tbuckley/cabot-search huggingface dataset:
PTH-105 Comparing outcomes of parenteral iron infusions (monofer®) in patients with and without inflammatory bowel disease
Authors: A Burn-Murdoch, E Mann, F Chariah, S Mann
Journal: Gut (2017)

Introduction  Iron deficiency anaemia (IDA) is a significant health problem accounting for over 70 000 annual hospital admissions in the UK (1). There is a drive to manage IDA earlier and more effectively, thereby improving quality of life and reducing hospital admissions. Intravenous (IV) iron has been shown to be better than oral iron in treating IDA related to inflammatory bowel disease (IBD) (2) as oral iron is often poorly tolerated. Although our institution uses Monofer (iron isomaltoside), there is a lack of real world data regarding its use in this patient group in the UK.  Aim: To review the aetiology of IDA, haemoglobin (Hb) outcomes and adverse events after Monofer in patients with and without IBD.  Method  Patients with IDA who had received Monofer over 18 months were identified from the Barnet Hospital Day Unit attendance log. Data were collected via electronic records for patient demographics, pre and post infusion Hb, infusion frequency and infusion reactions.  Results  Eighty-four patients with IDA received Monofer between January 2015 and July 2016. Nine patients (10.7%) suffered immediate infusion reactions. Of the remaining 75 IDA patients, 26 had IBD (15–UC; 11–Crohn’s disease; female=17; mean age=46 years) and 49 had non-IBD related conditions (19–idiopathic; 10–menorrhagia; 4–angiodysplasia; 16–other; female=41; mean age=62 years). Fifty-six patients (74.7%) received a single-dose; seven patients (9.3%) received two-doses; 12 patients (16%) received multiple-doses. The mean iron requirement per infusion was 957.7 mg in IBD patients and 987.2 mg in non-IBD patients. The mean pre-infusion Hb was 90.9 g/L in IBD and 88.0 g/L in non-IBD patients, with no difference in mean post-infusion Hb (IBD=116.4 g/L; non-IBD=117.9 g/L). The mean rise in Hb was 25.5 g/L (IBD) and 29.8 g/L (non-IBD).  Conclusion  IV iron offers a rapid, efficient method of correcting IDA. ECCO guidelines recommend IV replacement as treatment of choice in IBD patients (3). We have shown that IBD patients respond to Monofer with a similar Hb rise to non-IBD patients. Although the response is rapid, we have concerns about infusion reactions in 10% of all recipients. We now advocate pre-infusion of chlorpheniramine to minimise adverse reactions.  References  . ”Hospital Episode Statistics”. Healthand Social Care Information Centre.  . Lee TW, et al. (2012).  . Dignass AU, et al. (2015).  Disclosure of Interest  None Declared
Widening the landscape of heritable pulmonary hypertension mutations in paediatric and adult cases
Authors: Mélanie Eyries, David Montani, Sophie Nadaud, Barbara Girerd, Marilyne Levy, Arnaud Bourdin, Romain Trésorier, Ari Chaouat, Vincent Cottin, Céline Sanfiorenzo, Grégoire Prevot, Martine Reynaud-Gaubert, Claire Dromer, Ali Houeijeh, Karine Nguyen, Florence Coulet, Damien Bonnet, Marc Humbert, Florent Soubrier
Journal: European Respiratory Journal (2018)

