tbuckley/cabot-search huggingface dataset:
Abstract 1285: Production of interleukin-17 is increased in patients with gastrointestinal cancer and correlates with immune suppression involving MDSC, nutritional impairment, and poor prognosis
Authors: Masahiko Shibata, Kenji Gonda, Takahiro Nakajima, Shinji Ohki, Izumi Nakamura, Tatsuo Shimura, Koji Kono, Seiichi Takenoshita
Journal: Cancer Research (2015)

Abstract Although a causal relationship between inflammation and innate immunity of cancer is more widely accepted today, many of the precise cellular mechanisms mediating this relationship remain unclear. Th17 cells, which produce the proinflammatory cytokine IL-17, have been recognized as one of the key factors in regulation of inflammatory bowel disease and rheumatoid arthritis. IL-17 also has recently been reported to play an important role in induction of MDSC (myeloid-derived suppressor cells). This study demonstrated that, in patients with gastric and colorectal cancers, IL-17 production was correlated with MDSC level and with markers for nutritional impairment, immune suppression and chronic inflammation. IL-17 was significantly higher in patients with gastrointestinal cancer than in normal volunteers. In addition, IL-17 levels were significantly correlated with neutrophil counts and the neutrophil/lymphocyte ratio, and significantly inversely correlated with cell mediated immune response indicators (lymphocyte PHA-blastogenesis and IL-12 induction) and patients’ nutritional status (prealbumin levels). These patients were separated into two groups with the production of IL-17 and the overall survival of the patients with higher production of IL-17 was significantly worse than those with lower production of it. These results suggest that, in human gastrointestinal cancers, chronic inflammation involving IL-17 may be an important mechanism for disease progression through enhancement of induction of MDSC resulting immune suppression, or cachexia. The production of IL-17 was also demonstrated as one of the effective prognostic indicators in these patients. Controlling activation of Th17 cells may prove to be a valuable strategy for treatment of patients with gastrointestinal cancer. Further studies are warranted to explore this possibility. Citation Format: Masahiko Shibata, Kenji Gonda, Takahiro Nakajima, Shinji Ohki, Izumi Nakamura, Tatsuo Shimura, Koji Kono, Seiichi Takenoshita. Production of interleukin-17 is increased in patients with gastrointestinal cancer and correlates with immune suppression involving MDSC, nutritional impairment, and poor prognosis. [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 1285. doi:10.1158/1538-7445.AM2015-1285
251. Defining Conserved Structural Components of the AAV Capsid That Enable Tissue-Specific Transduction Following Systemic Administration
Authors: Jayme K. Warischalk, Samuel C. Eaton, R. Jude Samulski
Journal: Molecular Therapy (2016)

We have previously correlated the destabilization of hydrogen bond networks within recombinant adeno-associated viral (rAAV) capsid surface loop variable region 1 (VR1) to transduction efficiency following intramuscular injection. To investigate the utility of this finding for systemic applications, the capsid structures of rAAV serotypes 1 through 9 were computationally analyzed and VR1 residues participating in hydrogen bonding were individually deleted. Mutant capsids were assessed for tissue tropism and transduction efficiency following intravenous administration into mice. Ex vivo luciferase assays revealed increased muscle transduction and targeting in five of the nine serotypes (rAAV1, rAAV6, rAAV7, rAAV8, rAAV9); cardiac and skeletal muscle transduction were enhanced by up to 170-fold and 9027-fold over parental serotypes, while hepatic transduction was decreased up to 427-fold. VR1 stability also appeared critical to the remaining serotypes, as VR1 deletion mutations rendered rAAV2 and rAAV3b defective in transduction, and rAAV4 and rAAV5 defective in virion production. Intriguingly, amino acid insertions into VR1 produced an opposing phenotype: rAAV1, rAAV2, rAAV3b, and rAAV6 capsids could instead be targeted to transduce the liver with high efficiency, increasing hepatic transduction up to 132-fold. Finally, VR1 mutation synergized with established tyrosine-to-phenylalanine mutations to further increase transduction efficiency while maintaining preferential cardiac/skeletal muscle targeting.
312. Gene Correction of LGMD2A Patient-Specific iPS Cells for Targeted Autologous Cell Therapy
Authors: Sridhar Selvaraj, Antonio Filareto, James Kiley, Daniel Voytas, Michael Kyba, Rita Perlingeiro
Journal: Molecular Therapy (2016)

