tbuckley/cabot-search huggingface dataset:
S106 Peripheral blood neutrophils are primed and activated in bronchiectasis and are attenuated by the pro-resolving mediator lipoxin a4
Authors: P Bedi, B McHugh, DJ Davidson, AG Rossi, AT Hill
Journal: Thorax (2016)

<h3>Introduction</h3> Excessive neutrophilic airways inflammation is the central feature of bronchiectasis but little is known about the role of serum neutrophils in bronchiectasis. Lipid mediators derived from arachidonic acid such as Lipoxin (LX)A4 are known to regulate the inflammatory process and generate pro-inflammatory, anti-inflammatory and pro-resolving mediators. In this research work, we propose to describe the function of peripheral neutrophils in bronchiectasis and the effect of LXA4. <h3>Methods</h3> Three study groups were included in this study when clinically stable: 6 healthy volunteers; 6 patients with mild bronchiectasis with a Bronchiectasis Severity Index (BSI) score 0–4; 6 with severe bronchiectasis (BSI scores &gt;9). Freshly isolated peripheral neutrophils from the groups were treated with LXA4 or vehicle control and we assessed spontaneous neutrophil apoptosis at 20 hours, neutrophil activation, neutrophil degranulation, phagocytosis of GFP labelled <i>Pseudomonas aeruginosa </i>and expression of LXA4 receptor formyl peptide receptor (FPR)2. <h3>Results</h3> <b>In vehicle treated neutrophils</b>, there was increased viability and less apoptosis in bronchiectasis patients compared to healthy volunteers; Figure 1. There was a significant increase in CD11b upregulation; p = 0.01 and CD62L shedding; p = 0.01 in bronchiectasis patients compared to healthy volunteers. There was a significant increase in neutrophil degranulation with myeloperoxidase (MPO) release, in bronchiectasis patients; p = 0.04. There was an increase in neutrophil phagocytosis of GFP labelled <i>Pseudomonas aeruginosa</i> by neutrophils from bronchiectasis patients, p = 0.03, compared to healthy volunteers; Figure1. <b>In LXA4 treated neutrophils, </b>there was no effect of LXA4 on spontaneous neutrophil apoptosis. There was a significant reduction in n-formyl-methyl-leucyl-phenylalanine (fMLF)-induced CD11b upregulation and CD62L shedding by LXA4 in a dose dependent manner in all three groups. There was a significant reduction in cytochalasin-B and fMLF-induced activation of neutrophils and release of MPO, by LXA4 in all three groups. There was significant improvement in neutrophil phagocytosis of GFP labelled <i>Pseudomonas aeruginosa </i>in a dose dependent manner in all three groups. There was a statistically significant increase in FPR2 receptor expression in healthy volunteers compared to bronchiectasis patients when treated with LXA4 100nM, p = 0.03. <h3>Conclusion</h3> Serum neutrophils in bronchiectasis are primed and activated compared to healthy volunteers. The pro-resolving mediator LXA4 stabilised the neutrophil whilst promoting neutrophil phagocytosis.
Determination of uracil/UH2 ratio as a potential surrogate for DPD status in cancer patients presenting with severe toxicities during fluoropyrimidine treatment
Authors: C. Mercier, C. Yang, J. Ciccolini, M. Balti, A. Evrard, A. Blesius, L. Dahan, K. Richard, J. Seitz, B. Lacarelle, R. Favre
Journal: Journal of Clinical Oncology (2006)

2020 Background: DPD deficiency is a rare pharmacogenetic syndrome leading to overexposure to fluoropyrimidine drugs, with subsequent exacerbation of toxicity and, possibly, fatal outcome in the most severe cases. Methods: We developed a simple and rapid surrogate method for evaluating the DPD status of cancer patients. This method was retrospectively validated by following 860 patients treated with fluoropyrimidines over a 3-year period at our institute. We applied the Uracil to UH2 ratio measurement as an indirect insight into DPD functionality in a subset of 120 patients (14%), who had presented with severe toxicity (grade 3–5, WHO) after fluoropyrimidine administration. We also searched for the canonical IVS14+1G&gt;A single nucelotide permutation (SNP), which is associated with severe DPD deficiency. Results: More than 70% of the patients with severe toxicity and 80% of those with fatal outcome displayed U/UH2 ratios out of the range previously defined with a separate reference, non-toxic population thus strongly suggesting a correlation. In contrast, IVS14+1G&gt;A SNP was not found to be a reliable marker for predicting toxicities. Conclusions: Taken together, our data indicate U/UH2 ratio appears to be frequently implicated in the occurrence of iatrogenic events with fluoropyrimidine therapy. In addition, our simple and rapid HPLC method may meet the requirements of routine screening, allowing identification of patients who might be at risk of severe toxicity during fluoropyrimidine administration, at relatively low cost. The predictive value of our test is being investigated in a prospective study with pharmacokinetic support. No significant financial relationships to disclose.
