tbuckley/cabot-search huggingface dataset:
PTH-100 Increasing the detection rate of bile salt malabsorption
Authors: M Kurien, K E Evans, J S Leeds, A D Hopper, A M Harris, D S Sanders
Journal: Gut (2010)

<h3>Introduction</h3> Diagnosing and treating patients with chronic watery diarrhoea is a common clinical problem. Despite the accuracy and the availability of the SeHCAT (75 Selenium HomotauorCholic Acid Test), bile salt malabsorption remains an under recognised cause of chronic watery diarrhoea. We aimed to determine which clinical features and laboratory investigations would increase the likelihood of finding bile salt malabsorption as demonstrated by a positive SeHCAT test (retention &lt;10% at 7 days). <h3>Methods</h3> A retrospective analysis was undertaken of patient9s records for all patients who underwent a SeHCAT scan in an 8-year period between 2001 and 2009 in a tertiary Gastroenterology Department (Group 1 n=316). Patient demographics, symptoms, previous medical and surgical history, as well as laboratory investigations (including full blood count, serum folate, vitamin b12, ferritin and albumin) were analysed. Statistical analysis was performed using SPSS (V.17.0 for windows) with chi squared analysis used to compare the data. Concurrently a previously assessed cohort of patients with irritable bowel syndrome was examined to determine the potential utility of SeHCAT scanning (Group 2 n=314). <h3>Results</h3> Out of the 316 patients (Group 1) who underwent a SeHCAT, 273 patient records were located and analysed (191 female, 82 male; median age 49). 107 patients (39.2%) had a positive result. The mean time from first hospital visit to SeHCAT result was 30 weeks. Patient characteristics predictive of a positive SeHCAT were: terminal ileal Crohn9s (p&lt;0.01), terminal ileal resection (p&lt;0.01), inflammatory bowel disease (p&lt;0.01), previous small bowel surgery (p&lt;0.01) and previous cholecystectomy (p&lt;0.01). 36 of the 107 patients (36.4%) who had a positive SeHCAT also had ROME 3 criteria for irritable bowel syndrome. In the IBS control cohort (Group 2) only 6/314 (1.9%) patients had undergone a SeHCAT scan (p&lt;0.001 compared to current group) meaning that potentially 114 patients with bile salt malabsorption could have been missed. <h3>Conclusion</h3> Bile Salt Malabsorption is common and should be considered earlier in patients with predisposing factors (including inflammatory bowel disease, terminal ileal disease, previous small bowel surgery and post cholecystectomy). Consideration should also be given for bile salt malabsorption prior to the diagnosis of diarrhoea-predominant irritable bowel syndrome.
Outcomes of Early Relapse Following Non-Myeloablative Allogeneic Transplant for Lymphoma.
Authors: Ron Ram, Ted Gooley, David G. Maloney, Oliver W. Press, John M. Pagel, Stephen H. Petersdorf, Andrei R. Shustov, Mary E.D. Flowers, Brenda M. Sandmaier, Rainer F. Storb, Ajay K. Gopal
Journal: Blood (2009)
Gene and microRNA (miRNA) Expression Signatures and Prognostic Significance of CEBPA Mutations in Cytogenetically Normal (CN) Acute Myeloid Leukemia (AML) with High-Risk Molecular Features: A Cancer and Leukemia Group B (CALGB) Study.
