tbuckley/cabot-search huggingface dataset:
Abstract 1546: Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma
Authors: Hideyuki Takahashi, Koichi Sakakura, Kazuaki Chikamatsu
Journal: Cancer Research (2015)

Abstract Introduction: Evidence has accumulated indicating that cancer-associated fibroblasts (CAFs) play an important role in angiogenesis, invasion, and metastasis. Simultaneously, CAFs might actively participate in inducing immunosuppressive ability and promoting evasion from immunosurveillance. In the present study, we investigated whether CAFs within the tumor microenvironment contribute as one of key components of tumor immune evasion in head and neck squamous cell carcinoma (HNSCC). Materials and methods: CAFs and normal fibroblasts (NFs) were prepared from surgical tissue of HNSCC patients. Flow cytometric analysis was performed for the expression of A-smooth muscle actin (A-SMA) and co-stimulatory molecules. Inhibition of T-cell proliferation, T-cell apoptosis and induction of regulatory T cells (Treg) were also examined using flow cytometry. The mRNA expression of various cytokines was investigated by real-time qRT-PCR. Results: Generated CAFs and NFs were negative for CD11b, CD34, and CD45, and were positive for CD90 and FAP. The A-SMA expression of CAFs was higher than that of NFs. CAFs efficiently suppressed T cell proliferation as compared with NFs. Of note, this suppressive activity was found under co-cultivation with not only CAFs, but also supernatant from CAFs. CAFs, but not NFs expressed co-regulatory molecules, B7H1 and B7DC and CAFs showed increased expression levels of cytokine genes including IL-6, IL-8, TNF-A, TGF-β, and VEGF. Moreover, PBMCs co-cultured with supernatant from CAFs preferentially induced T-cell apoptosis and Treg as compared with those from NFs. Conclusion: Our findings suggest that, in the tumor microenvironment, CAFs might play a pivotal role in establishing an immunosuppressive network along with tumor cells, and subsequent facilitation to activate the immunosuppressive pathway. Citation Format: Hideyuki Takahashi, Koichi Sakakura, Kazuaki Chikamatsu. Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma. [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 1546. doi:10.1158/1538-7445.AM2015-1546
395. Developing Bone Marrow Transplant and Lentiviral Vectors for Friedreich Ataxia
Authors: Marguerite V. Evans-Galea, Sze HweeOng, Dongcheng Zhang, Matthew Burton, Chou H. Sim, Dean Phelan, Sarah E.M. Stephenson, Gabrielle R. Wilson, Donald F. Newgreen, Paul J. Lockhart, Martin B. Delatycki
Journal: Molecular Therapy (2015)

Debilitating neurological disorders such as Friedreich ataxia (FRDA) have limited treatment options in the clinic. The primary clinical features of FRDA include progressive ataxia and shortened life span, with complications of cardiomyopathy being the major cause of death. Current treatments aim to improve quality of life, but none can cure or slow the progression of neurodegeneration inherent to this disease. Most individuals with FRDA are homozygous for a GAA trinucleotide repeat expansion in the first intron of the frataxin gene (FXN). Although the GAA expansion does not alter the coding sequence of FXN, it leads to reduced levels of frataxin, a nuclear-encoded mitochondrial protein important for iron metabolism. The frataxin protein produced is structurally normal however, so an increase in protein levels is expected to be therapeutically beneficial. We are developing a series of lentiviral vectors that express FXN to increase frataxin expression in cells derived from individuals with FRDA. Our goal is to deliver the most promising vector via autologous bone marrow transplant to correct FRDA. We therefore examined the potential of transplant with wild-type donor bone marrow (BM) to correct frataxin deficiency in a FRDA mouse model that reflects elements of the human disease. Hematopoietic reconstitution in FRDA mouse recipients with GFP-positive donor BM demonstrated successful engraftment following transplant. Corrected recipients demonstrated low-level chimerism in several tissues post-transplant, with GFP-positive cells detected in the dorsal root ganglia and the spinal cord. Expression analyses indicate increased frataxin expression in the liver and we are performing behavioral analyses to examine the locomotor phenotype in corrected FRDA mice. This study highlights the potential of bone marrow transplant and lentiviral gene therapy as an alternate treatment approach for FRDA.
Transcriptome Analysis of Erythroid Cells Cultured from Diamond Blackfan Anemia Patients with Ribosomal and GATA1 Mutations Reveals Dysregulation of Inflammatory Response Genes
Authors: Kelly O'Brien, Adrianna Vlachos, Stacie M. Anderson, Crystiana Tsujiura, Lionel Blanc, Eva Atsidaftos, NIH Intramural Sequencing Center, Jason E. Farrar, Steven R Ellis, Jeffrey Michael Lipton, David M. Bodine
Journal: Blood (2015)
Advances in the medical management of skin and soft tissue infections
Authors: Sarah L McClain, Jefferson G Bohan, Dennis L Stevens
Journal: BMJ (2016)