Limb girdle muscular dystrophy type 2A (LGMD2A), an incurable autosomal recessive disorder and the most common form of LGMD, is characterized by symmetric and progressive weakness of limb-girdle muscles leading to loss of ambulation. LGMD2A is caused by mutations in the Calpain 3 (CAPN3) gene which encodes a muscle-specific intracellular calcium-sensitive cysteine protease, hypothesized to act as a gate keeper for proper assembly and maintenance of the sarcomere. A cell therapy based on induced pluripotent stem (iPS) cells has the potential for treating muscular dystrophy. We have demonstrated that transplantation of skeletal muscle progenitors obtained from disease-free human iPS cells can restore muscle contractility in a mouse model for Duchenne Muscular Dystrophy. The goal of this study is to apply gene editing tools to correct the CAPN3 mutation in LGMD2A iPS cells, and to determine the feasibility of an iPS-cell based autologous cell therapy for LGMD2A. Here we investigated two approaches to genetically correct a LGMD2A patient-specific iPS cell line with homozygous deletion of exon 17 to 24 in the CAPN3 gene. The first approach consisted of knocking in the coding region of CAPN3 cDNA with SV40 polyadenylation signal sequence downstream in exon 1 of the endogenous CAPN3 gene by CRISPR-CAS9 induced double stranded break (DSB) mediated homology directed DNA repair from exogenous donor template, allowing for universal correction of all types of CAPN3 mutations. PCR, sequencing and Southern blot analysis on iPS colonies post- genome editing confirmed the integration of the cDNA in exon 1 of the CAPN3 gene. The second approach involved inserting the missing exons 17-24 with SV40 polyadenylation signal sequence downstream contiguous with the exon 16 of the endogenous CAPN3 gene. PCR and sequencing analysis on iPS colonies post-genome editing confirmed proper integration in this approach as well. LGMD2A iPS cell clones, genetically corrected using these two gene editing methods will be differentiated into skeletal muscle progenitors using conditional expression of Pax7, as previously described by our group, and evaluated in vitro and in vivo for restoration of full length CAPN3. For the latter, we have generated an immunodeficient LGMD2A mouse model by combining the CAPN3-KO mouse model with NOD/SCID and IL2Rg mutations. This mouse is ideal for studies on the transplantation of human cells. In summary, we have corrected the CAPN3 mutation in LGMD2A iPS cells for the first time, and ongoing transplantation studies with corrected iPS cells will provide proof-of-principal for a potential new cell therapy that can permanently restore CAPN3 function in all LGMD2A patients.
Monitoring of circulating tumor cell trends in a prospective, randomized, placebo-controlled HER2/neu peptide vaccine trial.
Authors: G. T. Clifton, A. K. Sears, R. Patil, N. M. Shumway, M. G. Carmichael, D. C. Van Echo, J. P. Holmes, S. McCall, G. A. Merrill, S. Ponniah, G. E. Peoples, E. A. Mittendorf
Journal: Journal of Clinical Oncology (2011)

e11126 Background: Circulating tumor cells (CTC) may have a role as a prognostic marker and in monitoring therapeutic response in breast cancer (BrCa) patients. We are conducting a prospective, randomized phase II trial evaluating the HER2 peptide vaccines AE37 and GP2 in the adjuvant setting. AE37 is the Ii-Key hybrid of the AE36 peptide (HER2: 776-790) and GP2 is an HLA-A2+ -restricted peptide (HER2: 654-662). Both are capable of eliciting anti-HER2 tumor activity. We examined CTC trends in BrCa patients from our vaccine trial. Methods: Node positive or high-risk node negative BrCa patients with any level of HER2 expression disease-free after standard treatments were randomized to receive vaccine (either GP2 or AE37) + GM-CSF (immunoadjuvant) or GM-CSF alone. Vaccinations were given as six monthly intradermal inoculations. CTC were enumerated from 20 mL blood samples using the CellSearch System (Veridex, LLC Warren, NJ). CTC count was checked pre-vaccination and followed every 6 months for those with ≥1 CTC at baseline. p-values were calculated using Fisher’s exact test. Results: Baseline CTC levels were checked in 45 patients with 18 (40%) having ≥1 CTC. Follow-up CTC results were available for 12 patients. Eight of these patients had a subsequent CTC decrease while 4 patients had either increasing (2) or unchanged (2) CTC counts. In patients with a CTC decrease, 7 of 8 (87.5%) received vaccines compared to only 1 patient with a decrease after receiving GM-CSF alone. In those with no CTC decrease, only 1 of 4 (25%) received the vaccine while the remainder received GM-CSF only (p=0.067). In the 4 patients without CTC decrease, 2 developed BrCa recurrence with 1 death from metastatic disease. There were no events in patients with CTC decreases. Conclusions: Clinically disease-free BrCa patients with detectable baseline CTC levels in our adjuvant vaccine trial who experience a CTC decrease were much more likely to have received the vaccine than the control. Monitoring CTC trends may be a promising clinically-relevant surrogate marker for BrCa recurrence. However, in the adjuvant setting, CTC were detectable in only 40% of patients suggesting the need for a more sensitive test for broader applicability.
IgVH Germline and Mutated Chronic Lymphocytic Leukemia (CLL) Cases Exert a Diverse Responsiveness upon BCR Ligation.
Authors: Simona Tavolaro, Roberta Maggio, Nadia Peragine, Monica Messina, Franca Citarella, Simona Santangelo Miss, Marilisa Marinelli, Maria R. Ricciardi, Maria S. De Propris, Ilaria Del Giudice, Francesca R. Mauro, Sabina Chiaretti, Robert Foa, Anna Guarini
Journal: Blood (2007)
The Supra Perfusion Agent PEGylated Albumin and Its Tempol Derivative Improve Blood Oxygenation and Ameliorate Inflammatory Response in Sickle Transgenic Mice
Authors: Mary E. Fabry, Seetharama A. Acharya, Fantao Meng, Sandra M. Suzuka, Dhananjay K. Kaul
Journal: Blood (2011)
Abstract 1524: Establishing long-term circulating tumor cells (CTCs) in a 3D culture system in vitro
Authors: Marina C. Cabrera, Elaine Hurte
Journal: Cancer Research (2015)

