tbuckley/cabot-search huggingface dataset:
A COL17A1 Splice-Altering Mutation Is Prevalent in Inherited Recurrent Corneal Erosions
Authors: Verity F. Oliver, Katherine A. van Bysterveldt, Murray Cadzow, Bernhard Steger, Vito Romano, David Markie, Alex W. Hewitt, David A. Mackey, Colin E. Willoughby, Trevor Sherwin, Philip S. Crosier, Charles N. McGhee, Andrea L. Vincent
Journal: Ophthalmology (2016)

Corneal dystrophies are a genetically heterogeneous group of disorders. We previously described a family with an autosomal dominant epithelial recurrent erosion dystrophy (ERED). We aimed to identify the underlying genetic cause of ERED in this family and 3 additional ERED families. We sought to characterize the potential function of the candidate genes using the human and zebrafish cornea.Case series study of 4 white families with a similar ERED. An experimental study was performed on human and zebrafish tissue to examine the putative biological function of candidate genes.Four ERED families, including 28 affected and 17 unaffected individuals.HumanLinkage-12 arrays (Illumina, San Diego, CA) were used to genotype 17 family members. Next-generation exome sequencing was performed on an uncle-niece pair. Segregation of potential causative mutations was confirmed using Sanger sequencing. Protein expression was determined using immunohistochemistry in human and zebrafish cornea. Gene expression in zebrafish was assessed using whole-mount in situ hybridization. Morpholino-induced transient gene knockdown was performed in zebrafish embryos.Linkage microarray, exome analysis, DNA sequence analysis, immunohistochemistry, in situ hybridization, and morpholino-induced genetic knockdown results.Linkage microarray analysis identified a candidate region on chromosome chr10:12,576,562-112,763,135, and exploration of exome sequencing data identified 8 putative pathogenic variants in this linkage region. Two variants segregated in 06NZ-TRB1 with ERED: COL17A1 c.3156C→T and DNAJC9 c.334G→A. The COL17A1 c.3156C→T variant segregated in all 4 ERED families. We showed biologically relevant expression of these proteins in human cornea. Both proteins are expressed in the cornea of zebrafish embryos and adults. Zebrafish lacking Col17a1a and Dnajc9 during development show no gross corneal phenotype.The COL17A1 c.3156C→T variant is the likely causative mutation in our recurrent corneal erosion families, and its presence in 4 independent families suggests that it is prevalent in ERED. This same COL17A1 c.3156C→T variant recently was identified in a separate pedigree with ERED. Our study expands the phenotypic spectrum of COL17A1 disease from autosomal recessive epidermolysis bullosa to autosomal dominant ERED and identifies COL17A1 as a key protein in maintaining integrity of the corneal epithelium.
Abstract 13203: Novel Photoreleasable Caged Angiotensin-II Analogs to Study Intracrine Pharmacology in Intact Cells
Authors: Artavazd Tadevosyan, Myriam Letourneau, Benjamin Folch, Nicolas Doucet, Louis R Villeneuve, Terence E Hebert, Alain Fournier, David Chatenet, Bruce G Allen, Stanley Nattel
Journal: Circulation (2013)

Background: Angiotensin type 1 (AT1R) and type 2 (AT2R) receptors on intracellular membranes might play an important role in cardiac remodeling, but the importance of intracellular “intracrine” sig...
Retrospective application of Nottingham Prognostic Index (NPI) and Adjuvant! Online tool in newly diagnosed patients with early breast cancer in mid-western Ireland.
Authors: K. I. Quintyne, B. Woulfe, R. K. Gupta
Journal: Journal of Clinical Oncology (2010)

