tbuckley/cabot-search huggingface dataset:
Abstract 3020: Homology-directed repair in mouse mammary tissue
Authors: Elizabeth Kass, Mary Ellen Moynahan, Maria Jasin
Journal: Cancer Research (2015)

Abstract Numerous factors are linked to breast cancer risk including reproductive history, early exposure to radiation, age and genetic background. Defects in homology-directed repair (HDR)_considered the most accurate of the three major pathways for repairing double-strand breaks (DSBs) in DNA in mammalian cells_can lead to genomic instability and are associated with tumor predisposition. Mutations in multiple genes involved in HDR are linked to breast cancer susceptibility including BRCA1 and BRCA2. The mammary gland is highly influenced by its hormonal environment and undergoes significant changes during pregnancy, lactation and involution, but many questions remain about how the DNA damage response in mammary tissue, and specifically DNA DSB repair, is impacted by these developmental changes. A widely used reporter for studying DSB repair by HDR is DR-GFP in which direct repeats of two defective GFP genes are induced to recombine by I-SceI endonuclease cleavage of one of the repeats, resulting in a functional GFP gene. We have recently generated DR-GFP containing mice that express I-SceI under the control of a tetracycline-inducible promoter. Induction of I-SceI by doxycycline administration ex vivo results in substantially increased HDR in primary cultures of mammary epithelial cells compared to transient transfection experiments. To gain insight into the effects of breast cancer predisposing mutations on HDR in mammary epithelial cells, the I-SceI/DR-GFP mice were crossed to mice carrying hypomorphic mutations in Brca1 (Brca1tr/tr) or Brca2 (Brca2ex27/ex27). An approximately 3-fold reduction in HDR was observed in primary mammary epithelial cells from virgin Brca1tr/tr I-SceI DR-GFP mice compared to littermate controls, while an 8-fold reduction was observed in primary mammary epithelial cells from virgin Brca2ex27/ex27 mice. Primary ear fibroblasts from these animals showed similarly reduced HDR levels. In order to understand how DSB repair processes in the mammary gland are affected by developmental changes we are assessing HDR at different stages of mammary gland development in vivo. We observe a significant increase in HDR relative to overall repair in mammary tissue from mice at mid-pregnancy compared to virgin littermates. We are now attempting to determine if there is a relationship between repair proficiency, lineage specificity of mammary epithelial cells and fate after involution in mammary tissue from normal and BRCA mutant mice. Citation Format: Elizabeth Kass, Mary Ellen Moynahan, Maria Jasin. Homology-directed repair in mouse mammary tissue. [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 3020. doi:10.1158/1538-7445.AM2015-3020
Fluoroquinolone Prophylaxis in Acute Myeloid Leukemia (AML) Patients Undergoing Post-Remission Chemotherapy Reduces Hospital Admission Rates
Authors: Karissa Kusick, Marc Earl, Erika M. Gallagher, Jun-Yen Yeh, Anjali S. Advani, Matt Kalaycio, Edward A. Copelan, Mikkael A. Sekeres
Journal: Blood (2011)
Safety and efficacy of YM155 in diffuse large B-cell lymphoma (DLBCL)
Authors: B. D. Cheson, J. M. Vose, N. L. Bartlett, A. Lopez, R. H. Van der Jagt, A. W. Tolcher, D. D. Weisenburger, A. L. Seiz, S. Shamsili, A. T. Keating
Journal: Journal of Clinical Oncology (2009)