Heritable forms of pulmonary arterial hypertension (PAH) and pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis (PVOD/PCH) diverge by lung histopathological lesions, clinical and para-clinical presentation, their responsible genes, and mode of transmission. Since the identification of the BMPR2 gene in families affected by PAH, mutations in several other genes have been discovered for both forms. The mutation landscape in these new genes is not yet well known.We set up a next-generation sequencing-based targeted sequencing gene panel allowing known genes for PAH and PVOD/PCH to be analysed simultaneously. Genetic analysis was prospectively performed on 263 PAH and PVOD/PCH patients (adult and paediatric cases).Pathogenic mutations were identified in 19.5% of sporadic PAH patients (n=180), 54.5% of familial PAH patients and 13.3% of PVOD/PCH patients. BMPR2 was the most frequently mutated gene, followed by TBX4 in both paediatric and adult PAH. BMP9 mutations were identified in 1.2% of adult PAH cases. EIF2AK4 biallelic mutations were restricted to PVOD/PCH. A truncating mutation and a predicted loss-of-function variant were also identified in BMP10 in two severely affected sporadic PAH female patients.Our results confirm that mutations are found in genes beyond BMPR2 in heritable PAH, emphasise the role of TBX4 and BMP9, and designate BMP10 as a new PAH gene.
Nucleophosmin Phosphorylation as a Diagnostic and Therapeutic Target for Ischemic AKI
Authors: Zhiyong Wang, Erdjan Salih, Chinaemere Igwebuike, Ryan Mulhern, Ramon G. Bonegio, Andrea Havasi, Steven C. Borkan
Journal: Journal of the American Society of Nephrology (2018)

Background Ischemic AKI lacks a urinary marker for early diagnosis and an effective therapy. Differential nucleophosmin (NPM) phosphorylation is a potential early marker of ischemic renal cell injury and a therapeutic target. Methods Differential NPM phosphorylation was assessed by mass spectrometry in NPM harvested from murine and human primary renal epithelial cells, fresh kidney tissue, and urine before and after ischemic injury. The biologic behavior and toxicity of NPM was assessed using phospho-NPM mutant proteins that either mimic stress-induced or normal NPM phosphorylation. Peptides designed to interfere with NPM function were used to explore NPM as a therapeutic target. Results Within hours of stress, virtually identical phosphorylation changes were detected at distinct serine/threonine sites in NPM harvested from primary renal cells, tissue, and urine. A phosphomimic NPM protein that replicated phosphorylation under stress localized to the cytosol, formed monomers that interacted with Bax, a cell death protein, coaccumulated with Bax in isolated mitochondria, and significantly increased cell death after stress; wild-type NPM or a phosphomimic NPM with a normal phosphorylation configuration did not. Three renal targeted peptides designed to interfere with NPM at distinct functional sites significantly protected against cell death, and a single dose of one peptide administered several hours after ischemia that would be lethal in untreated mice significantly reduced AKI severity and improved survival. Conclusions These findings establish phosphorylated NPM as a potential early marker of ischemic AKI that links early diagnosis with effective therapeutic interventions.
A new symptom measure in gastrointestinal stomal tumors.
Authors: Loretta A. Williams, Dejka M. Araujo, Tito R. Mendoza, Mary L Sailors, Nazim N Ali, Furong Huang, Jonathan C. Trent, Charles S. Cleeland
Journal: Journal of Clinical Oncology (2013)