6139 Background: Prognostic tools used in oncology, have been derived to help stratify patients into specific risk-related groupings. Before the widespread use of the internet, the St Gallens' recommendations and the Nottingham Prognostic Index (NPI) were used in patients with early breast cancer; however more recently, there has been the development of the web-based tool, Adjuvant! Online (www.adjuvantonline.com), which provides more detailed information. We herein report our experience with the retrospective application of these prognostic tools and the comparative outcome for patients in Mid-Western Regional Hospital (MWRH), Limerick, Ireland. Methods: Study period: 01/01/2002-31/12/2002. Data was derived from (1) Mid-Western Cancer Centre (MWCC) Oncology Database (2) MWRH pathology records (3) MWRH patient files (4) MWRH Breast Multidisciplinary meeting records. Data was collated and entered into an Access database and exported into Predictive Analytics Software (PASW) for analysis. Results: Seventy seven patients with nonmetastatic breast cancer were analysed. Mean age: 53.4 years (range: 23-74 years). Median follow-up: 84 months. Patients were distributed into the following NPI groups, good, 26.0% (20/77), moderate, 50.6% (39/77) and poor risk, 23.4% (18/77); median survival did not show direct correlation with NPI risk, 83.3 months, good, 85.1 months, moderate and 76.2 months for poor-risk patients. Application of Adjuvant! Online showed a better correlation between the predicted survival (mean 72.9%, median 78.6%) versus the observed survival of our patient cohort (81.8%) and this was maintained within all sub-groups, including those who undertook no additional therapy, hormonal therapy and chemotherapy. Conclusions: Prognostic tools are useful in evaluating and predicting the possible outcome. Of the two tools used in this study, Adjuvant! Online was better able to predict overall survival for our cohort. These tools work well in the clinical setting, but should not be seen an alternative to good clinical judgement when assessing patients on an individual basis. No significant financial relationships to disclose.
Adequacy of published oncology randomized controlled trials to provide details needed for clinical application
Authors: J. M. Duff, H. L. Leather, E. O. Walden, K. D. LaPlant, T. J. George
Journal: Journal of Clinical Oncology (2009)

6536 Background: Randomized control trials (RCTs) provide evidence for life-saving and supportive therapies. Although manuscript submissions follow a standard scientific format, major oncology journals have minimal standards for reporting treatment administration. Published data investigating chemo and biologic therapy often lack details needed for effective and safe clinical application. Methods: All therapy-based phase III oncology RCTs published between 2005–2008 in the Journal of Clinical Oncology (JCO), The New England Journal of Medicine (NEJM), Journal of the National Cancer Institute (JNCI), Blood, and Cancer were eligible for inclusion. Physicians and oncology pharmacists were surveyed for details needed for clinical practice. Each article was evaluated for these mandatory elements ( Table ). Differences were calculated using the Chi-squared test. Results: Literature search identified 339 eligible articles, 77 were reviews or meta-analyses. 262 were included in the final analysis (165 JCO; 31 NEJM; 27 Cancer; 20 JNCI; 19 Blood). Only 31 (12%; median score 7.3) met the main objective of complete data reporting. The most consistently reported and missing elements are described in Table 1. Premedications, growth factor support, and dose adjustments for hematologic or organ toxicity were reported less than half the time (p&lt;0.0001). The presence of an online appendix did not significantly improve the results (data not shown). Conclusions: RCTs published in top tier oncology journals fail to consistently report full details needed for clinical application. Manuscript submission guidelines should be modified to promote consistent reporting with potential use of online appendices. Standardized editorial policy may allow safe and effective translation of trial drug findings into clinical practice. [Table: see text] No significant financial relationships to disclose.
Abstract 689: Notch Signaling Stimulates Expression Of Wnts And Contributes To Cardiac Markers Gene Expression In Human Progenitor Cell
Authors: Masamichi Koyanagi, Philipp Bushoven, Masayoshi Iwasaki, Carmen Urbich, Andreas M Zeiher, Stefanie Dimmeler
Journal: Circulation (2007)

It has been demonstrated that adult human circulating endothelial progenitor cells (EPC) can differentiate to a cardiomyogenic phenotype. Notch signaling promotes epithelial-to-mesenchymal transformation and plays a prominent role in heart and vessel development. Here, we investigated the role of Notch activation for cardiac differentiation of EPC in a co-culture system with neonatal rat cardiomyocyte (CM). EPC expressed the receptors Notch-1 and Notch-2, whereas CM expressed high level of Notch ligand Jagged-1. Therefore, we hypothesized that CM may activate Notch signaling within EPC. Indeed, after co-culture, Notch activation was detected in EPC by immunohistochemical detection of the intracellular cleavage fragment of Notch-1 (NICD), whereas NICD was only rarely detected in EPC before co-culture. Western blot analysis confirmed Notch cleavage after co-culture. RT-PCR directed against the human specific sequences of the Notch target genes Hey2 and Hes1 demonstrated a transient activation of the transcriptional activity of Notch in human EPC after co-culture with CM. Inhibition of γ-secretase significantly blocked Notch cleavages and NICD translocations. Furthermore, the expression of the cardiac marker protein γ-sarcomeric actinin and troponin T was significantly suppressed by γ-secretase inhibition (55.8 ± 8.1% and 54.0 ± 10.5% of control, respectively) or addition of soluble recombinant Jagged-1, indicating that Notch activation facilitates cardiac marker gene expression. Because non-canonical Wnts have previously been shown to promote cardiac differentiation, we additionally determined the influence of Notch activation on the expression of Wnt5a and. Wnt5a and Wnt11 expressions in the human cells was induced by the co-culture and was blocked by γ-secretase inhibitor. Likewise, stimulation of Notch signaling by immobilized Jagged-1 promoted NICD cleavage and Wnt5a expression in EPC. These data suggested that Notch is transiently activated upon co-culture of EPC with neonatal rat CM. γ-Secretase-dependent Notch activation is required for cardiac gene expression in human cells and induces the expression of non-canonical Wnt proteins, which may act in an paracrine manner to further amplify cardiac differentiation.
Abstract 16302: Notch3 Signaling Promotes M1 Macrophage Activation and Atherosclerosis: A Novel Therapeutic Target
Authors: Tetsuro Miyazaki, Kunio Morishige, Elena Aikawa, Jon C Aster, Masanori Aikawa
Journal: Circulation (2013)