8502 Background: Survivin is a member of the inhibitor of apoptosis proteins (IAPs) family which is responsible for preservation of cell viability and regulation of mitosis in tumor cells. YM155, a survivin suppressant, has exhibited anti-tumor activity in solid tumors and non-Hodgkins lymphoma (NHL), including DLBCL patients enrolled in Phase I and Phase II monotherapy studies. Methods: Two studies enrolled 43 DLBCL patients; a Phase I study enrolled patients with solid tumors and NHL (n=1 relapsing DLBCL and n=1 refractory DLBCL), and a Phase II study enrolled refractory DLBCL patients (n=41). YM155 was administered at 4.8 mg/m 2 /day (Phase I) and at 5 mg/m 2 /day (Phase II) as a 168-hour continuous infusion in a 21 day cycle. Patients could continue to receive YM155 until disease progression or unacceptable toxicity. Results: Data are presented for the first 27 patients (Phase I and Phase II) who have completed therapy. Median age was 61 (23–80) years and 63% were male. Three patients (11%) had partial responses (PR) confirmed by independent review using Cheson criteria (N=2; 1999 criteria and N=1; 2007 updated criteria). All responders received 2 prior regimens. Two responders were refractory to their last regimen and one had relapsed approximately 2 years after stem cell transplant (SCT). One patient responded after 2 cycles, completed 5 total cycles and proceeded to SCT (disease-free &gt; 3.7 years post SCT). A second patient responded after 3 cycles, completed 7 total cycles and proceeded to SCT in OCT08. The third patient responded after 12 cycles and received 26 total cycles (1.5 years) before disease progression. The most common (&gt;4%), treatment-related grade 3/4 adverse events included anemia (16.0%) and neutropenia, fatigue, hemoglobin decrease and deep vein thrombosis (8.0% each). Conclusions: YM155 is well tolerated and has modest single-agent, anti-tumor activity in relapsed/refractory DLBCL patients. Because of single-agent activity and preliminary data showing synergism when YM155 is combined with other agents additional clinical studies are being planned. [Table: see text]
PTU-055 Safety and tolerability of combination therapy for chronic hepatitis C: the Leeds experience: Abstract PTU-055
Authors: A C Ford, S A Sheridan, C M Wigglesworth, J Rehman, M A Aldersley, M H Davies, C E Millson, R L Jones
Journal: Gut (2010)

<h3>Introduction</h3> Combination therapy is the mainstay of treatment for chronic hepatitis C (CHC). However, some patients report debilitating adverse events (AEs), which may limit efficacy due to need for dose reduction or discontinuation of therapy. We report tolerability and safety of combination therapy in normal clinical practice, in a large cohort of CHC patients treated in a single tertiary referral centre in Leeds, UK. <h3>Methods</h3> AE data for individuals receiving combination therapy for CHC were collected prospectively between February 2001 and May 2008. Premature discontinuation of therapy due to AEs was recorded. Effect of experiencing an AE on achieving sustained viral response (SVR) 6 months after treatment end was examined by univariate analysis, with an OR and 95% CI. The association between patient demographics, type of interferon (α-2a or 2b), duration of therapy, genotype, presence of cirrhosis and likelihood of experiencing AEs was explored using multivariate analysis, and results expressed as ORs with 95% CIs. <h3>Results</h3> During the study period 356 individuals with CHC commencing combination therapy had adverse events data recorded (231 (65%) male, mean age 42 years, range 21–73). 228 (64%) reported at least one AE (Abstract 055). Therapy was discontinued due to AEs in 56 patients. Six individuals experienced decompensation, but there were no deaths related to therapy. AEs did not alter likelihood of achieving an SVR (63% (144/228) in those with an AE vs 61% (78/128) in those without (OR 1.10, 95% CI 0.69 to 1.76)). No predictors of AEs were identified. <h3>Conclusion</h3> Data from this large cohort of CHC patients treated with combination therapy demonstrate &gt;60% experience AEs, though most are minor, do not affect completion of therapy, and do not impact on SVR at 6 months.