e17508 Background: Symptom burden is the combined impact of disease- and treatment-related symptoms on daily functioning. A major barrier to effective symptom management in gastrointestinal stromal tumors (GIST) is inadequate assessment. Our aim was to develop a short, valid, reliable patient-reported outcome measure of GIST symptoms for research and practice. Methods: After giving IRB-approved informed consent, 110 patients with GIST completed the 13 symptom severity and 6 interference items of the core MD Anderson Symptom Inventory (MDASI) plus 9 GIST-specific symptom items generated from patient and expert input. Items were measured on a 0-10 scale (0 = none, 10 = worst imaginable). 65 patients completed the same items 1 day later. Patients also answered a single overall quality-of-life (QOL) question. Demographic and disease information was collected on all patients. Psychometric procedures determined reliability and validity of the MDASI-GIST. Results: Mean subject age was 59.2 years (standard deviation [sd] = 11.9). 54% of the subjects were female, 85% were white, 47% were employed, 55% were on imatinib, and 30% had no evidence of disease. Mean overall QOL rating was 8.1 (best = 10, sd = 2.0). Symptoms reported as most severe were fatigue (mean [M] = 2.65, sd = 2.66), drowsiness (M = 2.36, sd = 2.55), disturbed sleep (M = 2.18, sd = 2.55), and muscle soreness/cramping (M = 2.18, sd = 2.67). Two items (abdominal swelling and malaise) were eliminated for redundancy. Internal consistency (Cronbach α) and test-retest reliability of the 20 symptom items were 0.94 and 0.93, respectively, and of the 6 interference items were 0.94 and 0.87, respectively. The mean severity of the 20 symptom items was significantly correlated with QOL rating (correlation = -0.7, P &lt; 0.001). Mean GIST-specific symptom severity and symptom interference discriminated between patients who were employed and patients who were disabled (P = 0.05 and 0.03, respectively). Conclusions: We have validated an analytic tool, the MDASI-GIST, to quantify GIST symptom burden, assess side effects in treatment trials, and monitor symptoms in clinical care. Additional research on the longitudinal symptom burden of GIST, including differences based on type of therapy and response to therapy, is ongoing.
Using N-(2-hydroxypropyl)methacrylamide copolymer drug bioconjugate as a novel approach to deliver a Bcl-2-targeting compound HA14-1 in vivo
Authors: Matthew Oman, Jihua Liu, Jun Chen, David Durrant, Hung-Sheng Yang, Yongwen He, Pavla Kopeckova, Jindrich Kopecek, Ruey-Min Lee
Journal: Cancer Research (2005)

1424  We have recently investigated a macromolecular prodrug strategy for improved cancer chemotherapy based on two features: (a) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration, and (b) acid-sensitive or enzymatic release of the albumin-bound drug at the tumor site (1,2). In the present work we set out to develop albumin-binding prodrugs of doxorubicin that are cleaved by prostate-specific antigen (PSA). PSA is a serine protease that is over-expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. Based on our synthetic experience, we developed albumin-binding prodrugs with the structures MT-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO; MT-Asn-Ser-Ser-Tyr-–Phe-Gln-DOXO [MT = maleimidotriethyleneglycol acid; DOXO = doxorubicin), EMC-(Arg)-Arg-Ser-Ser-Tyr-Tyr-Ser-X-DOXO [EMC: e-Maleimidocaproic acid; X = amino acid]. All of the maleimide derivatives bound rapidly to the cysteine-34 position of endogenous and exogenous albumin and were efficiently cleaved by PSA at the P1-P′1scissile bond releasing a respective doxorubicin dipeptide. The derivatives containing arginine residues (EMC-(Arg)-Arg-Ser-Ser-Tyr-Tyr-Ser-X-DOXO) exhibited excellent water-solubility for intravenous administration. Subsequent biological evaluation was focused on a PSA-negative xenograft model (PC 3) and PSA-positive xenograft model (CWR22) in order to assess the selectivity of our therapeutic approach. EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO showed no in vivo activity in the PSA-negative PC-3 model, but good activity in the CWR22 PSA-positive model that was comparable to doxorubicin. Incubation studies with CWR22 tumor homogenates revealed, however, that the full potential of EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO had not been exploited considering that a less active doxorubicin dipeptide DOXO-Gly-Ser and not doxorubicin was released in PSA-positive prostate carcinoma tissues. We thus optimized the structure of this prodrug by substituting Arg for Gly in the C-terminal position. In incubation studies with CWR22 tumor homogenates, the resulting albumin conjugate of EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Arg-DOXO initially released Ser-Arg-DOXO which was further degraded to doxorubicin as the final cleavage product. In vivo studies with this optimized PSA specific prodrug are underway. Kratz et al., Journal of Medicinal Chemistry. 45, 5523-33, 2002 Mansour et al., Cancer Res. 63, 4062-4066, 2003
Abstract 16831: Identifying Barriers to Hypertension Care: Development and Validation of a Behavioral Assessment Tool for Optimizing Linkage and Retention to Hypertension Care in Kenya (LARK Hypertension Study)
Authors: Alexandra Douglas, Jackson Rotich, Peninah Kiptoo, Kennedy K Lagat, Kennedy Mutai, Emmanuel Tarus, Claire Kofler, Violet Naanyu, Diana Menya, Jemima H Kamano, Thomas S Inui, Allison DeLong, Carol R Horowitz, Valentin Fuster, Rajesh Vedanthan
Journal: Circulation (2015)

