tbuckley/cabot-search huggingface dataset:
ACTR-12. PHASE I/II STUDY OF SINGLE AGENT IBRUTINIB IN RECURRENT/REFRACTORY PRIMARY (PCNSL) AND SECONDARY CNS LYMPHOMA (SCNSL)
Authors: Christian Grommes, Igor Gavrilovic, Thomas Kaley, Craig Nolan, Antonio Omuro, Julia Wolfe, Elena Pentsova, Vaios Hatzoglou, Ingo Mellinghoff, Lisa DeAngelis
Journal: Neuro-Oncology (2016)

PCNSL is an aggressive primary brain tumor. Outcome and treatment options are poor for recurrent/refractory (r/r) disease. Ibrutinib has shown promising clinical response in some B-cell malignancies. This trial investigates Ibrutinib in patients with r/r PCNSL/SCNSL. Eligible patients had r/r PCNSL/SCNSL, age≥18, ECOG≤2, normal end-organ function, unrestricted number of CNS directed prior therapies. Systemic disease needed to be absent in SCNSL patients. Twenty patients were enrolled (3 at 560mg; 17 at 840mg). Median age: 69 (range 21–85); 12 were women. Median ECOG was 1 (0: 2, 1: 12, 2: 6). 65% had PCNSL; 35% SCNSL. Eleven had parenchymal disease, 3 isolated cerebrospinal fluid (CSF) involvement and 6 both. The median prior CNS directed therapy was 2; all methotrexate regimens. Despite clinical and radiographic response, 2 patients withdrew and 1 stopped due to toxicity (fungal infection). Four grade 4 toxicities were observed in 4 patients (lymphopenia (2), sepsis (1), neutropenia (1)). Ten patients developed grade 3 toxicities, including lymphopenia in 3 patients, thrombocytopenia (2), hyperglycemia (2), lung infection (2), neutropenia (1), colitis (1), and fungal encephalitis (1). The most common toxicities were hyperglycemia, anemia, and thrombocytopenia. After a median follow-up of 147 days, 18/20 patients were evaluated for response: 8 CR (3 in CSF; 5 in parenchyma), 6 PR, 1 SD and 3 PD; 75% (15/20) ORR. In 5 patients response has not been confirmed in a 2nd assessment. The median PFS is 5.5 months. The mean Ibrutinib concentration in the CSF at day 1 and 29 is 1.75ng/mL (3.97nM) and 2.51ng/mL (5.6nM). The CSF Ibrutinib concentrations reached in patients is above the IC50 (1nM) required in vitro to reduce growth of lymphoma cells. Patients with CNS lymphoma tolerate Ibrutinib with manageable toxicities. Ibrutinib might be a therapeutic alternative that should be further investigated in r/r CNS lymphoma patients.
OC-005 Does irritable bowel syndrome smell different from irritable bowel disease? A study of faecal volatile analysis in inflammatory bowel syndrome
Authors: I Ahmed, R Greenwood, C S Probert
Journal: Gut (2010)

<h3>Introduction</h3> Irritable bowel syndrome (IBS) is considered to be a functional disorder of gastrointestinal tract, the cause of which remains inadequately identified. Since there are no diagnostic markers, symptoms based criteria are currently used to confirm the diagnosis. Due to similar clinical presentation, it is yet a challenging task to distinguish it from inflammatory bowel disease (IBD) in both primary care and specialist settings. Volatile compounds are chemical which may be emitted from faeces and reflect the pathophysiological environment of the bowel. Understanding changes in their pattern could provide diagnostic information about various bowel disorders. <h3>Methods</h3> We aimed to analyse the faecal volatile pattern of patients with diarrhoea predominant IBS and compare it with IBD. We studied 90 individuals, 20 from diarrhoea predominant IBS, 50 from active IBD (CD=25, UC 25), and 20 from healthy individuals. Diagnosis of IBS was confirmed using symptoms based criteria (Manning, Rome III) while all individual with IBD had histological diagnosis. Fresh samples were aliquoted in 10 ml vials and faecal volatile were extracted using solid phase micro-extraction fibre injected into the head space and were analysed by gas chromatography/mass spectrometery. Volatile compounds were identified using NIST library and manual visualisation using fragmentation pattern. <h3>Results</h3> From 400 VOCs identified, 25 were selected using univariate analysis at 0.007 significant level. These were used in forward stepwise entry analysis to construct a predictive model which showed significant value in separating IBS from active IBD and healthy controls. On cross-validation, the IBS: IBD model remains significantly stable: 90% of patients were correctly diagnosed. This model has sensitivity of 95% and NPV 90%. <h3>Conclusion</h3> These interim results show that VOCs may be used to distinguish IBS from IBD and either from healthy controls. Further data will provide more information to identify this group more clearly from IBD and allow us to further validate this model.