Authors: Guido Marcucci, Kati Maharry, Michael D. Radmacher, Krzysztof Mrózek, Tamara Vukosavljevic, Peter Paschka, Susan P. Whitman, Christian Langer, Claudia D. Baldus, Amy S. Ruppert, Bayard L. Powell, Andrew J. Carroll, Michael A. Caligiuri, Jonathan E. Kolitz, Richard A. Larson, Clara D. Bloomfield
Journal: Blood (2007)
Abstract 2681: Stromal neuregulin-1 promotes adaptive resistance in mutant BRAF melanoma
Authors: Claudia Capparelli, Sheera Rosenbaum, Adam Berger, Andrew E. Aplin
Journal: Cancer Research (2015)

Abstract RAF inhibitors are first-line treatments for melanomas that harbor BRAF V600E/K mutations; however, patients invariably progress on these targeted therapies. While durable resistance is mediated frequently by stable alterations intrinsic to the tumor cells leading to ERK1/2 pathway reactivation, the compensatory activation of growth factor receptor tyrosine kinases (RTKs) modulates the level of initial response. The composition of the tumor microenvironment likely plays a key role in these compensatory/adaptive responses to targeted inhibitors. In this study, we demonstrate that NRG1 is expressed in fibroblasts, as well as cancer associated fibroblasts (CAFs) isolated from a mutant BRAF melanoma. Fibroblast derived-NRG1 was able to mediate the enhanced ErbB3 pathway activation in RAF-inhibited mutant BRAF melanoma cells. Furthermore, conditioned medium from fibroblasts and CAFs limits RAF inhibitor cytotoxicity in V600 BRAF-harboring melanomas. Importantly, ErbB3 and ErbB2 targeting antibodies partially reverse the protective effects of fibroblast-derived medium on ErbB3 pathway activation and cell growth properties of mutant BRAF-inhibited melanoma cells. Together, these data demonstrate a requirement for a paracrine-produced factor in the tumor microenvironment to promote resistance to RAF inhibitor in mutant BRAF melanoma and reinforce the idea that targeting ErbB3/ErbB2 signaling may improve the efficacy of RAF inhibitors. Citation Format: Claudia Capparelli, Sheera Rosenbaum, Adam Berger, Andrew E. Aplin. Stromal neuregulin-1 promotes adaptive resistance in mutant BRAF melanoma. [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 2681. doi:10.1158/1538-7445.AM2015-2681
Abstract 4362: Screening of investigational antimalarials for anticancer activity in high risk N-MYC amplified neuroblastoma (NB)
Authors: Don W. Coulter, Jonathan Vennerstrom, John G. Sharp, Yuxiang Dong, Xiaofang Wang, Erin McIntyre, Tim McGuire
Journal: Cancer Research (2015)

Abstract Introduction: NB is a pediatric tumor of neural crest origin. Patients who have N-MYC amplified metastatic tumors have poor outcomes. The importance of autophagy in protecting NB cells from chemotherapy has been postulated. In the following study we screened bisquinoline (BQ) and ozonide (OZ) antimalarials (potential autophagy inhibitors) in a highly N-MYC amplified NB cell line (BE-2) and a moderately amplified N-MYC NB cell line (IMR-32). A combination of monolayer cell culture and neurospheres were used to screen activity. Methods: Using a 96 well MMT based assay and 16 hour treatment with compounds dissolved in DMSO, cytotoxicity was calculated as a percent decline in absorbance compared to DMSO controls. 32 BQ and 13 OZ antimalarials were tested. All compounds were tested at a concentration of 1 mcg/ml; an achievable concentration in patients. Selected compounds that were cytotoxic in monolayer culture will be tested in neurosphere culture and then in a mouse xenograft model alone and combined with chemotherapy. Results: The bisquinolone antimalarials were consistently active in both BE-2 and IMR cell culture. Among the bisquinolones, Q1-9, Q2-5, Q2-61, and Q3-75 had the greatest cytotoxicity. There was no clear structure-activity-relationship for this small bisquinoline library. Among the ozonides, OZ465, OZ513, and OZ521 were the most active. From these data, we could infer that the presence of a weak base functional group was required, but was insufficient for cytotoxicity. Initial studies in BE-2 and IMR neurosphere culture using an LDH assay for cytotoxicity suggests similar activity. Monolayer results are shown in the Table below: SymbolDrug ClassBE-2*IMR-32*Q1-9BQ38.535.8Q2-5BQ29.844.4Q2-61BQ40.731.4Q3-75BQ40.619.3OZ465OZ3820.6OZ513OZ73.627.7OZ521OZ4415.9 *Percent decline in absorbance compared to DMSO control Conclusion: The above data indicates that two classes of antimalarials had moderate cytotoxicity in both 96-well monolayer assays as well as in a neurosphere assay (data not shown). The results suggest cytotoxic activity in high and moderately amplified N-MYC NB in both monolayers and neurospheres. Note: This abstract was not presented at the meeting. Citation Format: Don W. Coulter, Jonathan Vennerstrom, John G. Sharp, Yuxiang Dong, Xiaofang Wang, Erin McIntyre, Tim McGuire. Screening of investigational antimalarials for anticancer activity in high risk N-MYC amplified neuroblastoma (NB). [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 4362. doi:10.1158/1538-7445.AM2015-4362
Eosinophilic esophagitis and colonic mucosal eosinophilia in Netherton syndrome
Authors: Colombe Paluel-Marmont, Nathalia Bellon, Patrick Barbet, Stéphanie Leclerc-Mercier, Smail Hadj-Rabia, Christophe Dupont, Christine Bodemer
Journal: Journal of Allergy and Clinical Immunology (2016)
Use of genetic variations to predict toxicity associated with neoadjuvant chemoradiation for AJCC stage II/III rectal cancer.