Abstract Circulating tumor cells (CTCs) are cells that have detached from the primary tumor and entered the bloodstream with the potential to seed metastatic tumors in distal sites. High CTC numbers correlate with aggressive disease, increased metastasis, and decreased time to relapse. It has also been shown that cancer stem cells (CSCs) represent a proportion of the CTCs present in patients. Given that CSCs are resistant to chemotherapy and are responsible for tumor initiation, it is posited that the CSCs are the seeds of metastasis. However, direct evidence for this hypothesis is limited due to the fact that there are few methods for culturing and studying these rare cells. We used a 3D culture chamber system (RealBio D4 ™) to establish long-term cultures of human-derived pancreatic tumors and to assess the effect of gemcitabine treatment on the CSC population of these cultures. We observed that the system's 3D matrix supported culture development and incorporation of tissue organization and microenvironment. The chamber design allowed CTCs generated within the cultures to migrate out of the cell mass into the circulating nutrient medium where they were collected for characterization. Further, tumor tissue grown on the matrix showed an enrichment of CSCs after gemcitabine treatment analogous to the enrichment observed in vivo. Future studies will focus on characterizing isolated CTCs and circulating CSCs from pancreas and breast cancer models, determine their response to therapy, and elucidate the relationship of different CTC populations on tumor spread. Ultimately, these studies may support the use of CTCs and circulating CSCs as biomarkers in clinical trials. Citation Format: Marina C. Cabrera, Elaine Hurte. Establishing long-term circulating tumor cells (CTCs) in a 3D culture system in vitro. [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 1524. doi:10.1158/1538-7445.AM2015-1524
ACTL6A Is Co-Amplified with p63 in Squamous Cell Carcinoma to Drive YAP Activation, Regenerative Proliferation, and Poor Prognosis
Authors: Srinivas Vinod Saladi, Kenneth Ross, Mihriban Karaayvaz, Purushothama R. Tata, Hongmei Mou, Jayaraj Rajagopal, Sridhar Ramaswamy, Leif W. Ellisen
Journal: Cancer Cell (2016)
OC-028 Identification of SOX9 as a novel mechanism to explain aspects of liver fibrosis
Authors: J Pritchett, V S Athwal, E Harvey, F Oakley, D A Mann, N Hanley, K Piper-Hanley
Journal: Gut (2010)