The impact of fasting glucose on clinical-pathological features in epithelial ovarian cancer: results from a historic cohort
Authors: M. Barba, L. Pizzuti, L. Conti, C. Mandoj, G. Digiesi, A. Antenucci, D. Sergi, L. Di Lauro, A. Amodio, S. Carpano, F. Sperati, M. Valle, A. Garofalo, E. Vizza, C. Vincenzoni, G. Corrado, M. Maugeri-Saccà, P. Vici
Journal: Annals of Oncology (2015)
Genetic Variants of TNFAIP3 in Patients with HCV Related Lymphoma Are Associated with the Presence of Rheumatoid Factor (RF)
Authors: Gaetane Nocturne, Saida Boudaoud, Caroline Besson, Frederic Davi, Danielle Canioni, Patrice Cacoub, Olivier Hermine, Xavier Mariette
Journal: Blood (2014)
The Effect of Bortezomib, Cyclophosphamide, and Filgrastim On Complete Remission Rates and CD34+ Stem Cell Collections in Multiple Myeloma.
Authors: Tomer Mark, Megan C. Manco, Maureen Lane, Maureen Ward, Donna Skerrett, Scott Ely, Michael W. Schuster, Tsiporah B Shore, Roger N Pearse, Faiza Zafar, Selina Chen-Kiang, Morton Coleman, Ruben Niesvizky
Journal: Blood (2009)
Abstract 2166: Analyses of protein expression of PI 3-kinase/AKT signaling in response to altered expression of motor protein MYO1C
Authors: Kittichate Visuttijai, Katarina Ejeskär, Afrouz Behboudi
Journal: Cancer Research (2015)

Abstract In the previous work, a minimal region of recurrent deletion distal to the Tp53 gene was identified in BDII rat model for endometrial adenocarcinoma and the MYO1C gene was singled out as the tumor suppressor candidate in this region. Myo1c can bind to PIP2, the substrate of PI3-kinase, as well as to the mTOR complex, indicating a role for MYO1C in the PI3-kinase pathway. In this study, we assessed protein levels of 12 members of PI3-kinase/AKT signaling pathways in transient transfected HeLa cells expressing increasing amounts of MYO1C using Western blotting and densitometry analyses. Results revealed decreased protein levels of PTEN, AKT, and phosphorylated AKT, at both residues T308 and S473, and an increased expression of p110α protein in the cells transfected with the MYO1C gene expression constructs compared to the control cells transfected with empty plasmid. We next investigated potential effect of MYO1C protein depletion on serum-induced activation (phosphorylation) of AKT in the MCF10A cells that has de novo expression of MYO1C protein. Following serum stimulation, AKT was rapidly phosphorylated in its residue S473 (pAKTS473) in the cells transfected with MYO1C-siRNA, but with significantly lesser extent in the control cells. Overall, a negative correlation between the protein expression of MYO1C and AKT expression/activation was suggested, signifying a role for MYO1C as a negative regulator of PI3-kinsase/AKT signaling pathway. This is in agreement with the initial hypothesis of involvement of MYO1C in tumorigenesis pathways through its potential tumor suppressor activity. Further studies are required to fully understand the functional contribution of MYO1C to tumor development. Citation Format: Kittichate Visuttijai, Katarina Ejeskär, Afrouz Behboudi. Analyses of protein expression of PI 3-kinase/AKT signaling in response to altered expression of motor protein MYO1C. [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 2166. doi:10.1158/1538-7445.AM2015-2166
Autologous Stem Cell Transplantation (ASCT) for Elderly Patients (≥ 60 Years) with Non-Hodgkin’s Lymphoma (NHL): An Analysis Based on EBMT Registry.