Skin and soft tissue infections are some of the most common infectious disease diagnoses in both inpatient and outpatient settings. With bacterial resistance to antimicrobials growing, decision making on empiric antibiotics is becoming increasingly difficult. Additionally, the most recent guidance from a professional society on the treatment of skin and soft tissue infections was published in 2014 by the Infectious Diseases Society of America and is now two years old. New antimicrobial agents have been developed and approved for the treatment of skin and soft tissue infections since then, and more are in the pipeline. This review summarizes the evidence on treatments that are new or in development and the potential repurposing of old antimicrobials. The clinical utility of these treatments is also discussed.
Phase I Study of Lenalidomide in Acute Leukemia: Remissions in Post-Allogeneic Relapse of Acute Myeloid Leukemia.
Authors: Jason C. Chandler, Rebecca B. Klisovic, Mitch A. Phelps, Alison Walker, Ramiro Garzon, Xiaoxia Yang, Larry Schaaf, Sebastian Schwind, Heiko Becker, Shujun Liu, Chris Hickey, Cheryl Kefauver, Jon Mickle, Steven M Devine, Michael R. Grever, John C. Byrd, Guido Marcucci, William Blum
Journal: Blood (2009)
Abstract 386: Rapid in situ RNA analysis of circulating tumor cells using magnetic micropore-based sorting and Turbo FISH
Authors: Jin A Ko, Neha Bhagwat, Stephanie S. Yee, Erica Carpenter, Ben Stanger, David Issadore
Journal: Cancer Research (2015)

Abstract Pancreatic cancer is the fourth most common cause of cancer-related death in the US, with a five year survival rate of only 6%. Recently, we have shown that circulating pancreatic cells can be detected at the onset of the disease cycle (pre-Stage 1). Thus, there is both a great need for early diagnosis and an opportunity, due to the early presence of circulating tumor cells (CTCs). Currently, the gold standard for CTC detection cannot resolve these extremely sparse, heterogeneous CTCs, which do not have any single surface marker that allows them to be targeted. Additionally, conventional downstream analyses are limited to either protein expression of individual cells on-chip, which has limited sensitivity to relevant biomarkers, or genetic testing off-chip, which has limited practical clinical use. To address these challenges, we have developed a rapid (&amp;lt; 40 minute) clinical diagnostic for pancreatic cancer detection. Our approach combines magnetic micropore based negative selection of immunomagnetically labeled leukocytes with on-chip RNA fluorescence in situ hybridization (Turbo RNA FISH) to profile individual cells. With the high-specificity of FISH and its ability to be multiplexed, combined with the high sensitivity of track-etched magnetic micropore (TEMPO) to rare cells, we have demonstrated the potential to diagnose pancreatic cancer early in the disease cycle. A key innovation is the development of our magnetic micropore based sorting technique, which preserves the low cell-loss and specificity of microfluidic sorting but at &amp;gt;10x greater flow rates and an insensitivity to clogging, enabling use directly on whole blood. The TEMPO filter consists of an electroplated 1.25 μm NiFe, 30 μm pores, and 5.1×10E5 pores total. Using this chip, we have demonstrated extremely high sensitivity to rare cells (LOD ∼ 1 cell / 7.5 mL blood) and exponentially improved sorting efficiency by stacking multiple TEMPO filters in series. Furthermore, single molecules of targeted RNA in each individual CTC could be resolved. Citation Format: Jin A Ko, Neha Bhagwat, Stephanie S. Yee, Erica Carpenter, Ben Stanger, David Issadore. Rapid in situ RNA analysis of circulating tumor cells using magnetic micropore-based sorting and Turbo FISH. [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 386. doi:10.1158/1538-7445.AM2015-386
Incidences of Submicroscopic Deletions Are Variable According to Disease Entities and Chromosomal Translocations in Hematologic Malignancies: Investigation by FISH.
Authors: Hyun Jung Min, Hee Won Moon, Young-Ree Kim, Sung-Soo Yoon, SeonYang Park, Byoung Kook Kim, Hee Young Shin, Hyo Sup Ahn, Hee Chan Kim, Han Ik Cho, Dong Soon Lee
Journal: Blood (2005)
325. Targeted Gene Addition Strategies for the Treatment of X-Linked Lymphoproliferative Disease
Authors: Benjamin C. Houghton, Claudio Mussolino, Toni Cathomen, H Bobby Gaspar, Claire Booth
Journal: Molecular Therapy (2016)