Introduction: Hypertension is the leading risk factor for global mortality. Hypertension treatment rates are low, partly due to inadequate linkage and retention to care. The LARK Study evaluates the use of community health workers (CHWs), equipped with a behavioral assessment and a tailored behavioral change strategy, to improve linkage and retention to hypertension care in Kenya. Here we describe the development and validation of the assessment tool used by CHWs to identify patients’ barriers to care, facilitating behavioral change communication. Methods: We derived behavioral assessment items from prior research on barriers to hypertension care in Kenya. Patients, CHWs, and clinicians scored each item for clarity and representativeness, and provided qualitative feedback during focus groups. A content validity index (CVI), representing inter-rater agreement of scores, was calculated for each item. Multivariable linear mixed-effects models were used to compare CVIs and level of modification (none, minor, major, or deleted) by participant category. Results: We tested 70 items in 9 focus groups. Mean CVIs were greater than 0.9 in all study groups (Table). Multivariable adjustment revealed that patients and CHWs had significantly higher CVIs than clinicians. Despite this, qualitative feedback from patients and CHWsled to higher item modification rates. 37 items were retained in the linkage assessment and 57 items in the retention assessment. Conclusions: The mean CVI was greater than 0.9 in all study populations, indicating excellent inter-rater agreement of the overall clarity and representativeness of assessment items. However, CVI alone could not account for modifications suggested during qualitative discussions. A combination of quantitative and qualitative methods yielded the most informative evaluation of assessment items. These findings may be relevant to the validation of similar assessment tools in other low-resource settings.
Relevance of KRAS status in relation to clinical outcome of anti-VEGF-based therapy of metastatic disease in patients with right-sided primary colorectal cancer.
Authors: Radka Obermannova, Lenka Zdrazilova-Dubska, Karel Hejduk, Renata Chloupkova, Michal Vocka, Lenka Ostrizkova, Beatric Benscikova, Igor Kiss, Lubos Petruzelka
Journal: Journal of Clinical Oncology (2018)

785 Background: Right-sided location of primary colorectal carcinoma is associated with worse prognosis and predicts worse outcome of treatment of metastatic disease. Prognostic role of KRAS status in 1 st -line treatment with anti-VEGF of mCRC remains controversial. We aim to study prognostic role of KRAS in the context of primary tumor location for anti-VEGF-based therapy of mCRC. Methods: Data from 3 national comprehensive cancer centers in the Czech Republic were collected prospectively from 01/2009 - 09/2015. A retrospective analysis of outcomes of 1059 pts with mCRC with known KRAS status was performed. Patients were treated with 1st-line bevacizumab (bev) plus FOLFOX or CapOx, irrespective of the KRAS status (all-RAS since 2015). The primary objective of our retrospective analysis was assessment of OS and PFS in right-sided primary tumors in connection with KRAS status. OS and PFS were calculated using the Kaplan-Meier method. Results: KRAS mutation was significantly more common in right- vs left-sided mCRC. Unlike in left-sided subgroup, both PFS and OS was poor in right-sided subgroup irrespective of KRAS status. Targeted therapy in subsequent lines of treatment was evenly spread among primary location subgroups. 769 (71.4%) patients were treated by CTx alone. Conclusions: Known KRAS status (Table) is not relevant for the treatment with 1 st -line anti-VEGF plus CTx in righ-sided primary tumors. [Table: see text]
Focal prostate basal cell layer disruptions and leukocyte infiltration are correlated events: Implications for tumor invasion
Authors: Yan-Gao Man, Ting Shen, Yunge Zhao, Qing-Xiang Amy Sang
Journal: Cancer Research (2004)

