tbuckley/cabot-search huggingface dataset:
219. Assessment of IL-15/sIL-15Rα Gene Therapy on Lewis Lung Carcinoma Growing in Mouse Lung, Liver and Kidneys
Authors: Hao Sun, Yongjie Ma, Mingming Gao, Mohammad Al Saggar, Yahya Al Hamhoom, Dexi Liu
Journal: Molecular Therapy (2015)

Interleukin 15 (IL-15) is a multi-functional cytokine and plays an important role in stimulating proliferation and activation of NK and T cells. It binds to cells and signals through a complex formed between IL-15 and IL-15 receptor α (IL-15Rα). The objective of this study is to evaluate therapeutic activity of transferring IL-15 and soluble form of IL-15Rα gene (sIL-15Rα) against lung tumor growing in mouse lung, liver and kidneys. Antitumor activity of IL-15/sIL-15Rα gene transfer was compared to that of chemotherapy using gemcitabine, and the combination of IL-15/sIL-15Rα gene therapy and gemcitabine chemotherapy. Multi-organ tumor growth was established by hydrodynamic tail vein injection of 10^6 LL/2-Luc cells per mouse and tumor growth was monitored by luciferase-based bioluminescent imaging. Gene therapy was performed by hydrodynamic delivery of 2 mg/mouse of AG209 plasmid carrying IL-15/sIL-15Rα genes 3 days after tumor cell injection. Chemotherapy was conducted every 4 days by intra-peritoneal injection of gemcitabine (120 mg/kg) starting on day 3 after tumor cell injection. Luciferase assay on collected organs from tumor-bearing mice showed that hydrodynamic tail vein injection of LL/2-Luc cells resulted in a distribution of tumor cells in the lung (46%), liver (52%), and kidneys (6%). Compared to control animals with an average survival time of 10 days after hydrodynamic tail vein injection of tumor cells, animals with IL-15/sIL-15Rα gene transfer lived an average of 17 days, 1.7 folds longer than the control. Similar antitumor activity was seen in the gemcitabine treated animals, an increase in survival time of 1.75 folds. Combination therapy with IL-15/sIL-15Rα gene transfer and gemcitabine chemotherapy resulted in the best outcome with an average survival of animals for 33 days. Anatomic examination and bioluminescent imaging of tumor-bearing mice revealed that treatment with IL-15/sIL-15Rα gene transfer alone, or in combination with gemcitabine was effective in blocking tumor growth in the liver and kidneys, but failed to block tumor growth in the lung. These results demonstrate that same tumor growing in different organs responds to the same treatment differently. IL-15/sIL-15Rα gene transfer is effective in eliminating tumor growth in the liver and kidney. This work also suggests that mice with multi-organ tumor growth are valuable model for development of treatment strategy in dealing with late stage tumor with metastasis.