Background: Pro-inflammatory (“M1”) macrophages may exert atherogenic effects while “M2” macrophages may be anti-inflammatory. The Notch pathway, involving four receptors (Notch1-4), regulates vari...
Prevention of high-dose methotrexate acute toxicity using a rescue protocol combining hyper-alkalinization followed by continuous infusion of leucovorin in osteosarcoma patients
Authors: F. Goldwasser, O. Mir, S. Ropert, A. Babinet, J. Alexandre, J. Durand, V. Montheil, P. Anract
Journal: Journal of Clinical Oncology (2008)

10545 Background: Renal failure is a severe acute toxicity of high-dose methotrexate (HDMTX), observed in near 2% of patients (pts). To prevent this risk, HDMTX is routinely given as single agent and associated with alkaline hyper-hydration and followed by repeated intravenous (iv) bolus of leucovorin. We developed a protocol of hyper-alkalinization without need of hyper-hydration and gave leucovorin as iv continuous infusion (CI), to allow the outpatient administration and follow-up of osteosarcoma pts treated with HDMTX. Methods: pts received 500 ml of 8.4% sodium bicarbonate prior to HDMTX (H-2), and daily for 3d. The dose of HDMTX was 8 (4 pts) or 12 g/m2 (20 pts), administered as a 4-hour infusion. The iv route was stopped for 20h at the end of HDMTX to optimize its PK. Leucovorin rescue was 200 mg started at H24, as a 22h CI, repeated for 3d. Methotrexatemia was measured at H4 (Cmax), H24, H48 and H72 and urinary pH on each miction. Creatininemia was assessed on d1, 3 and 8. Results: Twenty-four consecutive pts (9 females, 15 males) were treated accordingly. Median age: 18 years (range: 15–20). Median number of cycles per pt: 16. A total of 322 cycles of HDMTX were evaluable for MTX pharmacokinetics and toxicity. Urinary pH was higher than 7.5, overnight, in all pts. The mean peak, H24 and H48 concentrations were 1084 μmol/l, 12.35 μmol/l and 0.46 μmol/l, respectively. In 12 cycles (3.7%), grade 1 creatininemia elevation (< 1.5 ULN) was noticed. No grade 4 toxicity occurred. No hospitalization for acute toxicity was required. Conclusions: Hyper-alkalinization plus continuous infusion of leucovorin allows the outpatient care of osteosarcoma pts treated with HDMTX. No significant financial relationships to disclose.
Correlation of bone marrow angiogenesis and response to thalidomide dexamethasone in multiple myeloma
Authors: S. Kumar, P. R. Greipp, J. L. Haug, M. A. Gertz, E. Blood, S. V. Rajkumar
Journal: Journal of Clinical Oncology (2006)