Glucocorticoid Receptor Expression Correlates with Clinical Outcome in Myeloma Patients Treated with Glucocorticoid-Containing Regimens.
Authors: Shuo Ma, Fenghuang Zhan, Chunguang Ma, Michael Tessel, Lijun Zhang, S. Vincent Rajkumar, Seema Singhal, Bart Barlogie, John Shaughnessy, Steven T. Rosen, Nancy Krett
Journal: Blood (2008)
405. IL-2 and TNF-a Coding Adenoviruses Enable Adoptive T Cell Therapy in Metastatic, Solid Cancer by Systemically Activating Tumor-Reactive TILs
Authors: Siri Tähtinen, Carolin Blattner, Markus Vähä-Koskela, Dipongkor Saha, Mikko Siurala, Riikka Havunen, Suvi Parviainen, Jochen Utikal, Viktor Umansky, Akseli Hemminki
Journal: Molecular Therapy (2016)

Adoptive T cell therapy (ACT) using genetically modified T cells has shown exceptional efficacy in the treatment of CD19+ hematological cancers. However, far less impressive results have been achieved in the treatment of solid tumors due to local immunosuppression, rendering tumor-infiltrating T cells (TILs) hypofunctional. We have previously shown that adenovirus (Ad) infection can enhance the efficacy of ACT (Tähtinen et al, CIR 2015) and that intratumoral administration of immunostimulatory cytokines can result in favorable alteration of tumor microenvironment (Tähtinen et al, PLOS One 2015). To combine the benefits of both approaches, we studied if replication-deficient Ad5-vectors coding for interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-a) would affect the activity of adoptively transferred, TCR-transgenic TRP-2(180-188) specific T cells in vivo. To gain clinically relevant mechanism-of-action data, we chose to use ret transgenic mouse model that develops spontaneous malignant skin melanoma which metastasizes into distant organs. Following ACT and intratumoral virus injection, a significant increase in activated PD-1+ CD8+ T cells was seen in both cutaneous lesions and in metastatic lymph nodes. Interestingly, a reverse correlation between tumor weight and the number of tumor-reactive PD-1+ TILs (p=0.0015) was observed, indicating that T-cell hypofunction was overcome and successful tumor lysis was achieved. Local expression of cytokines did not affect the levels of immunosuppressive immune cell subsets such as myeloid-derived suppressor cells (MDSCs) or T regulatory cells (Tregs), latter of which has previously been associated with systemic IL-2 therapy (Ahmadzadeh and Rosenberg, Blood 2006). Instead, Ad5-IL2 treatment induced upregulation of IL-2 receptor α-chain (CD25) in conventional CD4+CD25+Foxp3-cells, suggesting that these helper T cells contributed to CD8+ TIL activation. Finally, beneficial ratios between tumor-reactive PD-1+ CD8+ TILs and Tregs was observed in primary and secondary tumor sites, indicating that IL-2 and TNF-a coding adenoviruses can modify the cellular composition of the tumor microenvironment in favor of adoptively transferred T cells. In conclusion, IL-2 and TNF-a coding adenoviruses can break tumor-associated immunotolerance and significantly increase the levels of active, tumor-reactive T-cells both in injected cutaneous lesions and in non-injected metastatic lymph nodes. Importantly, this triple modality may represent an efficient approach to achieve "CD19-like" clinical responses in the treatment of solid, metastatic cancers currently incurable by standard therapies.