<h3>Introduction</h3> Fibrosis of the liver is characterised by progressive accumulation of extracellular matrix (ECM) proteins and is a major cause of morbidity and mortality in the UK. Several cell-types are responsible for this, but a major role is played by activation of the hepatic stellate cell (HSC). We have identified ectopic expression of the Sry-box transcription factor, SOX9, in activated HSCs as a novel mechanism to explain aspects of liver fibrosis. <h3>Methods</h3> Livers were collected from carbon tetrachloride induced fibrotic and control rats and processed for fixed tissue. Rat hepatic stellate cells (HSCs) were isolated using established perfusion techniques and cultured on tissue culture plastic to activate over 4, 7 and 10 days. The immortalised human LX2 cell line was also used. <h3>Results</h3> In fixed fibrotic rat livers α-smooth muscle actin (α-sma) was detected in activated HSCs with collagen type 1 (Col1) rich fibrotic tracts found disrupting normal tissue architecture. Nuclear Sox9 staining was detected in the same regions as α-sma and Col1. In quiescent HSCs isolated from rat liver, negative for α-sma and col1, Sox9 was absent. However during activation of HSCs, both Sox9 and Col1 were robustly expressed. In these activated Col1-expressing HSCs, Sox9 localised to the nucleus surrounded by α-sma positive cytoplasm. SOX9 knockdown in activated HSCs using RNA interference caused a commensurate reduction in Col1 protein expression (∼60%). The pro-fibrotic cytokine transforming growth factor β (TGF-β) induced expression of SOX9 by ∼3-fold in rat HSCs and ∼2.5-fold in the human stellate cell line LX2s. <h3>Conclusion</h3> We have identified SOX9 as a novel mediator of ECM in liver fibrosis. Our data demonstrate that SOX9 expression occurs during activation of HSCs, a major cell type responsible for liver fibrosis, when, under the influence of TGF-β signalling it causes Col1 production, the predominant collagen deposited in organ fibrosis. Lessening SOX9 levels similarly reduced Col1 production. These data suggest targeted reduction of SOX9 offers potential therapeutic application to ameliorate fibrosis and related conditions of the liver.
Differential Expression of Hem1 and CTLA-4 in B-CLL Patients with High and Low CD38 Expression.
Authors: Avadhut D. Joshi, John D. Dickinson, James C. Lynch, Philip J. Bierman, Gregory R. Bociek, Marcel P. Devetten, James O. Armitage, Shantaram S. Joshi
Journal: Blood (2005)
Abstract 506: TROY-EGFR signaling complex mediates glioblastoma cells invasion and survival
Authors: Alison Roos, Zachary Mayo, Jean Kloss, Serdar Tuncali, Harshil Dhruv, Michael E. Berens, Joseph C. Loftus, Nhan L. Tran
Journal: Cancer Research (2015)

Abstract Glioblastoma (GBM) is a highly lethal CNS malignancy in adults with a median survival of about 15 months. Effective therapeutic control of GBM is thwarted by the invasive nature of the tumor, which prevents complete surgical removal and results in tumor recurrence. Thus, there is a dire need to develop innovative approaches to target the invasive tumor cells for improved treatment of this disease. Expression of TROY, a member of the TNFR family, increases with glial tumor grade and inversely correlates with patient survival. Increased expression of TROY stimulates glioblastoma cell invasion and increases resistance to temozolomide (TMZ) and radiation treatment. We have demonstrated that TROY forms a novel complex with EGFR and modulates EGFR survival signaling. IHC analysis of GBM specimens showed that tumors with elevated TROY expression had a statistically positive correlation with increased EGFR expression. TROY expression enhanced EGFR phosphorylation, stabilized EGFR surface expression in the presence of ligand, and significantly increased EGF-stimulated GBM cell invasion. Consistent with invasion, co-expression of TROY with EGFR increased cell survival to TMZ. Moreover, we have shown that in cells treated with EGF, the TROY and ErbB4 receptor are recruited to the EGFR complex. Although the role of ErbB4 in GBM is not well defined, inhibition of ErbB4 expression suppressed tumor growth and invasion in multiple tumor subtypes, decreased EGFR surface retention, and limited EGF-induced cell migration. These data suggest that the TROY-EGFR-ErbB4 complex may represent an unappreciated therapeutic target to inhibit glioma invasion and decrease therapeutic resistance. Citation Format: Alison Roos, Zachary Mayo, Jean Kloss, Serdar Tuncali, Harshil Dhruv, Michael E. Berens, Joseph C. Loftus, Nhan L. Tran. TROY-EGFR signaling complex mediates glioblastoma cells invasion and survival. [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 506. doi:10.1158/1538-7445.AM2015-506
Abstract 3043: Discovery of a novel mitochondrial protein complex containing pro-apoptotic Noxa in leukemia
Authors: Jeffrey S. Gaynes, Eric A. Hanse, Ameeta Kelekar
Journal: Cancer Research (2015)

