo- and radio-therapies leading to poor patient outcomes. In addition, hypoxia promotes the immune escape of tumors via Treg recruitment and activation, and suppression of T cell and NK cell proliferation and effector functions. While immune checkpoint inhibitors (CPI) have shown promise in the clinic, GB patients might not experience clinical benefit with CPI treatment alone due to the immunosuppressive tumor microenvironment. Therefore, creating an immunopermissive microenvironment by reversing tumor hypoxia provides an attractive combinatorial approach to improve CPI efficacy. OMX is an oxygen carrier that can specifically deliver oxygen to hypoxic tumor regions without affecting oxygenation of tissues within the physiologic oxygen range. We have previously demonstrated that OMX is well tolerated in small (rats and mice) and large (sheep and dogs) animals. Following intravenous administration, OMX extravasates through leaky tumor vasculature, efficiently accumulates in, and oxygenates orthotopic rodent GB and spontaneous canine brain tumors. Consequently, OMX significantly reduces hypoxia and radiosensitizes multiple tumor models. Here we used a combination of immunohistochemical, flow cytometric, and multiplex cytokine analyses to evaluate OMX’ ability to weaken the immunosuppression in the tumor microenvironment. Moreover, we investigated capacity of OMX when combined with CPIs to improve mouse survival and identified biomarkers predictive of survival benefit. Similar to previously published findings, we demonstrated that T lymphocytes are mostly excluded from hypoxic tumor areas in the GL261 model. A single dose of OMX in GL261 tumor-bearing mice reduces tumor hypoxia, enhances T cell localization in previously hypoxic tumor areas, decreases Treg and increases activated cytotoxic T lymphocyte (CTLs) accumulation. Specifically, OMX increased by 3-fold the Teff/Treg ratio, indicating a switch from an immunosuppressive to an immunopermissive microenvironment. Similarly, when combined with CPI, OMX increases CTLs infiltration, proliferation and cytotoxic activity, and secretion of IFNg and IFNg-inducible cytokines that may polarize T cells towards a Th1 phenotype. Furthermore, the combination of OMX with CPI in late-stage GL261 tumor-bearing mice (day 13 to 16 post-implantation) increases mouse survival by ~80%. The survival benefit observed with OMX could be predicted with an identified circulating chemokine biomarker signature (post-hoc test). By delivering oxygen specifically to the hypoxic tumor microenvironment, OMX may restore anti-cancer immune responses in GB patients and synergize with radiotherapy and immunotherapy to enhance tumor control and improve patient outcomes.
The intestinal specific transcription factor Cdx2 can antagonize β-catenin target gene activation
Authors: Peter Peterson, David A. Jones
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

2823 

In the human colon, proliferation and differentiation are counter regulated. β-catenin is thought to stimulate proliferation through upregulation of myc and cyclin D1 in the base of the crypt while expression of APC down regulates these genes via repression of β-catenin in the upper region of the crypt. Coincidentally, the caudal-related homeodomain protein cdx2, which has important roles in regulating gastrointestinal development in vertebrates, is highly expressed in the upper region of the crypt. Thus, expression of β-catenin is associated proliferation in the base of the crypt and expression of the cdx proteins are correlated with the differentiated phenotype in the upper crypt. Interestingly, it has been shown that re-introduction of cdx2 into HT29 colon carcinoma cells promoted characteristics of differentiation as well as down regulation of Cyclin D1. This suggests that cdx2 can both induce differentiation and inhibit proliferation, however there is not currently a molecular explanation for how cdx2 accomplishes this dual function. Since colon tumors are characterized by increased proliferation and lack of differentiation, and cdx2 expression is lost in many colon nepotistic tissues, we used gene expression patterns in colon neoplasia as a starting point to investigate the role of cdx2 in regulating proliferation and differentiation related gene expression. Specifically, genes expressed at a lower level in colon neoplasia, relative to normal colon, were potential targets for cdx2 activation while genes expressed at a higher level were considered potential targets for β-catenin induction and cdx2 repression. Promoters of the most consistently over and under expressed genes were cloned in front of a luciferase reporter gene and assayed for responsiveness to β-catenin and cdx2. Several novel β-catenin and cdx2 targets were identified. Interestingly it was also found that cdx2 could inhibit β-catenin induction of the β-catenin responsive promoters but β-catenin did not inhibit cdx2 induction of cdx2 responsive promoters. Further, cdx2 responsive promoters were induced at a higher level by co-expression of cdx2 and APC than by cdx2 alone. These results suggest that the β-catenin /APC and cdx2 transcriptional programs can counter regulate each other which in turn may be responsible for the counter regulation of the proliferative and differentiated nature in both the development of the normal colon and colonic neoplasia.