7621 Background: Thalidomide (Thal) in combination with dexamethasone (Dex) is an effective therapy for myeloma (MM). Though initially evaluated in MM because of its anti-angiogenic properties, it is not clear how much this contribute to its anti-MM effects. We examined whether the degree of angiogenesis influences response to Thal + Dex, as well as effect of therapy on marrow angiogenesis. We also examined whether expression of angiogenic cytokines by MM cells affect response to therapy. Methods: A total of 207 pts with newly diagnosed MM were randomized on the ECOG phase III trial (E1A00) to either Thal-Dex or Dex alone. Bone marrow microvessel density (MVD) was determined on 88 pts at diagnosis and at 4 mos after therapy in 25 pts. Expression of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) by MM cells was determined by RTPCR on 60 pts at diagnosis and on 22 pts at 4 mos. In addition, the percentage of marrow PCs in apoptosis was determined at diagnosis and 4 mos in 43 pts. A decrease in the serum M protein by 50% or in its absence, a decrease in urine M protein by 50% was considered a response. Results: The median BM MVD at diagnosis was 33 (3–118), and was similar in the pts responding to therapy (36.4) and in the non responders (45.4). We also separately looked at those receiving the combination vs. Dex alone, and did not find any correlation. The expression of FGF and VEGF in the PCs did not predict response to therapy with either the combination or Dex. Among the 17 responding pts, MVD decreased by a mean of 12 compared to an increase in the mean MVD of 3 among the non responders (P = NS). There was no significant correlation between the level of FGF or VEGF expression and the marrow MVD. There was no correlation between the percentage of myeloma cells in apoptosis at baseline and response to therapy. Conclusion: While the anti-angiogenic activity of Thal may play a role in its anti-myeloma effect, baseline MVD or tumor cell expression of angiogenic cytokines do not predict resistance or response to Thal-Dex or Dex alone. The findings here confirm previous observations that marrow angiogenesis is not related to the degree of secretion of angiogenic cytokines by individual cells, but rather the cumulative effect of the tumor mass. No significant financial relationships to disclose.
Violence by patients admitted to a private psychiatric hospital
Authors: K Tardiff, P M Marzuk, A C Leon, L Portera, C Weiner
Journal: American Journal of Psychiatry (1997)

The authors determined the rates and patterns of violence toward persons by psychiatric patients before admission to the inpatient service of the Payne Whitney Clinic and determined which factors were associated with a greater risk of violence.During hospitalization, 763 patients were interviewed by a research assistant using a structured interview instrument. The interviewer inquired about demographic and socioeconomic information and about history of violence and alcohol and drug use.Having physically attacked another person in the month before admission was equally likely among male (13.6%) and female (14.7%) patients. The patterns of violence were similar for men and women in terms of target, severity of injuries, use of a weapon, and place of occurrence. Univariate analyses showed that only youth was associated with violence for male patients, while youth, low socioeconomic status, substance abuse, and axis II pathology were associated with a greater risk of violence for female patients. Logistic regression analyses showed that recent cocaine use was significantly associated with violence by female patients when age, socioeconomic status, and axis II pathology were controlled for. For male patients, recent heroin use was related to a greater risk of violence.The frequency of violence by female patients was 150% higher than it was in a study at the Payne Whitney Clinic a decade ago. The frequency of violence by male patients was 50% higher than it was a decade ago. In the current study, substance abuse was associated with greater risk of violence by patients.
Review of a single gynecologic oncologist's 26 years of experience in treating gestational trophoblastic neoplasia (GTN).
Authors: J. J. Diaz, B. Thomas, C. Paz-Pabon, E. Hernandez
Journal: Journal of Clinical Oncology (2010)

e15562 Background: Outcome analysis of GTN patients treated by a single gynecologic oncologist. Methods: A review of all patients with GTN treated from 1983-2009 by a single gynecologic oncologist who prospectively collected their demographic and clinical data. Results: 31 (78%) of 40 patients had a WHO score <7 and received single agent methotrexate (MTX) as primary therapy. All but one received MTX 0.4 mg/kg. daily for 5 days every 21 days (mean number of cycles, 3; 80% remission). Of 9 (22%) high-risk patients (WHO score > 6), 6 received MTX, actinomycin D, cyclophosphamide (MAC) (33% remission), and 3 received etoposide, MTX, actinomycin D, (EMA), and vincristine, cyclophosphamide or EMA and cisplatin, etoposide (67% remission). All MAC failures died of GTN. Overall, 35 of the 40 patients (87.5%) achieved a sustained remission. Conclusions: A 5-day MTX regimen given every 21 days is a convenient, well-tolerated and effective for patients with low-risk GTN. High-risk patients should receive an aggressive first line regimen such as EMA/CO. No significant financial relationships to disclose.
Sensitivity of primary hematopoietic tumors and tumor lines to the novel HDAC inhibitor PCI-24781
Authors: S. Balasubramanian, J. Ramos, M. Sirisawad, J. J. Buggy, R. A. Miller, S. Phan
Journal: Journal of Clinical Oncology (2007)