1775  The normal human prostate epithelium is physically separated from the stroma by both the basal cell layer and basement membrane. Due to this structural feature, the disruption of both the basal cell layer and basement membrane is an absolute pre-requisite for tumor invasion and metastasis. The disruption of the basement membrane is believed to result from an elevated production of proteolytic enzymes by the tumor and/or stromal cells, while the mechanism for basal cell layer disruptions is elusive. In a previous study, we found that a subset of mammary ductal carcinoma in situ contained focal disruptions in their myoepithelial (ME) cell layers, and that over 97% of these ME disruptions were subjacent to leukocytes (Yousefi et al. AIMM, in press). As the basal cell layer is believed to be equivalent to the ME cell layer, this study attempts to assess whether a similar event occurs in pre-invasive prostate tumors. Consecutive sections were prepared from prostate tumors containing simultaneous normal, prostatic intraepithelial neoplasia, and organ-confined carcinoma. Two immediate adjacent sections from each of 16 selected cases were double immunostained, one for cytokeratin (CK) 34betaE12 plus leukocyte common antigen, the other for CK 34betaE12 plus Ki-67. Acini and ducts lined by over 40 epithelial cells were examined for a focal basal layer disruption, defined as the absence of basal cells resulting in a gap equal to or greater than the combined size of 3 basal or epithelial cells. Focal basal cell layer disruption was found in all the cases, while the frequency among cases varied from less than 5% to over 15% of the acini and ducts examined. Focal leukocyte infiltration was seen in over 90% of the acini and ducts with focal basal cell layer disruptions, while in only about 30% of the acini and ducts without focal basal cell layer disruptions (p
Can Big Data Deliver on Its Promises?—Leaps but Not Bounds
Authors: Ithan D. Peltan, Sarah J. Beesley, Samuel M. Brown
Journal: JAMA Network Open (2018)

Ben J. Marafino, BS; Miran Park, PhD; Jason M. Davies, MD, PhD; Robert Thombley, MS; Harold S. Luft, PhD; David C. Sing, MD; Dhruv S. Kazi, MD, MS, MSc; Colette DeJong, MD; W. John Boscardin, PhD; Mitzi L. Dean, MS, MHA; R. Adams Dudley, MD, MBA
Abstract 16458: Cardiac Targeting Peptide Provides Efficient Transduction of Human Cardiomyocytes
Authors: Timothy N Feinstein, Xinxiu Xu, Cecilia Lo, Maliha Zahid
Journal: Circulation (2017)

Introduction: Our prior work utilizing a combinatorial in vitro and in vivo phage display strategy identified a 12-amino acid cardiac targeting peptide (CTP: APWHLSSQYSRT) that transduced the mouse...
UCHL1 expression is a poor prognostic marker in non-small cell lung cancer
Authors: Changqi Zhu, Suzanne K. Lau, Davina Lau, Ni Liu, Ming-Sound Tsao
Journal: Cancer Research (2006)

