tbuckley/cabot-search huggingface dataset:
Cross-sectional surveillance of Middle East respiratory syndrome coronavirus (MERS-CoV) in dromedary camels and other mammals in Egypt, August 2015 to January 2016
Authors: Mohamed Ali, Rabeh El-Shesheny, Ahmed Kandeil, Mahmoud Shehata, Basma Elsokary, Mokhtar Gomaa, Naglaa Hassan, Ahmed El Sayed, Ahmed El-Taweel, Heba Sobhy, Fasina Folorunso Oludayo, Gwenaelle Dauphin, Ihab El Masry, Abebe Wossene Wolde, Peter Daszak, Maureen Miller, Sophie VonDobschuetz, Emma Gardner, Subhash Morzaria, Juan Lubroth, Yilma Jobre Makonnen
Journal: Eurosurveillance (2017)

A cross-sectional study was conducted in Egypt to determine the prevalence of Middle East respiratory syndrome coronavirus (MERS-CoV) in imported and resident camels and bats, as well as to assess possible transmission of the virus to domestic ruminants and equines. A total of 1,031 sera, 1,078 nasal swabs, 13 rectal swabs, and 38 milk samples were collected from 1,078 camels in different types of sites. In addition, 145 domestic animals and 109 bats were sampled. Overall, of 1,031 serologically-tested camels, 871 (84.5%) had MERS-CoV neutralising antibodies. Seroprevalence was significantly higher in imported (614/692; 88.7%) than resident camels (257/339; 5.8%) (p < 0.05). Camels from Sudan (543/594; 91.4%) had a higher seroprevalence than those from East Africa (71/98; 72.4%) (p < 0.05). Sampling site and age were also associated with MERS-CoV seroprevalence (p < 0.05). All tested samples from domestic animals and bats were negative for MERS-CoV antibodies except one sheep sample which showed a 1:640 titre. Of 1,078 camels, 41 (3.8%) were positive for MERS-CoV genetic material. Sequences obtained were not found to cluster with clade A or B MERS-CoV sequences and were genetically diverse. The presence of neutralising antibodies in one sheep apparently in contact with seropositive camels calls for further studies on domestic animals in contact with camels.
ESR-alpha promoter methylation to predict survival in low-grade ovarian cancer.
Authors: Verena Engelstaedter, Rong Shi, Sabine Heublein, Christina Kuhn, Klaus Friese, Doris Mayr, Udo Jeschke
Journal: Journal of Clinical Oncology (2012)

e15529 Background: Ovarian cancer is one of the most lethal gynecologic malignancies and the leading cause of death among women with gynecological cancers. Different molecular markers have been studied for their prognostic relevance, but to date only CA 12-5 is used in routine diagnostic. Aberrant methylation of the estrogen receptor promoter (ESRp) was first described in colorectal cancer. Previous studies that described methylation of the ESRp in ovarian cancer suggested a potential role in cancer development. The aim of this study was to examine the methylation of the ESRp in a cohort of ovarian cancer patients in regard to its prognostic relevance. Methods: The study cohort consisted of 77 ovarian cancer patients that were diagnosed between 2000 and 2009 at the Department of OBGYN of the LMU Munich. A total of 50 patients died, 25 are still alive, 2 were lost to follow-up. Genomic DNA was isolated from paraffin-embedded cancer tissue and followed by bisulfite treatment. For detection of the methylated ESRp we used a sensitive real-time PCR. Results: Survival was significantly shorter for patients with aberrant promoter methylation within the subgroup of borderline, G1 and G2 tumors (31 patients; survival for methylated cases was 3.48 vs 4.91 years for unmethylated cases (p=0.010)). Within the small subgroup of borderline and G1 tumors (10 patients) survival for methylated cases was 4.73 vs 6.08 years for unmethylated cases (p=0.014). No significant difference of survival was observed for high grade (G3) ovarian cancer patients (p=0.745). Conclusions: We demonstrated for the first time that the methylation status of the ESRp might be a promising prognostic marker in ovarian cancer. ESRp methylation does not seem to be of prognostic relevance in high-grade ovarian cancer. In our study cohort a three-step grading system was used, but recent publications favor a two-step grading system. Thus, the G2 cases should be reevaluated to see whether they are G1 or G3. The difference in tumor etiology of low and high grade ovarian cancer might be responsible for the different prognostic relevance of ESRp methylation. Since our subgroup of borderline and G1 tumors is very small, these are preliminary results that have to be confirmed in a larger patient cohort.
IBL2001: Phase (ph) I/II study of a novel dose-dense (dd) schedule of indibulin for the treatment of metastastic breast cancer.
Authors: Tiffany A. Traina, Clifford Hudis, Joseph Gonzalez, Stephen Patrick Anthony, David A. Smith, Jason Claud Chandler, Jaroslaw Jac, Hagop Youssoufian, Larry Norton
Journal: Journal of Clinical Oncology (2012)