Authors: J. Ho, W. Li, M. P. Duldulao, Z. Chen, J. Kim, J. Garcia-Aguilar
Journal: Journal of Clinical Oncology (2011)

411 Background: Genetic polymorphisms have been associated with toxicity from chemotherapeutic agents for colon cancer, but none has been identified for rectal cancer. We examined the association between polymorphisms in genes for DNA repair, cell cycle progression, angiogenesis, and drug metabolism with toxicity from neoadjuvant chemoradiation treatment (CRT) for rectal cancer. Methods: Patients with AJCC stage II/III rectal adenocarcinoma were enrolled in a phase II multicenter trial examining timing of rectal cancer response to neoadjuvant CRT. There were two treatment arms: (I) radiation (XRT) and 5-FU followed by surgery and (II) XRT/5-FU and FOLFOX followed by surgery. Treatment toxicity, classified by the NCI Common Terminology Criteria guidelines as grade 3 and above, was recorded. DNA was extracted from normal rectal mucosa and analyzed for 22 polymorphisms in 17 genes. Results: We evaluated 110 patients (group I, n = 52; group II, n = 58). A total of 19 patients experienced grade 3+ adverse events (AE) [group I, n = 10 (19%); group II, n = 9 (16%)]. Gastrointestinal symptoms were the most common AE [group I, n = 5 (10%); group II, n = 4 (7%)]. The detection of lys allele (lys/lys or lys/gln genotypes) at codon 751 of the Xeroderma pigmentosum group D (XPD) gene was associated with increased toxicity in group II (p = 0.03), whereas homozygosity for the arg allele (i.e., arg/arg genotype) at codon 399 of the X-ray cross-complementing protein 1 (XRCC1) gene was associated with a significant increase in toxicity in both treatment groups (p = 0.009). Conclusions: Genetic polymorphisms in DNA damage repair genes XPD and XRCC1 are associated with toxicity in rectal cancer patients receiving CRT. The identification of gene polymorphisms that predict adverse events may help to optimize patient therapy while minimizing morbidities. No significant financial relationships to disclose.
STEM-18CULTURE CONDITION-INDUCED MESENCHYMAL TRANSITION IN PATIENT-DERIVED GLIOBLASTOMA STEM CELLS
Authors: Jian Teng, Cintia Carla da Hora, Rami Kantar, Hiroaki Wakimoto, Tracy Batchelor, Christian Badr, Bakhos Tannous
Journal: Neuro-Oncology (2015)

Rapid tumor growth is often accompanied by increased glycolytic metabolism and production of lactic acid creating an acidic tumor environment. Under these conditions, only tumor cells resistant to low pH are able to survive. Glioma stem cells tend to be localized to tumor niches where limited oxygen availability and low pH are predominant. Two glioma stem cells subtypes, proneural and mesenchymal, have been described with the latter displaying a more aggressive phenotype and increased therapeutic resistance. Plasticity between these two subtypes has been observed during tumor recurrence or in response to radiation therapy. Modeling glioblastoma mesenchymal plasticity could have many clinical implications. Here, we show that certain culture conditions reproducibly trigger mesenchymal transition of primary glioblastoma stem cells neurospheres. We identified a subpopulation of glioblastoma stem cells growing as floating cells even under differentiation conditions in the presence of serum. These floating cells displayed stem-like properties with a molecular and phenotypic mesenchymal signature, including resistance to radiation and targeted therapies along with a more aggressive tumor formation. Our results suggest that acidic pH in the cell culture medium promotes this mesenchymal transition. These findings provide a valuable approach to study phenotypic plasticity of glioblastoma, which could be applied to find novel therapeutic strategies to eradicate this aggressive tumor type and could be extended to other cancer types.