Abstract Apoptosis evasion and altered nutrient metabolism are recognized as major contributors to cancer development. However, the degree to which apoptosis and metabolism are integrated in malignant cells remains poorly understood. Previously our group observed alterations in mitochondrial function mediated by expression of the pro-apoptotic member of the Bcl-2 family Noxa. Here, we report the presence of a large 650 kilodalton multi-protein complex specific to the mitochondria of Jurkat leukemia cells that contains Noxa. We also detect a similar mitochondrial protein complex in cells expressing Noxa with a mutated BH3 domain, suggestive of an apoptosis-independent metabolic function for this Bcl-2 family member. Lastly, we present here the successful isolation of this complex aimed at identifying other complex components via mass spectrometry. This unique strategy included purifying the complex by gel-filtration chromatography, and then resolving the complex into an acrylamide gel by either size or charge, followed by separating the individual complex components by size. Future studies are geared towards identifying the other components of the complex, looking for presence of this complex in other cancers, and understanding how this complex may function in maintaining mitochondrial homeostasis in cancer. In summary, the data presented here strongly suggests a non-canonical function for Noxa in regulating mitochondrial function independent of apoptosis in leukemia, and possibly other malignancies. Note: This abstract was not presented at the meeting. Citation Format: Jeffrey S. Gaynes, Eric A. Hanse, Ameeta Kelekar. Discovery of a novel mitochondrial protein complex containing pro-apoptotic Noxa in leukemia. [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 3043. doi:10.1158/1538-7445.AM2015-3043
BMET-11. DURAL METASTASES FROM BREAST CANCER - CASE SERIES
Authors: David Macdonald, Joseph Megyesi, Kylea Potvin
Journal: Neuro-Oncology (2016)

Intracranial metastases from solid tumors are increasingly common, often brain or leptomeningeal metastases. Dural metastases are under-reported, present diagnostic and therapeutic challenges, and may mimic subdural hematoma or meningioma. This report describes 4 recent patients with dural metastases from breast cancer. A 64 year old woman, without known cancer, had 5 months of increasing headaches, left weakness, and focal seizures. Imaging showed an enlarging right frontal extra-axial enhancing mass with edema, initially thought to be a meningioma. At surgery the tumor involved overlying bone, replaced the dura, and invaded brain. Pathology was metastatic adenocarcinoma, ER/PR positive and Her-2 negative. Investigations showed a right breast primary, and lung and bone metastases. She received cranial radiotherapy (RT), letrozole and pamidronate. The tumor remains controlled after 42+ months. The 3 other patients all had prior known breast cancer, 2 ER/PR positive and Her-2 negative, and 1 triple negative (ER/PR/Her-2 negative), ages 45-70 years. Two had known systemic metastases prior to neurological presentation. Presenting symptoms included headache, seizures, focal weakness, and confusion. All had new or progressive systemic metastases, including bone, at diagnosis of dural metastases. None had intraparenchymal brain metastases. Two had resection of dural metastases, 1 with complicated postoperative course, with eventual improvement in both. Two received cranial RT, 1 refused RT, and all received hormonal therapy or chemotherapy, with initial clinical or MRI intracranial control for 6+, 7+ and 9 months. One patient had a small, asymptomatic dural recurrence 9 months after initial diagnosis, with new chemotherapy planned, and remains clinically well 11+ months after diagnosis. These cases illustrate the complexity of dural metastases. Although patients often have extensive metastatic disease, treatment can improve symptoms and prolong survival.
CK2 Kinase Inhibitors Display Anti-Myeloma Effects and Antagonize Osteoclast Activity in Models of Multiple Myeloma Bone Marrow Microenvironment
Authors: Sabrina Manni, Denise Toscani, Anna Colpo, Alessandra Brancalion, Fortunato Zaffino, Laura Quotti Tubi, Gianpietro Semenzato, Nicola Giuliani, Francesco Piazza
Journal: Blood (2012)
Randomized Double Blind Placebo Controlled PK/PD Study On the Effects of a Single Intravenous Dose of the Anti-Hepcidin Spiegelmer Nox-H94 On Serum Iron During Experimental Human Endotoxemia
Authors: Lucas van Eijk, Dorine W. Swinkels, John Aaron, Frank Schwoebel, Frank Fliegert, Luciana Summo, Vauleon Stéphanie, Coby Laarakkers, Kai Riecke, Peter Pikkers
Journal: Blood (2012)
Retraction notice to: PS124 – Efficacy and Safety of Induction Dosing of Vedolizumab for Reducing Biliary Inflammation in Primary Sclerosing Cholangitis (PSC) in Individuals with Inflammatory Bowel Disease [J Hepatol 64 (2016) S199]
Authors: B. Eksteen, J. Heatherington, J. Oshiomogo, R. Panaccione, G. Kaplan, S. Ghosh
Journal: Journal of Hepatology (2016)