Acute Left Ventricular Failure with Pulmnary Edema Following Pericardiocentesis for Cardiac Tamponade : A Case Report
Authors: Shiro Uemura, Tadashi Kagoshima, Toshio Hashimoto, Yasuhiro Sakaguchi, Naofumi Doi, Tamio Nakajima, Hisayuki Tabuse, Seiji Miyamoto, Kazuhiro Dohi
Journal: Circulation (1994)
Abstract 581: Mutational landscape of PIK3CA gene and its association with oral squamous cell carcinoma in Indian population
Authors: Sejal Shah, Siddharth Shah, Harish Padh, Kiran Kalia
Journal: Cancer Research (2015)

Abstract Oral Squamous Cell Carcinoma (OSCC) - the subset of Head and Neck Cancer is the sixth most common cancer worldwide and leading cancer in India. Western part of India (Gujarat) is a prime tobacco growing belt, henceforth, has a high tobacco consumption and increased occurrence of oral cancer. Phosphatidylinositol- 3- kinase (PI3K) is heterodimeric protein kinase composed of catalytic subunit, p110α, and a regulatory subunit, p85α; which regulates cell proliferation, apoptosis, and metastasis. The PIK3CA gene, encodes p110α catalytic subunit, when somatically mutated gets highly deregulated in number of cancers. Canonical mutations E542K, E545K and H1047R in p110α have proven to have higher oncogenic potential, subsequently activating downstream pathways. However, this observation has been reported in limited ethnicity in OSCC. Therefore, we have analyzed mutation profile of exon9 and 20 of PIK3CA gene in 50 OSCC primary tumors and corresponding control samples by direct sequencing in Indian population. We have observed two hot spots mutations E542K and E545K in exon 9, which were earlier reported to activate downstream signaling pathways and two synonymous mutations C3075T and C2985T in exon 20 in fourteen and one OSCC patients, respectively. Patients harboring oncogenic mutations were at advanced stage of OSCC having tobacco chewing history more than ten years. Additionally, we observed two Single Nucleotide Polymorphism rs114587137 (C&amp;gt;T) and rs17849071 (T&amp;gt;G) in intron 9 of PIK3CA gene, which was found germ line mutated in fifteen and three OSCC patients respectively. In summary, we found 4% (2/50) oncogenic mutation frequency of PIK3CA gene, which may play a crucial role through PI3K downstream signaling pathway in oral neoplasia. Our study supports the notion that lower oncogenic mutation frequency of PIK3CA gene has been found in Asian populations but comparable to that seen in western countries. The knowledge of the involvement of PIK3CA mutations in OSCC is of importance, because a specific kinase inhibitor of PIK3CA may potentially serve as an effective therapeutic target against OSCC as a personalized medicine. Citation Format: Sejal Shah, Siddharth Shah, Harish Padh, Kiran Kalia. Mutational landscape of PIK3CA gene and its association with oral squamous cell carcinoma in Indian population. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 581. doi:10.1158/1538-7445.AM2015-581
213. Detection of Integration Sites of CD19 Chimeric Antigen Receptor Gene in a Non-Viral Gene Transfer System
Authors: Motoharu Hamada
Journal: Molecular Therapy (2016)

BACKGROUND: Chimeric antigen receptor (CAR)-modified T cells targeting CD19 have exhibited marked activity in hematological malignancies, such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, and B-cell lymphomas. Many of these results have been obtained using CD19-CAR T cells established by retro- or lentiviral vectors. We developed a non-viral gene-transfer method using the piggyBac transposon system wherein the CD19-CAR gene was integrated into the genome by cut paste mechanism of the transposase. In this system, the expression of CAR was permanent, and the in vitro and in vivo cytotoxic activity on several cancer cell lines was confirmed. In the process of such gene transfer, however, insertional mutagenesis and subsequent activation of proto-oncogenes are a concern. In this report, we aimed to detect the integration sites of CAR genes to evaluate the safety of our CD19-CAR T cells. METHOD: CD19-CAR T cells were produced by transfecting two plasmids containing piggyBac and a CD19-CAR gene by electroporation. We detected the integration sites of CAR genes by inverse polymerase chain reaction and subsequent next-generation sequencing using MiSeq. An analytic pipeline was developed to identify and to classify the integration sites. Proto-oncogenes were defined according to the Cancer Gene Census of the Catalogue of Somatic Mutations in Cancer database. RESULTS: We detected 181 independent integration sites of which five were in exons (CASP10, F2R, CYP51A1-AS1, ULBP2, and SLC24A2) and 113 in introns. The integration sites demonstrated no preference for specific sites. Five integration sites (2.8%) were in the introns of known proto-oncogenes (CDK6, MAML2, RAD51B, RUNX1, and EP300). This percentage of integrations into proto-oncogenes is comparable with that of random integration (2.4%) and lower than that of retro- and lentiviral vectors (6.3-10.4%) according to previous report using marker genes (Galvan et al. J Immunother 2009). CONCLUSION: We confirmed that our piggyBac-mediated transduction system randomly transduced the CAR gene into the genomic DNA. Therefore, this system is considered safer than viral vector system in terms of genotoxicity for CAR transduction into human T cells; however, the possibility of leukemic transformation caused by insertional mutagenesis should be carefully monitored by in vivo clonal analysis.