PTH-042 Endogenous cholecystokinin in the regulation of gastric emptying in lean and obese humans
Authors: E A Patel, R B Jones, T J Little, M D Amato, J T McLaughlin, D G Thompson
Journal: Gut (2010)

<h3>Introduction</h3> Cholecystokinin (CCK), a gut peptide released postprandially from the small intestine, has been shown to reduce food intake and slow gastric emptying (GE) in man. Resistance to gut peptides involved in energy homeostasis such as leptin has also been demonstrated in obese individuals. Similarly, a reduction in sensitivity to CCK may lead to increased food intake and ultimately affect body weight. It is not known if the effects of CCK are consistent between obese and lean individuals. The aim of this study was to determine the effect of the CCK1 receptor antagonist, dexloxiglumide, on GE of a nutrient releasing meal, in lean and obese subjects. <h3>Methods</h3> Ten obese (BMI; 47 kg/m<sup>2</sup> ±7) and 10 non-obese (BMI; 22 kg/m<sup>2</sup> ±2) participants ingested the CCK1 receptor antagonist, dexloxiglumide, or placebo. An hour later, 500 ml of skimmed milk containing <sup>13</sup>C-acetate was consumed. A <sup>13</sup>C-acetate breath test was used as a proxy measure for the rate of GE. <h3>Results</h3> GE of skimmed milk was slower in obese subjects when compared to lean subjects in both placebo (p=0.013) and dexloxiglumide conditions (p=0.017). When compared to placebo, dexloxiglumide accelerated GE of skimmed milk in both lean (p=0.034) and obese subjects (p=0.022), however, the percentage increase in GE rate with dexloxiglumide vs placebo was greater in obese compared to the lean subjects (p=0.017). There was a direct relationship between the rate of GE and BMI in both placebo (p=0.00), and dexloxiglumide conditions (p=0.04). <h3>Conclusion</h3> These results demonstrate that the response to dexloxiglumide does not appear to be reduced, but rather increased in obese subjects, suggesting that sensitivity to CCK is not impaired in obesity. These results also suggest an overall slower rate of GE in obese compared to lean subjects, which could be a contributing factor in the pathogenesis of obesity.
Increasing Number of Passes Beyond 4 Does Not Increase Sensitivity of Detection of Pancreatic Malignancy by Endoscopic Ultrasound–Guided Fine-Needle Aspiration
Authors: Mehdi Mohamadnejad, Daniel Mullady, Dayna S. Early, Brian Collins, Carrie Marshall, Sharon Sams, Roy Yen, Mona Rizeq, Maria Romanas, Samia Nawaz, Ozlem Ulusarac, Thomas Hollander, Robert H. Wilson, Violette C. Simon, Vladimir Kushnir, Stuart K. Amateau, Brian C. Brauer, Srinivas Gaddam, Riad R. Azar, Srinadh Komanduri, Raj Shah, Ananya Das, Steven Edmundowicz, V. Raman Muthusamy, Amit Rastogi, Sachin Wani
Journal: Clinical Gastroenterology and Hepatology (2016)
A Phase I Study of XL019, a Selective JAK2 Inhibitor, in Patients with Primary Myelofibrosis, Post-Polycythemia Vera, or Post-Essential Thrombocythemia Myelofibrosis
Authors: Neil P. Shah, Patrycja Olszynski, Lubomir Sokol, Srdan Verstovsek, Ronald Hoffman, Alan F. List, Jorge Cortes, Hagop M Kantarjian, D. Gary Gilliland, Douglas O Clary, Lynne A. Bui, Martha Wadleigh