TPS1143 Background: Indibulin (Zybulin, ZIO‑301) is a new, synthetic agent that inhibits tumor cell growth at the G2/M phase through destabilization of microtubule dynamics. It binds tubulin at a different site than taxanes and vinca alkaloids. Indibulin does not interact with acetylated (neuronal) tubulins and has not exhibited the neurotoxicity associated with other tubulin binders. Indibulin has potent antitumor activity in human cancer cell lines, including multidrug-, taxane-, and vinblastine-resistant lines. Norton-Simon modeling based on cell line data suggested that dd administration could optimize efficacy while limiting toxicity. Methods: Eligible are patients (pts) with metastatic or unresectable locally advanced breast cancer, measurable or non-measurable disease, and any number of prior therapies. The objective of the Ph I portion is to determine the maximum tolerated dose (MTD) of indibulin when given in a dd fashion (5 days treatment, 9 days rest (14 total) using standard 3+3 dose escalation schema. Ph II will seek to estimate the proportion of pts progression free at 4 months when treated with indibulin at the dose determined in the Ph I. Secondary endpoints are overall response rate, proportion of subjects with stable disease &gt;6 months and toxicity profile of indibulin. Optimal Simon two-stage design with an unpromising rate of pts who have not progressed at four months as 20% and a promising rate of 40% with a type I error of 5% and power of 80% will be used. 13 pts will initially enter the 1 st stage of the ph II portion. If there are 3 or fewer pts who do not experience disease progression at 4 months in the first stage of ph II, the study will be terminated and declared to have a negative result. If 4 or more pts do not progress at 4 months, enrollment in the ph II of the study will be extended to 43 pts. A total of 45 pts will be enrolled to allow for a 5% drop out rate to account for pts who may not be evaluable for the primary endpoint due to toxicity or study withdrawal rather than progression of disease or death prior to 4 months. If ≥13 out of 43 pts are progression-free at 4 months, the study will be considered to have a positive result and indibulin would be considered worthy of further testing in this disease.
Biomarker modulation in patients (pts) receiving TRC105 (T) and bevacizumab (B) in a phase Ib clinical trial.
Authors: Yingmiao Liu, Jeffrey Melson Clarke, Mark D. Starr, John C. Brady, Herbert Pang, Christel Rushing, Delia Alvarez, Bonne J. Adams, Charles P. Theuer, Herbert Hurwitz, Andrew B. Nixon
Journal: Journal of Clinical Oncology (2014)