PO36LATE LANGUAGE AND COMMUNICATION IMPAIRMENTS IN YOUNG ADULT SURVIVORS OF THE CHILDHOOD POSTERIOR FOSSA TUMOURS
Authors: Olha Hodgson, Nicola Pitchford, Rob Dineen, Denis Schluppeck, David Walker
Journal: Neuro-Oncology (2015)

INTRODUCTION: Cognitive impairments in childhood Posterior Fossa Tumour (PFT) survivors are well documented. Yet, there is limited knowledge about the extent of difficulties with linguistic processing in this patient group, which could impact negatively on long-term care and rehabilitation practices. METHOD: 12 patients (16-21 years at test; 4 male), at least 12 months post-PFT resection, were recruited as part of the larger ongoing study. They were assessed using the Clinical Evaluation of Language Fundamentals, 5th edition, Frenchay Dysarthria Assessment (FDA), Raven's Standard Progressive Matrices (RPM) and Purdue Pegboard test (PPT). RESULTS: Group mean performance on the Core Language Scale (CLS) and separate language indices were in the lower average range, with at risk/borderline performance in reading, listening comprehension and structured writing. Patient scores ranged from very low (-2SD) to above average (+2SD) and performance was predicted by age of diagnosis, tumour histology and treatment. Medium to strong correlations were found between language processing and non-verbal IQ (CLS and RPM r = 0.6), motoric speech (Expressive Language Index and FDA r = 0.7), and manual dexterity (FDA and PPT preferred hand r = 0.8), indicating interdependence across these domains. CONCLUSION: Young people treated for PFT in childhood display long-term deficits in both receptive and expressive language skills that are associated with reduced non-verbal IQ. Expressive language abilities are strongly underpinned by motoric speech and manual dexterity skills. Rehabilitation support of PFT survivors, aimed at improving language and communication abilities, is vital for smooth transition into adulthood.
128. Deletion of GAA Repeats Expansion from the Intron 1 of the Frataxin Gene Using CRISPR/Cas9 System
Authors: Dominique L. Ouellet, Joël Rousseau, Arnaud Perrin, Khadija Cherif, Jacques P. Tremblay
Journal: Molecular Therapy (2015)

In the past few years, the CRISPR/Cas9 system has rapidly proven its efficiency as a tool to modulate gene expression in mammalian cells. Modified Cas9 proteins can cut or nick DNA with a lot of specificity when used with appropriate RNA guides expressed from polymerase III promoters. We use this technique in Friedreich Ataxia (FRDA), an inherited autosomal disease known to be caused by a decrease of the mitochondrial frataxin protein. Genetic analysis revealed a GAA repeat expansion within the intron 1 of the frataxin (FXN) gene. The DNA conformation of the repeat has been reported to cause transcriptional issues as mRNA levels drop significantly in FRDA patients. Cells derived from the YG8R mouse model present 2 null mouse FXN genes but contain a FXN transgene obtained from a FRDA human patient. We used different pairs of RNA guide combinations and target the pre- and post-GAA sequence in mouse YG8R and human FRDA cells in order to remove completely the repeat expansion. Depending of the pair, between 1% and 15% of clones derived from YG8R cells show complete deletion of the GAA repeat. The analysis of the YG8R clones revealed some discrepancies between clones obtained from different pairs of transfected RNA guides and further analyses are under investigation. The deletion of the GAA repeats expansion might be a highly valuable gene therapy approach for FRDA patients.