Human macrophage ferroportin biology and the basis for the ferroportin disease
Authors: Manuela Sabelli, Giuliana Montosi, Cinzia Garuti, Angela Caleffi, Stefania Oliveto, Stefano Biffo, Antonello Pietrangelo
Journal: Hepatology (2016)

Ferroportin (FPN1) is the sole iron exporter in mammals, but its cell‐specific function and regulation are still elusive. This study examined FPN1 expression in human macrophages, the cells that are primarily responsible on a daily basis for plasma iron turnover and are central in the pathogenesis of ferroportin disease (FD), the disease attributed to lack‐of‐function FPN1 mutations. We characterized FPN1 protein expression and traffic by confocal microscopy, western blotting, gel filtration, and immunoprecipitation studies in macrophages from control blood donors (donor) and patients with either FPN1 p.A77D, p.G80S, and p.Val162del lack‐of‐function or p.A69T gain‐of‐function mutations. We found that in normal macrophages, FPN1 cycles in the early endocytic compartment does not multimerize and is promptly degraded by hepcidin (Hepc), its physiological inhibitor, within 3‐6 hours. In FD macrophages, endogenous FPN1 showed a similar localization, except for greater accumulation in lysosomes. However, in contrast with previous studies using overexpressed mutant protein in cell lines, FPN1 could still reach the cell surface and be normally internalized and degraded upon exposure to Hepc. However, when FD macrophages were exposed to large amounts of heme iron, in contrast to donor and p.A69T macrophages, FPN1 could no longer reach the cell surface, leading to intracellular iron retention. Conclusion : FPN1 cycles as a monomer within the endocytic/plasma membrane compartment and responds to its physiological inhibitor, Hepc, in both control and FD cells. However, in FD, FPN1 fails to reach the cell surface when cells undergo high iron turnover. Our findings provide a basis for the FD characterized by a preserved iron transfer in the enterocytes (i.e., cells with low iron turnover) and iron retention in cells exposed to high iron flux, such as liver and spleen macrophages. (H epatology 2017;65:1512‐1525)
Vitamin K–Dependent Carboxylation of Matrix Gla Protein Influences the Risk of Calciphylaxis
Authors: Sagar U. Nigwekar, Donald B. Bloch, Rosalynn M. Nazarian, Cees Vermeer, Sarah L. Booth, Dihua Xu, Ravi I. Thadhani, Rajeev Malhotra
Journal: Journal of the American Society of Nephrology (2017)

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification. The ability of MGP to inhibit calcification requires the activity of a vitamin K–dependent enzyme, which mediates MGP carboxylation. We investigated how MGP carboxylation influences the risk of calciphylaxis in adult patients receiving dialysis and examined the effects of vitamin K deficiency on MGP carboxylation. Our study included 20 patients receiving hemodialysis with calciphylaxis (cases) and 20 patients receiving hemodialysis without calciphylaxis (controls) matched for age, sex, race, and warfarin use. Cases had higher plasma levels of uncarboxylated MGP (ucMGP) and carboxylated MGP (cMGP) than controls. However, the fraction of total MGP that was carboxylated (relative cMGP concentration = cMGP/[cMGP + uncarboxylated MGP]) was lower in cases than in controls (0.58±0.02 versus 0.69±0.03, respectively; P =0.003). In patients not taking warfarin, cases had a similarly lower relative cMGP concentration. Each 0.1 unit reduction in relative cMGP concentration associated with a more than two-fold increase in calciphylaxis risk. Vitamin K deficiency associated with lower relative cMGP concentration in multivariable adjusted analyses ( β =−8.99; P =0.04). In conclusion, vitamin K deficiency–mediated reduction in relative cMGP concentration may have a role in the pathogenesis of calciphylaxis. Whether vitamin K supplementation can prevent and/or treat calciphylaxis requires further study.