Using Whole Exome Sequencing in Pediatric Acute Lymphoblastic Leukemia Germline, Diagnosis, and Relapse Trios to Discover Novel Relapse Enriched Mutations for Clonal Backtracking By Ddpcr
Authors: Jason Saliba, Nikki Ann Evensen, Julia Meyer, Igor Dolgalev, Daniel Newman, Ashfiyah Chowdhury, Jacob Nersting, Jinhua Wang, Kjeld Schmiegelow, William L. Carroll
Journal: Blood (2016)
PTU-077 TIMP-1 inhibits pancreatic stellate cell apoptosis: implications for pancreatic fibrosis: Abstract PTU-077
Authors: M Patel, J E Collins, A J Fowell, R C Benyon, D R Fine
Journal: Gut (2010)

<h3>Introduction</h3> Pancreatic fibrosis is a characteristic feature of chronic pancreatic injury and is thought to result from a change in the balance between synthesis and degradation of extracellular matrix proteins. Pancreatic stellate cells (PSC) have the capacity to synthesise both matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitor of metalloproteinase (TIMPs). These may play a key role in pancreatic fibrogenesis by protecting extracellular matrix from degradation and supporting the survival of fibrogenic PSC. Therefore it was hypothesised that TIMP-1 has proproliferative and anti-apoptotic effects on culture activated PSC. <h3>Methods</h3> Culture activated rat PSC were used between passages 2 and 4 and serum deprived prior to all experiments. Apoptosis was induced with cycloheximide (50 mm/l) in the presence or absence of recombinant rat TIMP-1 (1–200 ng/ml). Apoptosis was quantified using acridine orange and counting of apoptotic bodies. PSC proliferation was determined by [<sup>3</sup>H]-thymidine incorporation. Culture-activated rat PSC were transfected with TIMP-1 and a negative control siRNA by electroporation. Cytotoxicity of siRNA was assessed by lactate dehydrogenase activity assay. Culture supernatants were collected to quantitate TIMP-1 protein knockdown following electroporation. <h3>Results</h3> TIMP-1 showed a dose dependent inhibition of cycloheximide induced PSC apoptosis. TIMP-1 at 100 ng/ml and 200 ng/ml significantly reduced apoptosis by up to 61% at 6 h, and up to 74% at 24 h (see table). Although there was a trend towards TIMP-1 stimulation of increased proliferation, this did not reach statistical significance. TIMP-1 electroporation was an effective means of silencing PSC TIMP-1 expression. Peak knockdown of target TIMP-1 protein was 77% at 24 h for TIMP-1 compared to negative control siRNA (p&lt;0.05). There was no increase in cell toxicity in TIMP-1 siRNA treated cells compared with electroporation alone. <h3>Conclusion</h3> These data suggest that TIMP-1 reduces PSC apoptosis in the presence of cycloheximide, with no significant effect on proliferation. These data also suggest that siRNA are an effective means of silencing TIMP-1 in PSC. This may represent an important therapeutic target in the treatment of pancreatic fibrosis.
PTU-027 What is the yield of gastrointestinal cancer from investigation of “2-week wait” referrals with iron deficiency anaemia?
Authors: K Lovett, R F Logan
Journal: Gut (2010)

Introduction Previous studies have found that in the UK iron deficiency anaemia (IDA) is often inadequately investigated resulting in a delayed diagnosis of gastrointestinal (GI) cancer. The presence of an IDA therefore has been included in the “2WW” referral criteria for urgent GI investigation introduced in England in 2000. Over this period there has been a >50% increase in use of blood tests in primary care and an increase in the prescribing of low dose aspirin which we have shown to be associated with a 2.5-fold increase in the prevalence of IDA.[1][1] Methods We examined the “2WW” referral forms for upper and lower GI cancer sent to Nottingham University hospitals over 4 months in 2007 and identified all referrals with mention of anaemia. Clinical details were then extracted from hospital electronic records, case records and where necessary by contacting the GP. IDA criteria were a haemoglobin <13 g/dl in males or <12 in females and an MCV <84, or MCH <28, or serum ferritin <25. Results Between June-September 2007 there was a total of 981 referrals in which anaemia was mentioned in 204 (20%); in 60 (29%) this was the sole criterion for referral. Mean age was 71 years (122F/82M) and 40% were taking low dose aspirin. In 144 the presence of upper or lower GI symptoms was also mentioned on the referral form. An IDA was present in 133/204 (65%) 42 of whom had no GI symptoms reported. Investigation identified a cause for the anaemia in 83 of whom 26 had a GI cancer (9 oesophago-gastric, 15 colorectal and 2 hepato-pancreatic). In 6 of the patients found to have GI cancers the presence of an IDA was the sole indication for referral. Non-GI malignancies were detected in 6; an ovarian and a lung cancer were found in 2 referrals with an IDA and haematological malignancies were present in 4 with non-IDA. In 17, the GP stated that the IDA had been detected during a routine “MOT” check up for CV disease or diabetes and in none of these cases was a GI or other malignancy detected; 8/17 were taking low dose aspirin. Conclusion Presence of anaemia is a common referral criterion but in only two-thirds is this an IDA. Yield of GI cancer is 16% in those with an IDA and was similar in those with or without GI symptoms. However cancer yield is low in those investigated on account of a mild IDA detected at routine check-ups. Alternative management strategies need to be developed for this group. [1]: #ref-1
Risk-Adapted Therapy in Adults Previously Untreated Hodgkin’s Lymphoma (HL) with ABVD Followed by Involved Field Radiotherapy (IFRT).