Journal: Blood (2008)
Abstract 4780: Nucleosome organization and accessibility of p53 response elements in the chromatin context
Authors: Peter R. LoVerso, Victor B. Zhurkin, Feng Cui
Journal: Cancer Research (2015)

Abstract p53 is one of best known human proteins that induces or represses hundreds of genes and plays a pivotal role in preventing tumor development. Recent studies established unambiguously that p53 is a nucleosome-binding protein. The rotational positioning of a nucleosome is critical to determine the accessibility of a p53 site. In particular, the p53 site in a nucleosome is accessible if it is bent in the direction similar to that found in the p53-DNA co-crystals; the site becomes inaccessible if the orientation is changed by ∼180°. Importantly, we have shown that p53 response elements (REs) associated with cell cycle arrest are often exposed on the nucleosomal surface, suggesting a new role of nucleosomes in mediating the p53 binding and subsequent gene induction. The present study aims to make a detailed analysis of nucleosome organization of all p53 functional REs in normal and cancer cells. Published genome-wide nucleosome maps from lymphoblastoid (normal) and K562 (cancer) cell lines are used. In general, the p53 REs are located in nucleosome-enriched regions, in accordance with previous findings that p53 can interact with nucleosomal DNA. At the level of individual sites, the p21 5′ RE resides in a genomic region with high nucleosome occupancy, consistent with earlier studies. The GADD45 RE that was believed to be in nucleosome-free region, is, however, characterized with medium-to-high nucleosome occupancy. To evaluate the accessibility of p53 REs in different functional groups such as cell cycle arrest, apoptosis and DNA repair, we used a more rigorous set of nucleosomes, containing 134 million 147-bp fragments (about 7x genome coverage). The REs in the cell cycle arrest group (such as p21) and the DNA repair group (such as GADD45) are often accessible in the chromatin context, consistent with fast induction of these genes after p53 activation. Interestingly, apoptotic REs are divided - the REs associated with the mitochondrial pathway (BAX and p53AIP1) are accessible, while the REs associated with the death receptor pathway (FAS and KILLER) are inaccessible, suggesting different mechanisms for induction of apoptotic genes in vivo. Finally, we observe a clear correlation between the nucleosome occupancy and accessibility of p53 REs. That is, the REs with the higher nucleosome occupancy tend to be accessible, while the REs with lower nucleosome occupancy are likely to be inaccessible to p53. Citation Format: Peter R. LoVerso, Victor B. Zhurkin, Feng Cui. Nucleosome organization and accessibility of p53 response elements in the chromatin context. [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 4780. doi:10.1158/1538-7445.AM2015-4780
Safety and activity of IPI-504 (retaspimycin hydrochloride) and docetaxel in pretreated patients (pts) with metastatic non-small cell lung cancer (NSCLC).