PTH-016 Prevalence of post-discharge symptoms following colonoscopy and possible causal associations: quality assurance audit with telephone survey in 514 patients
Authors: V S Athwal, K Bodger, S Sarkar
Journal: Gut (2010)

<h3>Introduction</h3> Focus on quality assurance in colonoscopy intensified as a prequel to the launch of the UK National Bowel Cancer Screening Programme. Previous research has examined auditable standards such as caecal intubation rate, adenoma detection and major complications but much less is known about the prevalence of post-discharge symptoms which may be self-limiting and not require readmission or formal medical input. <h3>Aim</h3> To determine the prevalence of post-discharge symptoms in patients that underwent colonoscopy and the possible causal associations. <h3>Methods</h3> As part of our Quality Assurance audit programme, a structured telephone survey was administered to 514 patients who had undergone colonoscopy (with air insufflation) at our University Hospital (July 07–Oct 08). The survey consisted of questions regarding overall experience, procedure comfort, intravenous cannula site problems, and post-discharge symptoms of; bleeding, nausea and vomiting, bloating and pain. Demographics, colonoscopy details and interview responses were collated. Characteristics of a “symptomatic group” (reporting any pain, bloating or n/v) (“SympGp”) were compared with “asymptomatic group” (“AsympGp”) and results expressed as either per cent or mean (SD). <h3>Results</h3> Overall prevalence: IV site symptoms: 6%; PR bleeding: 5.4%; Nausea or Vomiting: 0.6%; Bloating: 11%; Pain: 9.5%. 100 patients (19.5%) reported one or more symptoms of pain, bloating, nausea or vomiting (SympGp). Predictably, SympGp rated their overall experience (1–10 point scale: 10=best score) less favourably (7.5 (2.4) vs 8.1 (2.3), p=0.04) and their comfort during procedure (1–5 scale; 1=best score) was lower (2.4 (1.3) vs 1.9 (1.1), p=0.001). SympGp were more often female (55% vs 43.5%) and were younger (58 vs 64 years, p&lt;0.0001). However, the ASA score, trainee involvement, therapy rates and procedure times were not significantly different from the AsympGp (p&gt;0.05). Midazolam doses used were higher in the SymptGp (2.1 mg (1.3) vs 1.7 mg (1.2), p=0.03), but Fentanyl doses were similar (p=0.18). <h3>Conclusion</h3> Post-discharge symptoms are not uncommon with almost 1:16 experiencing cannula site symptoms, 1:20 bleeding and 1:5 symptoms of nausea/vomiting, pain or bloating. These latter patients had more procedure discomfort and less favourable overall experience despite larger doses of sedation. Younger, female patients were more likely to report post-discharge symptoms but trainee involvement, therapy, IV opiate administration and procedure time had no effect. Given the prevalence of these symptoms, repeating a similar audit using CO2 insufflation would be interesting.
PO33CORRELATION BETWEEN EXTEND OF RESECTION IN DIFFUSION TENSOR MR AND GLIOBLASTOMA PATIENT OUTCOME
Authors: Jiun-Lin Yan, Natalie R. Boonzaier, Timothy Larkin, Stephen Price
Journal: Neuro-Oncology (2015)

INTRODUCTION: Extent of resection (EOR) based on the T1 contrast MRI had been shown as an important prognostic factor in glioblastoma patients. However, tumor can extend beyond these areas. These invasive regions can be detected using diffusion tensor imaging (DTI) due to subtle white mater change. This study is to analyze the influence of extending resection into the DTI-determined invasive region with patient outcome. METHOD: Immediate (within 72 hours) post-operative MRI were reviewed from 14 patients who had undergone 5-ALA guided resection of a glioblastoma. Post-operative images were further co-registered with pre-operative images for calculating volumetric change. DTI was split into isotropic (p) and anisotropic (q) components. Extent of resection was assessed in p map, q map, T2 Flair and T1 contrast enhanced MR images by using 3D volumetric calculator. RESULTS: The EOR of the p map showed significant correlation to both event free survival and progression free survival (PFS) (r2 = 0.3991, 0.4415; p value = 0.015, 0.0257). Further multiple regression study with age and EOR based on T1 contrast MR revealed a higher correlation between PFS and EOR (r2 = 0.632, p value =0.01). There was no correlation with overall survival or with the EOR of q map and FLAIR to any clinical outcomes. CONCLUSION: DTI can detect tumor outside T1 contrast enhanced image and extending resections beyond this region appears to be associated with a prolonged progression free survival.