Authors: Santiago Pavlovsky, Claudia S. Corrado, Miguel A. Pavlovsky, Mario Giunta, Lucia Zoppegno, Virginia Prates, Francisco Lastiri, Ider Cerutti, Maria C. Narbaitz, Silvia Rudoy, Fernando Cavagnaro, Alejandra Kurchan, Elsa Palomino, Cesar Campo
Journal: Blood (2004)
Prognostic Impact of Cytogenetic Abnormalities On Outcomes of Newly Diagnosed Multiple Myeloma Patients Treated with Thalidomide-Dexamethasone Incorporated Into Double Autologous Stem-Cell Transplantation: An Analysis of 593 Patients
Authors: Elena Zamagni, Nicoletta Testoni, Carolina Terragna, Paola Tacchetti, Mauro Fiacchini, Francesca Patriarca, Patrizia Tosi, Francesco Di Raimondo, Giulia Marzocchi, Maria Teresa Petrucci, Lucio Catalano, Sandra Durante, Silvestro Volpe, Monica Galli, Luciano Masini, Antonio Ledda, Annamaria Brioli, Claudia Crippa, Alessandro Gozzetti, Franco Narni, Catello Califano, Claudia Cellini, Sara Bringhen, Giuliana Leopardi, Lucia Pantani, Michela Ceccolini, Massimo Offidani, Giulia Perrone, Beatrice Anna Zannetti, Michele Baccarani, Michele Cavo
Journal: Blood (2010)
Central Nervous System (CNS) Involvement In Pediatric Relapsed Acute Myeloid Leukemia: Results and Lessons From Study Relapsed AML 2001/01
Authors: Gertjan Kaspers, Martin Zimmermann, Dirk Reinhardt, Brenda Gibson, Rienk Tamminga, Olga Aleinikova, Hortensia Armendariz, Michael Dworzak, S. Ha, Lisa Hovi, Alexei Maschan, Andre Baruchel, Yves Bertrand, Bassem Razzouk, Carmelo Rizzari, Petr Smisek, Owen Smith, Batia Stark, Ursula Creutzig
Journal: Blood (2010)
ZAP-70 Disrupts Dipeptidyl Peptidase 2 (DPP2)-Regulated Quiescence in Chronic Lymphocytic Leukemia (CLL).
Authors: Alexey V. Danilov, Olga Danilova, Andreas Klein, Jennifer Brown, Arthur P. Rabinowitz, Kenneth B Miller, Brigitte T Huber
Journal: Blood (2009)
Abstract 4785: Deficiency of cystathionine beta synthase gene does not affect tumor formation and survival of Eμ-myc mice
Authors: Sapna Gupta, Warren D. Kruger
Journal: Cancer Research (2015)

Abstract Aberrant DNA methylation is a hallmark of many types of cancers. S-adenosylhomocysteine (AdoHcy) is a strong inhibitor of DNA methytransferases. Deficiency of cystathionine beta synthase gene (Cbs) causes elevation of AdoHcy in variety of tissues. Here we have generated an Eμ-myc mouse model which is either wild type, heterozygous or homozygous for a deletion allele of Cbs (Eμ myc+ Cbs+/+; Eμ myc+ Cbs+/−; Eμ myc+ Cbs−/−). Homozygous Cbs deficient mice in both Eμ myc+ and Eμ myc− background were born at Mendelian frequency indicating that there is no synthetic lethality between Cbs and Eμ myc. In aging, we observed no significant difference in survival of Eμ myc+ Cbs+/+, Eμ myc+ Cbs+/− and Eμ myc+ Cbs−/− mice (Median survival of 150, 149 and 117 days respectively). However, preliminary data shows that tumor tissue from Eμ myc+ Cbs−/− animals has greatly elevated levels of AdoHcy compared to other genotypes. Our studies suggest that elevated levels of AdoHcy has no effect on tumor formation in Eμ myc mice. Citation Format: Sapna Gupta, Warren D. Kruger. Deficiency of cystathionine beta synthase gene does not affect tumor formation and survival of Eμ-myc mice. [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 4785. doi:10.1158/1538-7445.AM2015-4785
Abstract 2445: DNA recognition by XR5944, a novel bis-intercalator and potent anticancer drug
Authors: Clement Lin, Raveendra I. Mathad, Neil Sidell, Danzhou Yang
Journal: Cancer Research (2015)

Abstract DNA is a major target for drugs used in cancer therapy. However, DNA interactive chemotherapeutics are limited by adverse effects due to their poor selectivity. The bis-phenazine compound XR5944 is a DNA bis-intercalator and potent anticancer drug which reached phase I clinical trials. The DNA binding mode and mechanism of XR5944 are unique, allowing it to recognize and bind the estrogen response element (ERE) sequence to inhibit ERα activity and making it highly effective against ER-positive breast cancer in vitro. Understanding XR5944's novel mechanism of DNA recognition may allow the further development of anti-cancer agents capable of overcoming drug resistance to current anti-estrogen treatments by directly targeting transcriptional control, bypassing the hormone-receptor