PTH-211 Improving standards of care for patients receiving total parental nutrition (tpn) at a district general hospital. a completed audit cycle: Abstract PTH-211 Table 1
Authors: R Clifford, N Appleton, C McFaul
Journal: Gut (2015)

<h3>Introduction</h3> Total parenteral nutrition (TPN) is an invasive feeding method, with stringent indications due to higher associated cost and morbidity. The National Confidentiality Enquiry into Patient Outcome and Death (NCEPOD) review – A Mixed Bag,<sup>1</sup>identified good clinical practice in only 19% of patients receiving TPN as recently as 2010. We present improvements in standards of care for patients receiving TPN, which were found on completion of an audit cycle at our institution. <h3>Method</h3> Retrospective data collection was undertaken on all patients receiving TPN from December 2013–January 2014 at The Countess of Chester Hospital (Audit 2). This was compared to the same dataset extracted from November 2010–February 2011 (Audit 1). NCEPOD<sup>1</sup>and NICE<sup>2</sup>guidance recommendations were used as gold standards. <h3>Results</h3> Over the 13 month period, 64 patients received TPN. The median age was 68 (range 23–89); male:female ratio 1.5:1. Median duration of TPN was 8 days (range 1–144 days). TPN was commenced in level 1 care in 59.4% of cases; level 2/3 40.6%. 36 patients (56%) received TPN via a dedicated PICC line and 28 (44%) through a central line. Data comparison between audit 1 and 2 is tabulated below. <h3>Conclusion</h3> Early involvement and supervision by the nutrition support team remained at a high standard. Following earlier recommendation, major improvements were seen in the monitoring of daily bloods, obtaining central venous access, and documentation of weekly weight measurements. A multi-disciplinary electronic referral and assessment proforma is now being developed to enable NCEPOD targets to continue to be met. <h3>Disclosure of interest</h3> None Declared.
The Heterogeneity of Ly6Chi Monocytes Controls Their Differentiation into iNOS+ Macrophages or Monocyte-Derived Dendritic Cells
Authors: Shinelle Menezes, Daisy Melandri, Giorgio Anselmi, Thibaut Perchet, Jakob Loschko, Juan Dubrot, Rajen Patel, Emmanuel L. Gautier, Stéphanie Hugues, M. Paula Longhi, Jake Y. Henry, Sergio A. Quezada, Grégoire Lauvau, Ana-Maria Lennon-Duménil, Enrique Gutiérrez-Martínez, Alain Bessis, Elisa Gomez-Perdiguero, Christian E. Jacome-Galarza, Hannah Garner, Frederic Geissmann, Rachel Golub, Michel C. Nussenzweig, Pierre Guermonprez
Journal: Immunity (2016)

Inflammation triggers the differentiation of Ly6Chi monocytes into microbicidal macrophages or monocyte-derived dendritic cells (moDCs). Yet, it is unclear whether environmental inflammatory cues control the polarization of monocytes toward each of these fates or whether specialized monocyte progenitor subsets exist before inflammation. Here, we have shown that naive monocytes are phenotypically heterogeneous and contain an NR4A1- and Flt3L-independent, CCR2-dependent, Flt3+CD11c−MHCII+PU.1hi subset. This subset acted as a precursor for FcγRIII+PD-L2+CD209a+, GM-CSF-dependent moDCs but was distal from the DC lineage, as shown by fate-mapping experiments using Zbtb46. By contrast, Flt3−CD11c−MHCII−PU.1lo monocytes differentiated into FcγRIII+PD-L2−CD209a−iNOS+ macrophages upon microbial stimulation. Importantly, Sfpi1 haploinsufficiency genetically distinguished the precursor activities of monocytes toward moDCs or microbicidal macrophages. Indeed, Sfpi1+/− mice had reduced Flt3+CD11c−MHCII+ monocytes and GM-CSF-dependent FcγRIII+PD-L2+CD209a+ moDCs but generated iNOS+ macrophages more efficiently. Therefore, intercellular disparities of PU.1 expression within naive monocytes segregate progenitor activity for inflammatory iNOS+ macrophages or moDCs.