X-linked lymphoproliferative disease is an immunodeficiency arising from mutations in the SH2D1A gene encoding SAP, a key regulator of immune function expressed in T cells, natural killer, and natural killer T cells. Haemopoietic stem-cell transplantation is curative, and we have shown proof of concept of haemopoietic stem-cell gene therapy in a mouse model. Preliminary data suggests that adoptive transfer of T cells corrected using lentiviral gene therapy can correct immune defects. However, targeted gene editing of T cells may allow for physiologically regulated SAP expression. We constructed SAP-specific TALE-effector nucleases (TALENs) capable of generating a site-specific double-stranded break close to the translation start codon, allowing correction of most described SH2D1A mutations. TALEN activity was validated with a surveyor assay in HEK293T cells. To facilitate optimisation of delivery methods, we designed a fluorescent reporter assay that, when stably integrated into a cellular DNA, provides a fluorescence signal when repair of DNA double-stranded breaks (DSB) created by TALENs occurs. Using the reporter assay in Jurkat cells we observed reduced toxicity and highly efficient delivery using an mRNA nucleofection platform, with 23% of treated cells showing repair mediated fluorescence. We therefore proceeded to deliver TALEN mRNA to human primary T cells, and demonstrated the generation of double-stranded breaks in 25% of the bulk population. To harness the repair of DSB, we constructed a homologous recombination donor in a non-integrating lentiviral vector format to mediate delivery of cDNA with low toxicity. Combined with TALEN mRNA nucleofection, homologous recombination-driven incorporation of donor in T cells was possible. This methodology could be applied to an autologous T-cell gene therapy strategy, although the low level of homologous recombination remains a limiting factor. We plan to test our strategy in patient cell lines to restore SAP expression and cytotoxic function of cytotoxic T lymphocytes.
Abstract 4901: Comparison of gene expression platforms: RNA-Seq, Fluidigm, and Nanostring
Authors: Erica B. Schleifman, Maipelo Motlhabi, Craig Cummings, Rin Nakamura, Linda Bosch, Rajesh Patel, An Do, Andrew Watson, Thomas Sandmann, Walter Darbonne, Ian McCaffery, Eric Peters, Rajiv Raja
Journal: Cancer Research (2015)

Abstract Accurately measuring the expression of genes in formalin-fixed paraffin embedded (FFPE) tumor tissues has long been a struggle due to the inherent degradation of RNA isolated from these materials. Accurate quantification of gene expression levels in FFPE samples can enable the testing of biomarker hypotheses in the clinic and can potentially be used for patient stratification or selection in clinical trials. Platforms such as Fluidigm, Nanostring and microarrays are currently the high-throughput technologies utilized. Each of these platforms has different drawbacks and challenges such as lack of sensitivity, reproducibility or dynamic range when working with degraded FFPE samples. Currently, whole transcriptome RNA sequencing (RNA-Seq) is the only platform that offers a truly high-throughput, sensitive, and reproducible method to accurately quantify mRNA levels in RNA derived from FFPE samples. RNA-Seq, however has not yet been widely evaluated and adapted for use with degraded FFPE samples. Here we report the direct comparison of whole transcriptome RNA-Seq with two platforms that are currently compatible with FFPE derived RNA, Fluidigm and Nanostring, to determine the accuracy and feasibility of using this technology on degraded RNA. Utilizing a collection of matched fresh frozen (FF) and FFPE samples we analyzed gene expression using all three platforms to allow for a direct evaluation of each technology. By comparing the results to the matching FF sample, we were able to determine the accuracy and sensitivity of each platform when using degraded FFPE derived RNA. By titrating down the input of FFPE RNA into the RNA-Seq library prep we were also able to define the optimal input of FFPE RNA needed to accurately and reproducibly quantify gene expression. This work allows for a systematic comparison of different gene expression platforms for their use with degraded FFPE RNA. Citation Format: Erica B. Schleifman, Maipelo Motlhabi, Craig Cummings, Rin Nakamura, Linda Bosch, Rajesh Patel, An Do, Andrew Watson, Thomas Sandmann, Walter Darbonne, Ian McCaffery, Eric Peters, Rajiv Raja. Comparison of gene expression platforms: RNA-Seq, Fluidigm, and Nanostring. [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 4901. doi:10.1158/1538-7445.AM2015-4901
Lymphocytopenia Is Associated with an Increased Risk of Severe Infections in Patients with Multiple Myeloma Treated with Bortezomib-Based Regimens
Authors: Sung-Hoon Jung, Jae-Sook Ahn, Seung-Ji Kang, Deok-Hwan Yang, Yeo-Kyeoung Kim, Hyeoung-Joon Kim, Je-Jung Lee
Journal: Blood (2012)
Association of p16 and pEGFR expression with high-risk HPV in head and neck squamous cell carcinoma.
Authors: R. Altaha
Journal: Journal of Clinical Oncology (2011)