Authors: G. J. Riely, S. N. Gettinger, R. G. Stoller, N. Y. Gabrail, G. K. Dy, G. J. Weiss, C. Tunkey, G. Skliris, S. Strychor, J. Dunbar, D. DeLucia, R. W. Ross, J. E. Gray
Journal: Journal of Clinical Oncology (2011)

7516 Background: IPI-504, a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17-AAG), is an intravenously (IV) administered heat shock protein 90 (Hsp90) inhibitor that causes degradation of a variety of mutated or amplified oncoproteins. The combination of IPI-504 with taxanes has demonstrated additive activity in murine xenograft tumor models. Methods: An expansion of a Phase Ib trial was undertaken to evaluate IPI-504 in combination with docetaxel in pts with NSCLC and Karnofsky performance status of ≥70. Pts had pathologically confirmed metastatic NSCLC; all had received 1 to 2 prior chemotherapy regimens without prior docetaxel. Docetaxel 75 mg/m2 IV was given once every three weeks (wks), while IPI-504 300 mg/m² IV was administered once per wk. All pts were evaluated for safety, pharmacokinetics and tumor response (RECIST). Archival tissue samples were required for KRAS genotyping. Results: The 23 pts included in this analysis received an average of 4 cycles (range 1-13) on study. Median age was 61 years, 13 (57%) were female, and 18 (78%) were current or former smokers, with a median tobacco exposure of 30 pack-years. The majority of adverse events were Grade 1 or 2, and the most common treatment-related adverse events were fatigue (57% total, 4% ≥Grade 3), diarrhea (35%, 9%), nausea (30%, 13%), vomiting (30%, 13%), neutropenia (30%, 30%), and anemia (26%, 4%). Docetaxel pharmacokinetics were unaltered by IPI-504 co-administration. 6 of the 23 pts (26%) had a partial response (PR), including 3 of 7 pts with squamous cell carcinoma. Efficacy analysis in overall population and exploratory subgroups is below (Table). Conclusions: IPI-504 in combination with docetaxel was well tolerated and resulted in clinical activity in pts with pretreated, metastatic NSCLC. A randomized trial is ongoing to evaluate this combination compared to docetaxel plus placebo in this pt population. Clinical activity. Patients n ORR n, (%) Previously treated NSCLC 23 6 (26) Current or former smokers 18 6 (33) Squamous cell carcinoma 7 3 (43) KRAS wild type 13 4 (31) Abbreviation: ORR, overall response rate (all PRs).
The safety and effectiveness of ledipasvir−sofosbuvir in adolescents 12‐17 years old with hepatitis C virus genotype 1 infection
Authors: William F. Balistreri, Karen F. Murray, Philip Rosenthal, Sanjay Bansal, Chuan‐Hao Lin, Kathryn Kersey, Benedetta Massetto, Yanni Zhu, Bittoo Kanwar, Polina German, Evguenia Svarovskaia, Diana M. Brainard, Jessica Wen, Regino P. Gonzalez‐Peralta, Maureen M. Jonas, Kathleen Schwarz
Journal: Hepatology (2016)

No all-oral, direct-acting antiviral regimens have been approved for children with chronic hepatitis C virus (HCV) infection. We conducted a phase 2, multicenter, open-label study to evaluate the efficacy and safety of ledipasvir-sofosbuvir in adolescents with chronic HCV genotype 1 infection. One hundred patients aged 12-17 years received a combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir once daily for 12 weeks. On the tenth day following initiation of dosing, 10 patients underwent an intensive pharmacokinetic evaluation of the concentrations of sofosbuvir, ledipasvir, and the sofosbuvir metabolite GS-331007. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at 12 weeks posttreatment. Median age of patients was 15 years (range 12-17). A majority (80%) were HCV treatment-naive, and 84% were infected through perinatal transmission. One patient had cirrhosis, and 42 did not; in 57 patients the degree of fibrosis was unknown. Overall, 98% (98/100; 95% confidence interval 93%-100%) of patients reached sustained virologic response at 12 weeks. No patient had virologic failure. The 2 patients who did not achieve sustained virologic response at 12 weeks were lost to follow-up either during or after treatment. The three most commonly reported adverse events were headache (27% of patients), diarrhea (14%), and fatigue (13%). No serious adverse events were reported. Area under the concentration-time curve (tau) and maximum concentration values for sofosbuvir, ledipasvir, and GS-331007 were within the predefined pharmacokinetic equivalence boundaries of 50%-200% when compared with adults from phase 2 and 3 studies of ledipasvir and sofosbuvir.Ledipasvir-sofosbuvir was highly effective at treating adolescents with chronic HCV genotype 1 infection; the dose of ledipasvir-sofosbuvir currently used in adults was well tolerated in adolescents and had an appropriate pharmacokinetic profile. (Hepatology 2017;66:371-378).
Effect of Stem Cell Source on Transplant Outcomes in Adults with Acute Leukemia: A Comparison of Unrelated Bone Marrow (BM), Peripheral Blood (PB) and Cord Blood (CB)
Authors: Mary Eapen, Vanderson Rocha, Andromachi Scaradavou, Eliane Gluckman, Mary Laughlin, Cladd Stevens, Mary M. Horowitz, John E. Wagner
Journal: Blood (2008)