14062 PCI-24781 (formerly CRA-024781) is a novel HDAC inhibitor that is in phase I clinical trials in patients with solid and hematopoietic malignancies. PCI-24781 has favorable pharmacokinetic and pharmacodynamic profiles in animal models and in humans. In the present study we show that PCI-24781 potently induces cell death in a variety of hematopoietic cell lines derived from B-cell, T-cell and myeloid malignancies, and in primary acute leukemic blasts from bone marrow aspirates. In tumor cell lines, growth inhibition and apoptosis were noted at drug concentrations ≡ 0.125 μM and were accompanied by known biochemical markers of HDAC inhibition including histone and tubulin hyperacetylation. To demonstrate the potential clinical utility of PCI-24781 in hematologic tumors, primary leukemia samples were isolated from patients and screened for resistance to PCI-24781-induced growth arrest in vitro. Of these 25 primary samples (10 acute myelogenous leukemia (AML), 6 multiple myeloma (MM) and 9 acute lymphocytic leukemia (ALL)), some of which were derived from patients who had failed standard therapy, none was resistant to PCI-24781 at 0.5 μM and only 4 (1 AML, 2 MM, and 1 ALL) were considered resistant at 50 nM. Gene expression analysis using DNA microarrays on these primary tumor samples revealed alterations of gene expression consistent with HDAC inhibition and defined potential pathways of activity for this compound in these tumors. These results demonstrate that hematopoietic tumors and tumor-derived cell lines are highly sensitive in vitro to the novel HDAC inhibitor PCI-24781. The high sensitivity of primary tumor cells to treatment with PCI-24781 in vitro coupled with the favorable pharmacokinetics of this compound in humans suggests that patients with hematopoietic malignancies would be responsive to treatment with PCI-24781 in clinical trials. No significant financial relationships to disclose.
High-Dose Sequential Chemotherapy With Recombinant Granulocyte Colony-Stimulating Factor and Repeated Stem-Cell Support for Inflammatory Breast Cancer Patients: Does Impact on Quality of Life Jeopardize Feasibility and Acceptability of Treatment?
Authors: Geneviève Macquart-Moulin, Patrice Viens, Thao Palangié, Marie-Laure Bouscary, Thierry Delozier, Henri Roché, Maud Janvier, Michel Fabbro, Jean-Paul Moatti
Journal: Journal of Clinical Oncology (2000)

PURPOSE: This study was designed to investigate the quality of life (QOL) of patients enrolled onto the High-Dose Chemotherapy for Breast Cancer Study Group trial (PEGASE 02), a French pilot multicenter trial of the treatment of inflammatory breast cancer (IBC) aimed at evaluating (1) toxicity and feasibility of sequential high-dose chemotherapy (HDC) with recombinant human granulocyte colony-stimulating factor (filgrastim) and stem-cell support and (2) response to HDC in terms of pathologic response and survival. PATIENTS AND METHODS: QOL measures were performed at inclusion and four times subsequently up to 1 year using an ad hoc side-effect questionnaire (19 physical symptoms) and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30). RESULTS: Of the 95 patients entered, the overall QOL questionnaire completion compliance was 75.6%. During cycle 3 of HDC, the number of symptoms was high (mean ± SD QOL score, 10 ± 3), with fatigue, hair loss, appetite loss, nausea, change in taste, vomiting, fever, and weight loss reported by more than 60% of patients. Toxicity and distress associated with HDC were reflected in the decline of four EORTC QLQ-C30 scores: global QOL (P = .001), and physical, role, and social functioning (P &lt; .001 for all statistics). However, QOL deterioration disappeared after treatment completion, except for physical functioning (P = .025). One year after inclusion, most QOL scores returned to baseline, and both emotional functioning and global QOL scores were even higher than baseline (P = .030 and P = .009, respectively). CONCLUSION: If it is confirmed that improvements in pathologic response rates with HDC effectively translate into increased probabilities of survival for IBC patients, adoption of such treatment as PEGASE 02 will not involve crucial choices between length of life and QOL and should not be delayed for QOL arguments.
Total sitting time and the risk of incident diabetes in Danish adults (the DANHES cohort) over 5 years: a prospective study
Authors: Christina B Petersen, Adrian Bauman, Janne S Tolstrup
Journal: British Journal of Sports Medicine (2016)

To test the hypothesis that total sitting time is associated with incident diabetes, after adjustment for physical activity and obesity.72 608 Danish adults from the DANHES cohort reported their total sitting time in 2007-2008 and were followed-up for 5 years, in relation to register-based incident diabetes mellitus. Cox regression analyses were used, and the effect-modifying influence of obesity and physical activity assessed.The age-sex adjusted HR for developing diabetes among those who sat 10+ h/day as compared to <6 h/day was 1.35 (95% CI 1.17 to 1.57). The relative risks were similar by gender, but were largely attenuated by adjustment for potential confounding factors including physical activity, and statistically non-significant for all categories of body mass index except the obese.The association between total sitting time and incident diabetes is substantially moderated by physical activity and obesity. Total sitting time remains a risk factor for diabetes only in inactive and obese populations.