5578 Background: A study was conducted to evaluate the hrHPV status, phosphorylated EGFR (pEGFR) and P-16 expression of tumor tissues of patients with Head and Neck Squamous Cell Carcinoma (HNSCC). Methods: In 140 HNSCC formalin fixed paraffin embedded tumor tissues, qPCR performed to detect hrHPV (16,18,31,39,45,51,52,68) and immunohistochemistery performed to evaluate P-16 and pEGFR expression (0= negative, positive=1,2,3). Results: Seventy out of 140 samples (50%) were positive for hrHPV, HPV16 (n=16), HPV18 (n=48), HPV51 (n=5), HPV31 (1). HPV positivity/negativity was compared to p16 (0,1,2,3) values and a significant association (Chi-Sq=7.65, p=0.0057) was found. A similar analysis correlating HPV with pEGFR showed no significant association (p=0.216). A multiple logistic regression was used to investigate the joint association between p16 and pEGFR on HPV status. After an analysis indicated no interaction between the two factors we fit the no interaction model. The results were highly significant for p16 (p=0.002) and nearly significant but in the unexpected direction for pEGFR (p=0.074). Conclusions: In tumor tissues of patients with HNSCC, hrHPV is associated with P-16 expression, and there might be an independent association between hrHPV and pEGFR.
Lipin-2 regulates NLRP3 inflammasome by affecting P2X7 receptor activation
Authors: Gema Lordén, Itziar Sanjuán-García, Nagore de Pablo, Clara Meana, Inés Alvarez-Miguel, M. Teresa Pérez-García, Pablo Pelegrín, Jesús Balsinde, María A. Balboa
Journal: The Journal of Experimental Medicine (2016)

Mutations in human LPIN2 produce a disease known as Majeed syndrome, the clinical manifestations of which are ameliorated by strategies that block IL-1β or its receptor. However the role of lipin-2 during IL-1β production remains elusive. We show here that lipin-2 controls excessive IL-1β formation in primary human and mouse macrophages by several mechanisms, including activation of the inflammasome NLRP3. Lipin-2 regulates MAPK activation, which mediates synthesis of pro-IL-1β during inflammasome priming. Lipin-2 also inhibits the activation and sensitization of the purinergic receptor P2X7 and K+ efflux, apoptosis-associated speck-like protein with a CARD domain oligomerization, and caspase-1 processing, key events during inflammasome activation. Reduced levels of lipin-2 in macrophages lead to a decrease in cellular cholesterol levels. In fact, restoration of cholesterol concentrations in cells lacking lipin-2 decreases ion currents through the P2X7 receptor, and downstream events that drive IL-1β production. Furthermore, lipin-2-deficient mice exhibit increased sensitivity to high lipopolysaccharide doses. Collectively, our results unveil lipin-2 as a critical player in the negative regulation of NLRP3 inflammasome.
Expression of HMGA2 Collaborates with JAK2V617F to Progress Myeloproliferative Neoplasms
Authors: Koki Ueda, Kazuhiko Ikeda, Kazuei Ogawa, Akiko Shichishima-Nakamura, Kotaro Shide, Kazuya Shimoda, Yuko Hashimoto, Philip J Mason, Monica Bessler, Yasuchika Takeishi
Journal: Blood (2015)
ATPS-02CONTINUOUS ADMINISTRATION OF THE NOVEL IRON-MIMETIC GALLIUM MALTOLATE INHIBITS GLIOMA GROWTH<i>IN VITRO</i>AND<i>IN VIVO</i>
Authors: Mona Al-Gizawiy, Kimberly Pechman, Andrew Lozen, Janine Wereley, Christopher Chitambar, Kathleen Schmainda
Journal: Neuro-Oncology (2015)