Toward Defining the Threshold Between Low and High Glucose Variability in Diabetes
Authors: Louis Monnier, Claude Colette, Anne Wojtusciszyn, Sylvie Dejager, Eric Renard, Nicolas Molinari, David R. Owens
Journal: Diabetes Care (2016)

To define the threshold for excess glucose variability (GV), one of the main features of dysglycemia in diabetes.A total of 376 persons with diabetes investigated at the University Hospital of Montpellier (Montpellier, France) underwent continuous glucose monitoring. Participants with type 2 diabetes were divided into several groups-groups 1, 2a, 2b, and 3 (n = 82, 28, 65, and 79, respectively)-according to treatment: 1) diet and/or insulin sensitizers alone; 2) oral therapy including an insulinotropic agent, dipeptidyl peptidase 4 inhibitors (group 2a) or sulfonylureas (group 2b); or 3) insulin. Group 4 included 122 persons with type 1 diabetes. Percentage coefficient of variation for glucose (%CV = [(SD of glucose)/(mean glucose)] × 100) and frequencies of hypoglycemia (interstitial glucose <56 mg/dL [3.1 mmol/L]) were computed.Percentages of CV (median [interquartile range]; %) increased significantly (P < 0.0001) from group 1 (18.1 [15.2-23.9]) to group 4 (37.2 [31.0-42.3]). In group 1, the upper limit of %CV, which served as reference for defining excess GV, was 36%. Percentages of patients with %CVs above this threshold in groups 2a, 2b, 3, and 4 were 0, 12.3, 19.0, and 55.7%, respectively. Hypoglycemia was more frequent in group 2b (P < 0.01) and groups 3 and 4 (P < 0.0001) when subjects with a %CV >36% were compared with those with %CV ≤36%.A %CV of 36% appears to be a suitable threshold to distinguish between stable and unstable glycemia in diabetes because beyond this limit, the frequency of hypoglycemia is significantly increased, especially in insulin-treated subjects.
Abstract 5004: Expression profiling of receptor tyrosine kinases in high-grade neuroendocrine carcinoma of the lung: A comparative analysis with adenocarcinoma and squamous cell carcinoma
Authors: Yuki Matsumura, Shigeki Umemura, Genichiro Ishii, Koji Tsuta, Shingo Mastsumoto, Keiju Aokage, Tomoyuki Hishida, Junji Yoshida, Yuichiro Ohe, Hiroyuki Suzuki, Atsushi Ochiai, Koichi Goto, Kanji Nagai, Katsuya Tsuchihara
Journal: Cancer Research (2015)

Abstract Background: As the comprehensive genomic analysis of small cell lung cancer (SCLC) progresses, novel treatments for this disease need to be explored. With attention to the direct connection between the receptor tyrosine kinases (RTKs) of tumor cells and the pharmacological effects of specific inhibitors, we systematically assessed the RTK expressions of high-grade neuroendocrine carcinomas of the lung (HGNEC), including SCLC and large cell neuroendocrine carcinoma (LCNEC). Patients and Methods: Fifty-one LCNEC and 61 SCLC patients who underwent surgical resection were enrolled in this research. As a control group, 202 patients with adenocarcinomas (ADCs) and 122 patients with squamous cell carcinomas (SQCCs) were also analyzed. Using immunohistochemical staining (IHC), we stained all tumors with antibodies for 10 RTKs; c-Kit, EGFR, IGF1R, KDR, ERBB2, FGFR1, c-Met, ALK, RET and ROS1. We scored the expression of these RTKs for all enrolled tumors, and compared them according to the histological types. Results: The LCNEC and SCLC