Pleuropulmonary Blastoma and its association with other childhood neoplasms
Authors: Y. H. Messinger, L. P. Dehner, D. A. Hill, G. Williams, J. R. Priest
Journal: Journal of Clinical Oncology (2004)

8542 Background: Pleuropulmonary Blastoma (PPB) is a rare childhood tumor of the chest wall and lung with three distinct pathology subtypes: type I—entirely cystic; type II—cystic and solid; type III—entirely solid. Poor outcomes have been observed in patients with types II and III PPB. Common sites of metastatic involvement are the brain and bones. In numerous cases, other dysplastic and/or neoplastic conditions occur in the PPB patient or in young, close relatives. Methods: The PPB Registry, established in 1988, collects diagnostic, treatment, and outcome data about this disease for patients worldwide. Results: Registry and literature cases reveal the following conditions associated with PPB in 30 families: Familial cases: -9 patients with relatives having childhood or young adult cancers -3 families with 2 PPB patients in each; an additional family with a child with PPB and another child with a brain sarcoma undistinguishable from PPB -6 patients with relatives having dysplasia in childhood or young adulthood Metachronous or synchronous conditions: -4 patients with additional cancers -5 patients with bilateral PPB -12 patients with additional dysplastic conditions Common associated dysplastic conditions are lung cysts and cystic nephroma. Other associated neoplastic conditions include germ-cell tumors, brain tumors, lymphoma and leukemia, sarcomas, histiocytosis, Wilms' tumor, thyroid tumors, neuroblastoma, and Sertoli-Leydig tumor. Conclusion: 19 of 82 registry patients (23%) with central PPB pathology review have a constitutional or familial association with other neoplasias/dysplasias. At least 3 PPB patients have relatives with germ cell tumors, an association that needs further exploration. Similarly, the preponderance of renal malformations/tumors implies a possible common genetic pathway. PPB is an extraordinary marker for familial childhood dysplasia and neoplasia which deserves intensive molecular study. No significant financial relationships to disclose.
Long Term Follow up of the Combination of Bortezomib with Dexamethasone as Initial Treatment for AL Amyloidosis
Authors: Efstathios Kastritis, Maria Roussou, Magdalini Migkou, Maria Gavriatopoulou, Constantinos Pamboukas, Sosana Delimpassi, Evelina Charitaki, Eurydiki Michalis, Kaladaridou Anna, Plastiras Sotirios, Dimitrios Gogos, Agrios Ioannis, Evangelos Terpos, Meletios A. Dimopoulos
Journal: Blood (2010)
Abstract 3376: Ras activation in aberrant crypt foci is associated with decreased expression of cell cycle regulators and disruption of stromal homeostasis
Authors: Allen Mo, Nicole A. Horelik, Stephen Jackson, Thomas J. Devers, Daniel W. Rosenberg
Journal: Cancer Research (2015)

Abstract Aberrant crypt foci (ACF) are the earliest detectable premalignant lesion within the colon. A majority of ACF harbor somatically acquired mutations to cancer-related genes. ACF may be an indicator for a colonic mucosa at-risk for cancer development, however only a small subset of ACF have the potential to progress to malignancy. We believe that the majority of ACF activate growth inhibitory programs that ultimately result in their growth arrest and regression. In order to begin to define the gene expression changes that occur within these early microscopic lesions and their underlying stroma, we have developed a novel method that combines laser capture micro-dissection with targeted RNA-seq analysis. In the following study, gene expression profiles of thirteen human ACF biopsy specimens harboring known oncogenic mutations (K-ras, B-raf, N-ras, and APC) were compared to matched normal mucosa. Two gene panels were used to assess the status of important cell regulatory pathways: an apoptosis panel comprised of 267 genes and a customized cell senescence