BACKGROUND: Limited treatment options and an aggressive nature make glioblastoma multiforme (GBM) a highly deadly cancer associated with poor prognosis and short survival. Gallium (Ga), an iron-mimetic metal, disrupts tumor iron homeostasis, thus effecting potential antineoplastic activity. Here we present compelling evidence that gallium maltolate (GaM) has a profound antitumor effect on GBM in vitro and in vivo. METHODS: The in vitro cytotoxic effects of GaM were measured by MTT assay in human U87 and D54 GBM cells, and cells isolated from normal rat brain. The in vivo antineoplastic effect of GaM was studied in a xenograft model that involved stereotactic inoculation of U87 cells into the right hemisphere of 8-week old male athymic rats. Following tumor growth confirmation on Day 8 post-inoculation by magnetic resonance imaging (MRI), rats received continuous intravenous (IV) administration of GaM (50 µM) for 10 days. Follow-up MRI occurred on Day 18 post-inoculation. RESULTS: In vitro, GaM profoundly inhibited the proliferation of both U87 and D54 GBM cell lines, but not control cells. The IC50 decreased 46% from 79.8 µM (3-day incubation) to 42.8 µM (5-day incubation) in U87 cells, and 24% from 51.4 µM (3 days) to 38.9 µM (5 days) in D54 cells. Removing GaM on days 3 and 5, and maintaining cells for another 5 days, caused a further decrease in IC50 (U87: 47.4% and 21.8%, respectively; D54: 11.8% and 10.3%, respectively). In vivo, rats receiving IV GaM tolerated the drug well, and no adverse effects were observed. Contrast-agent enhancing tumor volume on T1-weighted MRI increased in both treated (n = 8) and untreated (n = 7) animals, but significantly less so in treated rats. Mean percent increase in cerebral blood volume, determined from steady-state post-MION images, was 45% (controls) and 28% (treated rats) (p < 0.05). CONCLUSION: Gallium maltolate shows great promise for therapeutic potential in GBM.
Erlotinib beyond progression study: Randomized phase II study comparing chemotherapy plus erlotinib with chemotherapy alone in EGFR TKI-responsive, advanced non-small cell lung cancer (NSCLC) that subsequently progresses.
Authors: B. Halmos, P. Fu, N. A. Pennell, G. A. Otterson, T. Mekhail, M. R. Snell, J. P. Kuebler, S. M. Gadgeel, A. Conrad, A. T. Stefanski, A. Dowlati
Journal: Journal of Clinical Oncology (2011)

TPS211 Background: EGFR-driven NSCLCs are dependent on the EGFR pathway for proliferation which EGFR TKIs potently block. Progression occurs when resistance to erlotinib develops—through the emergence of EGFR—T790M or MET gene amplification. This event is likely specific to any given individual tumor clone and therefore on relapse only some tumor clones carry resistance mutations, others likely remain dormant while the EGFR pathway is inhibited providing rationale for maintenance therapy. This concept is supported by clinical observations demonstrating of “tumor flares” in patients taken off of EGFR TKI therapy on progression. Similar analogies exist in prostate cancer/maintenance of castrate state, breast cancer/maintenance trastuzumab. This study seeks preliminary evidence that such a strategy can lead to meaningful benefits in advanced non-small cell lung cancer. Methods: Randomized, phase II study of pemetrexed chemotherapy versus pemetrexed chemotherapy plus erlotinib in patients who derived a clinical benefit from erlotinib but now have evidence of progressive disease (NCT00660816). Pemetrexed is given at standard dose of 500 mg/m2 every 3 weeks to a maximum of 8 cycles while erlotinib is given at 150 mg oral daily dose on days 2-19 of each cycle. Our main hypothesis is that maintenance erlotinib in this patient population could extend PFS by 50%, from 3 to 4.5 months and we seek to enroll 78 patients by randomized phase II screening design to allow 80% power to detect such a difference. Standard eligibility criteria include progression following at least twelve weeks of treatment with single-agent erlotinib during which time the patients experienced a clinical benefit. 23 of planned 78 patients have been enrolled and current enrollment averages 1-2 new patients per month. An amendment to allow either pemetrexed or docetaxel as the chemotherapy base is under review to further enhance accrual. Translational studies, including EGFR and other gene mutation analyses will also be performed.
DKK-1 and sFRP-3 Expression by Myeloma Cell and Bone Marrow Plasma Levels in Multiple Myeloma and MGUS Patients: Potential Relationship with Bone Status.
Authors: Nicola Giuliani, Francesca Morandi, Sara Tagliaferri, Luca Agnelli, Katia Todoerti, Mario Pedrazzoni, Monica Crugnola, Giorgio Lambertenghi Deliliers, Vittorio Rizzoli, Antonino Neri
Journal: Blood (2006)