patients exhibited similar clinicopathological characteristics. The IHC scores for each RTK were almost equivalent between the LCNEC and SCLC groups, but they were significantly different from those of the ADC or SQCC groups. Especially, c-Kit was the only RTK that was remarkably expressed in both LCNECs and SCLCs. On the other hand, about 20% of the HGNEC tumors exhibited strongly positive RTK expression, and this rate was similar to those for the ADC and SQCC tumors. Intriguingly, strongly positive RTKs were almost mutually exclusive in individual tumors. Conclusions: Compared with ADC or SQCC, LCNEC and SCLC had similar expression profiles for the major RTKs. The exclusive c-Kit positivity observed among HGNECs suggested that c-Kit might be a distinctive RTK in HGNEC. These HGNECs which have strongly positive RTKs could be the targets of personalized therapies. Citation Format: Yuki Matsumura, Shigeki Umemura, Genichiro Ishii, Koji Tsuta, Shingo Mastsumoto, Keiju Aokage, Tomoyuki Hishida, Junji Yoshida, Yuichiro Ohe, Hiroyuki Suzuki, Atsushi Ochiai, Koichi Goto, Kanji Nagai, Katsuya Tsuchihara. Expression profiling of receptor tyrosine kinases in high-grade neuroendocrine carcinoma of the lung: A comparative analysis with adenocarcinoma and 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 5004. doi:10.1158/1538-7445.AM2015-5004
Non Pegilated Liposomal Doxorubicin (TLC-D99; Myocet ™) Can Be Safely and Effectively Used As Part of the R-COMP Regimen in Patients with Diffuse Large B-Cell Lymphoma Who Show Contraindications to Anthracyclines Due to Concomitant Moderate/Severe Heart Disease. Results of the HEART01 Phase II trial by the Fondazione Italiana Linfomi (NCT01009970)
Authors: Michele Spina, Stefano Luminari, Andrés J.M. Ferreri, Francesco Zaja, Monica Balzarotti, Flavia Salvi, Moira Micheletti, Gerardo Musuraca, Elda Viel, Stefano Volpetti, Emanuela Anna Pesce, Marta Bruno Ventre, Massimo Federico
Journal: Blood (2012)
Extramedullary Infiltrates of AML: Biological and Clinical Features in a Single Centre Experience.
Authors: Paola Carluccio, Domenico Pastore, Arcangelo Liso, Francesco Albano, Anna Mestice, Margherita Giannoccaro, Michele Santodirocco, Patrizia Mongelli, Palma Manduzio, Giorgina Specchia, Vincenzo Liso
Journal: Blood (2006)
ChIP-on-Chip Analysis Using Dominant Negative Form of PAX5 Fusion Gene Revealed Genes Associated with Tumorigenesis Were Directly Regulated by PAX5 in a Human B Cell Line, NALM6
Authors: Norihiko Kawamata, Fabienne Isken, Stefanie Goellner, C. Müller-Tidow, H. Phillip Koeffler
Journal: Blood (2008)
Clinical Activity of Azacitidine In Combination with the Oral mTOR Inhibitor Everolimus (RAD001) In Relapsed and Refractory AML: Interim Analysis of a Phase Ib/II Study
Authors: Andrew H Wei, Sonali Sadawarte, John Catalano, Anthony P. Schwarer, Sharon Avery, Sushrut S. Patil, Andrew Spencer
Journal: Blood (2010)
Genomic Analysis of Adult B-ALL Identifies Changes in Copy Number Profile at Relapse and IKZF1/CDKN2A Co-Deletion at Diagnosis As a Marker of Shorter Survival
Authors: Shiven B. Patel, Clinton C. Mason, Martha Glenn, Christian N. Paxton, Sarah T. South, Melissa H. Cessna, Julie D. Asch, Erin F. Cobain, Dale Bixby, Lauren B. Smith, Shalini C. Reshmi, Julie M. Gastier-Foster, Joshua D. Schiffman, Rodney R. Miles
Journal: Blood (2015)