panel consisting of 20 genes. In the apoptosis panel, the expression of 81 genes were differentially expressed in ACF compared to matched normal mucosa. Expression of HRK, a potent activator of apoptosis, was the most significantly down-regulated gene (6.75-fold, q &amp;lt;0.01) in every ACF when compared to normal mucosa. Inactivation of HRK function occurs in a variety of tumor types, including prostate cancer, astrocytomas and lymphomas. ACF with mutations occurring within the MAP-K pathway (K-ras, B-raf, N-ras) showed strong activation of downstream ras-associated genes and down-regulation of cell cycle regulators (CDK4 (p = 0.01), CCNB1 (p = 0.04), CCNA2 (p = 0.01), and TP53 (p = 0.04)). Interestingly, these expression panels were distinct from ACF harboring somatic mutations to APC. Analysis of microdissected stroma directly underlying the aberrant crypt structures revealed 25 differentially expressed genes, with dysregulation of several inflammatory mediators (IL2, IL2RA, IL6, TGFB2, BMP4) and extracellular matrix remodeling targets (TIMP1, TIMP2). Our findings suggest that ras-activated ACF may cause significant changes in cell cycle regulation, as well as alterations in stromal extracellular matrix maintenance and inflammatory response. Citation Format: Allen Mo, Nicole A. Horelik, Stephen Jackson, Thomas J. Devers, Daniel W. Rosenberg. Ras activation in aberrant crypt foci is associated with decreased expression of cell cycle regulators and disruption of stromal homeostasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3376. doi:10.1158/1538-7445.AM2015-3376
Prognostic importance of inflammation, apoptosis, and angiogenesis markers in high-grade glial tumors.
Authors: U. Demirci, U. E. Bagriacik, S. Buyukberber, U. Coskun, M. Yaman, A. Ozet, K. Uslu, M. Benekli
Journal: Journal of Clinical Oncology (2011)

e12522 Background: High-grade glial tumors (HGGT) are aggressive tumors. We evaluate the prognostic importance of M65, M30, TNFα, CD105, VEGF, IL6, which are markers of inflammation, apoptosis, and angiogenesis, in HGGTs. Methods: Postoperative pretreatment serums were collected from 44 newly diagnosed HGGT patients. Control group (n=44) consisted of healthy people. Serum M30, M65, CD 105, VEGF, IL6 and TNFα levels were evaluated. Results: Median age of 44 patients with GBM (n=38, %86.3) and anaplastic glioma (n=6, %13.) was 59 (range: 30-80). Thirty-one patients were diagnosed with gross total excision, 10 with subtotal excision and 3 with stereotactic biopsy. Temozolomide concurrent with RT was performed in 37 patients. RT alone was performed in 6 patients. One patient did not receive RT because of poor performance status. Thereafter 24 patients received consolidation temozolomide monotherapy. In 37 patients, proggression free survival (PFS) and overall survival (OS) were 6 (%95 CI; 5.16-6.83) and 16 months (%95 CI; 13.07-18.93) respectively. CD105 (p=0.000) and TNFα (p=0.000) levels were statistically lower, however VEGF (p=0.030) levels were higher in patient group. Statistically insignificant low IL6 levels and high plasma apoptotic markers as M65 (p=0.085) ve M30 (p=0.292) levels were detected. In multiple regression analysis, biological markers did not show significance in survival (0.05<p). Conclusions: In HGGTs, low TNFα and IL6 levels with reduced proinflammatory activity and immunity, besides increased apoptotic activity and VEGF related angiogenesis were detected. Serum levels of markers. Markers N Mean Range P M30 (U/L) Patient Control 44 43 153.43 110.06 57.60-1006.27 57.60-259.05 0.292 M65(U/L) Patient Control 44 43 417.87 298.71 195.31-1590.51 191.64-600.40 0.850 IL6 (pg/mL) Patient Control 44 44 7.23 7.56 0.50-27.71 0.33-29.33 0.957 TNFα (pg/mL) Patient Control 44 44 14.01 45.57 0.60-87.24 0.95-93.05 0.000 VEGF (pg/mL) Patient Control 44 44 626.73 380.49 99.76-5200.53 72.76-1584.12 0.030 CD 105 (ng/mL) Patient Control 44 44 5.51 9.98 0.35-21.23 2.00-23.71 0.000