complex currently targeted by anti-estrogen treatments. In this study, we used nuclear magnetic resonance (NMR) spectroscopy to determine the structure of XR5944 in complex with its preferred DNA duplex sequence identified its binding mode. The structure of the 2:1 complex of XR5944 with the naturally occurring TFF1-ERE exhibits several unexpected features. Our NMR structure shows the two phenazine moieties are well stacked and the carboxamide amino linker lies in the major groove of DNA. At both binding sites in the 2:1 complex, XR5944 intercalates strongly at one site but weakly at the other. The binding sites within a native promoter sequence appear to be context- and sequence- dependent. Taken together, our results highlight that the DNA binding of a bis-intercalator is different from the simple addition of two single intercalation sites. Our study suggests that improved XR5944 derivatives targeting EREs may be designed through optimization of aminoalkyl linker and intercalation moieties. Citation Format: Clement Lin, Raveendra I. Mathad, Neil Sidell, Danzhou Yang. DNA recognition by XR5944, a novel bis-intercalator and potent anticancer drug. [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 2445. doi:10.1158/1538-7445.AM2015-2445
High Rate of FLT3 Mutations In Adult ETP-ALL.
Authors: Martin Neumann, Ebru Coskun, Ouidad Benlasfer, Sandra Heesch, Stefan Schwartz, Nicola Goekbuget, Dieter Hoelzer, Wolf-Karsten Hofmann, Eckhard Thiel, Claudia Baldus
Journal: Blood (2010)
Abstract A30: Chronic inflammation induces severe stromal damage and early pancreatic tumors in mice with activated Akt1 and KRas
Authors: Sarah B. Gitto, Kathryn A. Cline, Amr S. Khaled, Deborah A. Altomare
Journal: Cancer Research (2016)

Abstract Inflammation and the immune environment is implicated as a risk for pancreatic ductal adenocarcinoma (PDAC), especially in chronic conditions. However, a mechanistic link is unknown. Recently, radiotherapy followed by immune checkpoint inhibitors are being tested and show promising results, thereby introducing immune modulation as a new investigational area for the treatment of pancreatic cancer. A potential barrier is that pancreatic fibrosis and desmoplastic reactivity are common characteristics of PDAC and makes therapeutic delivery difficult. To define how inflammation and desmoplasia effects the immune-pancreatic stromal environment and progression of PDAC, we have chronically injected caerulein into genetically engineered mice that we previously showed spontaneously develop PDAC through the cooperation of mutant active Akt1 and KRas. We show that injected Akt1Myr/KRasG12D mice have increased tissue remodeling, stellate cell activation, collagen production, and mucin production when compared to KRasG12D mice. They also have increased ductal proliferation, accelerated tumor formation, and increased immune cell infiltration in the pancreas ducts and stroma compared to control PBS- and caerulein-injected KRasG12D mice. Pro-inflammatory cytokines and macrophages likely activate stellate cells, which in turn facilitate additional cytokines to enhance a pro-tumor immune environment. Other than macrophages, the role that innate immune cells contribute to pancreatic cancer has not been well studied. Ongoing studies will delineate the immune cell infiltration, cytokine levels, and the effect on tumor formation in double mutant Akt1Myr/KRasG12D mice. Understanding the mechanisms by which inflammation affects tumor formation can lead to strategies to inhibit pro-tumor changes, impede PDAC development and improve overall patient survival. Citation Format: Sarah B. Gitto, Kathryn A. Cline, Amr S. Khaled, Deborah A. Altomare.{Authors}. Chronic inflammation induces severe stromal damage and early pancreatic tumors in mice with activated Akt1 and KRas. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A30.
Venous Thromboembolism Prophylaxis with Aspirin for Multiple Myeloma Patients Receiving Thalidomide Combination As First-Line Treatment
Authors: Edvan de Queiroz Crusoe, Mariana Massarenti, Manuella Almeida, Priscilla Cury, Fabiana Higashi, Luiza Vieira, Marina Rossato, Ana Lucia Peres, Anna Carolina Castro, Ana Luiza Silva, Vania T M Hungria
Journal: Blood (2014)