Authors: Esa Jantunen, Carmen Canals, Didier Blaise, Alessandro Rambaldi, Herve Tilly, Eulogio Conde, Christian Gisselbrecht, Peter Dreger, G.J. Ossenkoppele, Bernardino Allione, M. Pfreudschuh, Charles Craddock, Anna Sureda
Journal: Blood (2007)
Signaling Profile and Anti-Tumor Activity of the Novel HSP90 Inhibitor NVP-AUY922 in Multiple Myeloma.
Authors: Thorsten Stühmer, Angela Zöllinger, Daniela Siegmund, Manik Chatterjee, Evelyn Grella, Stefan Knop, Martin Kortüm, Christian Unzicker, Michael R. Jensen, Cornelia Quadt, Patrick Chène, Joseph Schoepfer, Carlos Garcia-Echeverria, Herrmann Einsele, Harald Wajant, Ralf C. Bargou
Journal: Blood (2007)
Pharmacogenomic Study of Carfilzomib in Relapsed/Refractory Multiple Myeloma Suggests That Carfilzomib Is a More Potent Proteasome Inhibitor Than Bortezomib
Authors: Qing Zhang, Christoph Heuck, Ya-Wei Qiang, Frits van Rhee, Sarah Waheed, Clyde Bailey, Susan B. Panozzo, Joshua Epstein, Bart Barlogie, Saad Z Usmani
Journal: Blood (2012)
Abstract 2775: Prognostic significance of triple miRNAs, miR-9, miR-221, and miR-200c in breast cancer
Authors: Chun-Wen Cheng, Jyh-Cherng Yu, Yi-Hsien Hsieh, Po-Ming Chen, Hsiao-Wei Wang, Hui-Chun Wang, Chen-Yang Shen
Journal: Cancer Research (2015)

Abstract MicroRNAs (miRNA) mediated epithelial-mesenchymal transition have been considered as a major event in cancer aggression and accounted for cancer progression. However, clinical association between synergistic effect of deregulated expression levels of the EMT-related miRNAs, including miR-9, miR-221, and miR-200c, and breast cancer prognoses remains underestimated. Initially, tissue samples were from 184 enrolled female patients, with invasive ductal carcinoma, followed up for more than ten years. miRNA expression levels between paired laser capture microdissected tumor and non-tumor cells from the primary tumor site was analyzed by quantitative real-time PCR (qRT-PCR). Differentially expressed status of the target miRNA in tumors relative to non-tumor parts (T/N ratio) was assessed their relationship with pathological characteristics and clinical outcomes of breast cancer. While miR-9 or miR-221 showed significantly higher expression level in tumor cells compared to the non-tumor ones, miR-200c exhibited the opposite (p&amp;lt;0.05). Based on the ROC curve, T/N ratio of 2.80- and 1.96-fold increase for miR-9 and miR-221, whereas, 1.80-fold decrease for miR-200c as risk genotypes, respectively. According to these cutoffs, high miR-9 expression in tumors was associated with advanced tumor stages (p&amp;lt;0.05); significant risk associations were shown between LNM-positive tumors and miR-9 (OR = 3.12) or miR-221 (OR = 1.88) (p&amp;lt;0.05). A joint effect on risk elevation of tumor invasion and nodal metastasis was seen in tumors having miR-9 overexpression alongside increased miR-221 or reduced miR-200c expression (p-trend&amp;lt;0.05). Considering the combined effect of these three miRNAs, patients harboring greater numbers of deregulated expression levels in tumors were found to have a higher risk of poor prognoses (high-stage (p-trend = 0.003) and LNM (p-trend = 0.028)) and reduced probability of 10-year overall survival, showing hazard ratio of 2.39 (p&amp;lt;0001 for trend test). In conclusion, deregulated levels of miR-9, miR-221, and miR-200c, may serve as prognostic biomarkers to predict disease progression and shorter OS in breast cancer. Citation Format: Chun-Wen Cheng, Jyh-Cherng Yu, Yi-Hsien Hsieh, Po-Ming Chen, Hsiao-Wei Wang, Hui-Chun Wang, Chen-Yang Shen. Prognostic significance of triple miRNAs, miR-9, miR-221, and miR-200c in breast cancer. [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 2775. doi:10.1158/1538-7445.AM2015-2775
Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ‐glutamyltransferase cholestasis
Authors: Yi‐Ling Qiu, Jing‐Yu Gong, Jia‐Yan Feng, Ren‐Xue Wang, Jun Han, Teng Liu, Yi Lu, Li‐Ting Li, Mei‐Hong Zhang, Jonathan A. Sheps, Neng‐Li Wang, Yan‐Yan Yan, Jia‐Qi Li, Lian Chen, Christoph H. Borchers, Bence Sipos, A.S. Knisely, Victor Ling, Qing‐He Xing, Jian‐She Wang
Journal: Hepatology (2016)

Hereditary cholestasis in childhood and infancy with normal serum gamma‐glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B ) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low‐GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow‐up. Liver biopsy specimens revealed giant‐cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP‐deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated‐cholestasis patients (11 of 38 vs. 0 of 13). Conclusion : MYO5B deficiency may underlie 20% of previously undiagnosed low‐GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (H epatology 2017;65:1655‐1669).
Ventricular arrhythmias in children The validity of exercise stress tests for their diagnosis and management.
Authors: Yoshiho Ryujin, Yoshio Arakaki, Osahiro Takahashi, Tetsuro Kamiya
Journal: Circulation (1984)

One hundred ninety-six children ranging in age from 4 years to 15 years with premature ventricular contraction (PVC) on a resting electrocardiogram (ECG) underwent exercise tests and 29 of them were found to have significant ventricular arrhythmias. They included 8 patients with 2 PVC's in row, 8 patients with 3-4 PVC's in row, and 13 patients with more than 5 PVC's in row (ventricular tachycardia: VT). These 29 patients were evaluated with exercise tests by two-step exercise ECG (TSE) and by treadmill (TM), and with 24 hour continuous ECG monitoring (Holter monitoring). 141 ECG's, 77 TSE's, 77 TM's and 46 Holter monitoring were obtained in total, and the incidence of the each study revealing findings compatible with the final diagnosis was 3%, 15%, 51% and 26%, respectively. For detection of 2 PVC's in row, the sensitivity of TSE and TM was not different, but for picking up 3-4 PVC's in row and VT, TM was significantly superior to TSE. Among the VT patients, there were a few cases in whom neither TM nor Holter monitoring alone was sufficient to confirm the diagnosis. Children with symptoms suggestive of ventricular arrhythmias should be carefully evaluated with a combination of exercise tests and Holter monitoring.