1194  Background: UCHL1 is a susceptible gene for Parkinson’s disease and has both deubiquitinase and ubiquitin ligase activities. It is commonly overexpressed in a variety of carcinomas including lung cancers. UCHL1 expression in esophageal squamous cell carcinoma and pancreatic carcinoma may also be downregulated by promoter hypermethylation. UCHL-1 is also involved in neural cell apoptosis. Materials & Methods: Quantitative-PCR (qPCR) was used to assay the expression levels of UCHL1 in two independent cohorts of non-small cell lung carcinoma (NSCLC). Cohort 1 consisted of 116 stage I-III tumors and 38 non-neoplastic tissues. The mean±95% CI of the normal was used to define the range of normal expression. Cohort 2 consisted of 172 resected NSCLC samples with similar clinical features as cohort 1. UCHL1 expression was also assessed in 10 NSCLC xenografts. Results: In cohort 1, 29.3% (34/116) overexpressed, while 3.4% (4/116) underexpressed UCHL1. Overexpression was more common in Stage I patients (32.9%) and in squamous cell carcinoma (SQCC) (51.5%). UCHL1 expression levels were also higher in smokers (p=0.012). In stage I, UCHL1 overexpression was positively correlated with differentiation grade (p=0.014) and significantly associated with shorter survival time [HR=2.57 (95%CI 1.18-5.61), p=0.017]. The survival difference remained significant even in multivariate analysis for all cases [HR=1.05 (1.02-1.08), p=0.002]. However, it was noteworthy that the 4 cases (including 2 in Stage I) that had low UCHL1 expression succumbed to NSCLC within 3 years. Cohort 2 validated findings of cohort I. Survival analysis showed a significant association between UCHL1 expression and shorter overall survival after adjustment for stage and differentiation [HR=1.25 (1.05-1.53), p=0.03]. In NSCLC xenografts, tumor growth was positively correlated with high UCHL1 expression. Interestingly, although tumors with the lowest levels of UCHL1 expression (RVH6849 and A549) grew slower than those with high expression, they also grew faster than those with intermediate expression. Moreover, the expression of UCHL1 was correlated with higher tumorigenicity in an in vitro study. Conclusion: Overexpression of UCHL1 was more frequent in early stage NSCLC and in SQCC, and was associated with shorter overall survival. However, downregulation of UCHL1 also appeared to be associated with poor prognosis.
Abstract 13910: Variation in Survival After Out-of-Hospital Cardiac Arrest Between Emergency-Medical-Services Agencies
Authors: Masashi Okubo, Robert Schmicker, David Wallace, Ahamed Idris, Graham Nichol, Michael Austin, Brian Grunau, Lynn Wittwer, Neal Richmond, Laurie Morrison, Michael Kurz, Sheldon Cheskes, Peter Kudenchuk, Dana Zive, Tom Aufderheide, Henry Wang, Heather Herren, Christian Vaillancourt, Daniel Davis, Gary Vilke, Frank Scheuermeyer, Myron Weisfeldt, Jonathan Elmer, Riccardo Colella, Clifton Callaway
Journal: Circulation (2017)

Introduction: Although there is substantial regional variation in survival after out-of-hospital cardiac arrest (OHCA), the reasons for this variability are poorly understood. We sought to investig...
High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors
Authors: Saman Maleki Vareki
Journal: Journal for ImmunoTherapy of Cancer (2018)

Tumors responding to immune checkpoint inhibitors (ICIs) have a higher level of immune infiltrates and/or an Interferon (IFN) signature indicative of a T-cell-inflamed phenotype. Melanoma and lung cancer demonstrate high response rates to ICIs and are commonly referred to as "hot tumors". These are in sharp contrast to tumors with low immune infiltrates called "cold tumors" or non-T-cell-inflamed cancers, such as those from the prostate and pancreas. Classification of tumors based on their immune phenotype can partially explain clinical response to ICIs. However, this model alone cannot fully explain the lack of response among many patients treated with ICIs. Dichotomizing tumors based on their mutation profile into high tumor mutation burden (TMB) or low TMB, such as many childhood malignancies, can also, to some extent, explain the clinical response to immunotherapy. This model mainly focuses on a tumor's genotype rather than its immune phenotype. High TMB tumors often have higher levels of neoantigens that can be recognized by the immune system. In the current era of immunotherapy, with the lack of definitive biomarkers, we need to evaluate tumors based on both their immune phenotype and genomic mutation profile to determine which patients have a higher likelihood of responding to treatment with ICIs.