Abstract 2314: d16HER2 splice variant regulates the activity of HER2-positive breast cancer-initiating cells
Authors: Lorenzo Castagnoli, Ada Koschorke, Gaia C. Ghedini, Lorenzo Galvani, Valentina Ciravolo, Cristina Ghirelli, Arianna Palladini, Alessia Lamolinara, Manuela Iezzi, Pier Luigi Lollini, Tiziana Triulzi, Patrizia Nanni, Elda Tagliabue, Serenella M. Pupa
Journal: Cancer Research (2015)

Abstract The transmembrane tyrosine kinase receptor HER2, overexpressed in ∼20% of human breast cancers (BCs), identifies an aggressive tumor subtype and is reportedly an important regulator of breast cancer-initiating cell activity (BCIC). We found that ∼90% of HER2+ BC patients constitutively express a splice isoform of wild-type HER2 (WTHER2) gene characterized by the lack of exon 16 (d16HER2), a deletion that promotes the generation of a particularly aggressive HER2 isoform and that forms stable and constitutively activated d16HER2 homodimers. Our comparison of the tumorigenic potential of the human d16HER2 and WTHER2 genes in the corresponding transgenic mouse models revealed a significantly shorter tumor latency period (p&amp;lt; 0.001) and a higher tumor incidence in the d16HER2 mice (p&amp;lt;0.001), suggesting a role for this variant in HER2-driven activation of BCICs. In this context, our preliminary analyses of HER2-positive primary mammary tumor cell lines MI6 and MI7 derived from spontaneous transgenic d16HER2 mice showed a significantly higher mammosphere-forming efficiency and higher levels of stem cell marker transcripts, including CD44, Wnt, Notch and Bmi1, compared to transgenic mouse WTHER2 tumor cells (WTHER2_1 and WTHER2_2). Mammospheres generated from human HER2-overexpressing breast cancer cell lines BT474 and MDA-MB-361, which also express the d16HER2 variant, exhibited an increase in the relative abundance of d16HER2 mRNA compared with that in the same parental cells cultured in adhesion conditions, as indicated by qPCR analyses. Experiments in mice injected into the mammary fat pad with the d16HER2- and WTHER2-positive cell lines at different serial dilutions indicate a consistently higher “stemness potential” of MI6 and MI7 cells compared to WTHER2_1 and WTHER2_2 cells, strongly suggesting that the d16HER2 variant plays a greater role than WTHER2 in regulating BCICs of HER2-driven mammary tumors. Supported by Minister of Health and AIRC Citation Format: Lorenzo Castagnoli, Ada Koschorke, Gaia C. Ghedini, Lorenzo Galvani, Valentina Ciravolo, Cristina Ghirelli, Arianna Palladini, Alessia Lamolinara, Manuela Iezzi, Pier Luigi Lollini, Tiziana Triulzi, Patrizia Nanni, Elda Tagliabue, Serenella M. Pupa. d16HER2 splice variant regulates the activity of HER2-positive breast cancer-initiating cells. [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 2314. doi:10.1158/1538-7445.AM2015-2314
Abstract #2675: Boswellic acids induced apoptosis in human glioblastoma T98G (p53 mutant) and U87MG (p53 wild-type) cell lines
Authors: Arabinda Das, Naren Banik, Swapan Ray
Journal: Cancer Research (2009)

Glioblastoma is the deadliest brain tumor in humans and it remains incurable. Conventional therapeutic strategies (surgery, radiation therapy, and chemotherapy) for glioblastoma still do not yield most satisfying results and the adjuvant chemotherapy fails to date to increase survival time significantly in glioblastoma patients. To improve the outcome of glioblastoma treatment, additional therapeutic strategies are urgently necessary. Boswellic acids are pentacyclic triterpenes found in gum resin of Boswellia serrata, which produces various phytochemical anti-inflammatory agents that may be alternative drugs to corticosteroids in the treatment of cerebral edema. Here, we report that two boswellic acids, beta-boswellic acid (BBA) and 11-keto-beta-boswellic acid (KBBA), at low micromolar concentrations show cytotoxic effects in two human glioblastoma T98G (p53 mutant) and U87MG (p53 wild-type) cell lines. We studied the abilities of BBA and KBBA for induction of apoptotic death in T98G and U87MG cells and the molecular pathways leading to apoptosis. The viability of T98G and U87MG cells decreased following treatment with increasing doses of BBA and KBBA. Our dose-response studies indicated that treatment of T98G and U87MG cells with 25 \#956;M BBA and 25 \#956;M KBBA for 24 h could produce morphological and biochemical features of apoptosis. Apoptosis was associated with an increase in intracellular free [Ca2+] as determined by fura-2 assay. Western blotting demonstrated that apoptosis occurred due to an increase in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c into the cytosol, and activation of calpain, caspase-9, and caspase-3. Increased activities of caspase-9 and caspase-3 were also confirmed by colorimetric assays. These results indicated that BBA and KBBA could be used at low doses for activation of proteolytic activities of calpain and caspases for induction of apoptosis in human glioblastoma T98G and U87MG cells. Our studies also suggest that BBA and KBBA mediated induction of apoptosis does not depend on the functional p53 status of the human glioblastoma cells. Further studies in different animal models of glioblastoma are warranted to determine whether boswellic acids may be useful as highly potent phytotherapeutic agents for the management of human glioblastomas in vivo. This investigation was supported in part by the R01 grants (CA-91460 and NS-57811) from the National Institutes of Health (Bethesda, MD, USA).  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2675.
Epigenetic profiling of prostate cancer tissue to identify men with high-risk disease.
Authors: Leander Van Neste, Jeffrey Falk, Ming-Chou Lee, Joseph Bigley, Wim Van Criekinge, E. David Crawford
Journal: Journal of Clinical Oncology (2014)

197 Background: Prostate cancer (PCa) prognosis and aggressiveness are guided by Gleason Scores (GS). Moreover, biopsied prostate tissue might not be representative of the actual disease. Epigenetics could provide a quantitative method for confirming or upgrading disease status obtained by GS, providing additional information with regard to aggressiveness. Methods: Eighty-four prostatectomy samples from PCa patients with GS6 (n=6), GS3+4 (n=41), GS4+3 (n=26) and GS greater than or equal to 8 (n=11) were epigenetically profiled, for GSTP1, APC, RASSF1, RARB, and GAL3 methylation, using methylation-specific PCR. Unsupervised hierarchical clustering, based on Ward’s method, was performed to discover an association between DNA-methylation patterns and GS. Methylation ratios were scaled across all samples by calculating, per gene, a Z-score. Results: Hierarchical clustering analysis resulted in three distinct clusters. One cluster with a relative, general depletion of methylation, a second cluster with high methylation levels for most genes, particularly for RARB, and a third cluster exhibiting intermediate methylation signals and lower, but distinct, RARB methylation. Kendall’s rank correlation tau indicated a significant positive correlation between GS and methylation levels of all five genes, with tau ranging from 0.010 to 0.376 (all p values&lt;0.05). Methylation levels of all five genes were significantly lower in the samples with GS less than or equal to 3+4 versus those with GS greater than or equal to 4+3 (all p values&lt;0.05). Clustering showed that 100% of the GS6 and 80% of the GS3+4 patient’ samples were associated with low methylation signals. In contrast, 81% and 82% of the GS4+3, and GS greater than or equal to 8 samples respectively, fell into the category with intermediate to high methylation levels. Conclusions: Methylation levels of all genes correlated with GS and were significantly lower in patient' samples with GS6 and GS7 (3+4) compared to GS7 (4+3) and GS greater than or equal to 8. This study shows that epigenetic profiling of selected genes has prognostic value and may help to identify patients with aggressive PCa.
Prolonged Survival of Neonatal Platelets Helps Meet the High Platelet Demand During This Period of Rapid Growth, and Is Associated with High Bcl-2 Levels
Authors: Zhi-Jian Liu, Karin M. Hoffmeister, Zhongbo Hu, Chaitanya Chavda, Francisca Ferrer-Marin, Martha Sola-Visner
Journal: Blood (2011)