11020 Background: Endoglin (END; CD105) is a membrane-bound cell surface receptor expressed on proliferating endothelial cells implicated in resistance to VEGF inhibition. T, an anti-End monoclonal antibody, potentiates anti-VEGF therapy in in vitro and in vivo models. The combination of T plus B was well tolerated and was active in pts who progressed on prior B treatment. Methods: Pts with advanced refractory solid tumors were treated with escalating doses of T plus B. Pts received 1 week of B monotherapy prior to the addition of T. Thirty-eight biomarkers related to tumor growth, angiogenesis, and inflammation were analyzed using an optimized multiplex ELISA platform. Samples from 38 pts were collected at baseline (BL), 1 week (C1D8), 2 week (C1D15), 4 week (C2D1), and end of study (EOS). Biomarker concentrations on study were compared to baseline using the Wilcoxon signed rank test with statistical significance assumed at p<0.05. Results: After 1 week of B monotherapy (C1D8), PlGF was elevated and ANG-2, soluble END (sEND), TSP2, and VEGFR1 were decreased. Following the addition of T, only Ang-2 remained significantly decreased, while the following analytes were significantly elevated at C1D15, C2D1 and EOS: CRP, sEND, E-Selectin, IL-6, PAI-1 (active and total), P-Selectin, SDF-1, TGF-b1, and VCAM-1. Increases in sEND and PlGF are consistent with observations from pts treated with either T or B alone, respectively. The inflammatory markers, CRP and IL-6, and TGFb-regulated proteins, PAI-1 active and sEND, all exhibited greater than a 5-fold increase on average at EOS. Interestingly, the elevation of the END ligand, TGFb1, in response to T plus B treatment, has not been observed in pts treated with either agent alone. Conclusions: Treatment of pts with either T or B alone is associated with modulation of multiple angiogenic and inflammatory biomarkers. However, the combination of both agents led to increases in many inflammatory and TGFb-related proteins that persisted throughout the study. The differences across the biomarker patterns from pts treated with T plus B suggest increased bioactivity for the combination and support the role of T potentiating anti-VEGF therapies in pts.
Clinical benefit of second EGFR-TKI retreatment on overall survival in patients with advanced non-small-cell lung cancer harboring EGFR-mutation positive after failure of the initial EGFR-TKI treatment: A retrospective analysis.
Authors: Masanao Nakashima, Takashi Hirose, Yasunari Oki, Yasunori Murata, Tomohide Sugiyama, Hiroo Ishida, Kentaro Okuda, Toshimitsu Yamaoka, Tohru Ohmori, Tsukasa Ohnishi
Journal: Journal of Clinical Oncology (2013)

e19164 Background: The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) bring the best result to EGFR-mutation positive non-small cell lung cancer patients, but most lead to drug resistance. These acquired resistances are associated with T790M mutation or Met amplification, HGF expression. To assess whether affects overall survival in these patients, we did a retrospective study comparing survival outcomes in 2 nd EGFR-TKI treated patients with controls without 2 nd EGFR-TKI screened during the same time period. Methods: We examined overall survival in thirty-two of 52 patients with advanced, EGFR-mutation-positive NSCLC who treated 1 st EGFR-TKI (gefitinib) from January 2009 to December 2012. We identified 16 patients who were given 2 nd EGFR-TKI (erlotinib) after failure of the initial gefitinib treatment (retreatment group) with 16 patients who were not given 2 nd EGFR-TKI but given only chemotherapy (control group), 20 patients who might treat with 2 nd EGFR-TKI or chemotherapy at that time were excluded in progress after failure of the initial gefitinib treatment. To assess differences in overall survival, we assessed subsets of clinically comparable 2 nd EGFR-TKI retreatment group. Results: Among 16 patients who were given 2 nd EGFR-TKI, retreatment group who were given one or two cytotoxic chemotherapy from 1 st EGFR-TKI to 2 nd EGFR-TKI, median overall survival from initiation of the diagnosis with advanced IIIB/IV stage or surgical recurrent NSCLC was 24.2 months. 16 patients of control group who were given from second to seven line cytotoxic chemotherapy, overall survival was 15.8 months (p=0.021). Retreatment group who were given 2 nd EGFR-TKI was significantly longer than control group in EGFR mutation positive patients. Response rate and disease control rate with 2 nd EGFR-TKI retreatment are 12.5% and 31.3%. Conclusions: In patients with advanced, EGFR mutation positive NSCLC, retreatment group who were given 2 nd EGFR-TKI therapy was associated with improved survival compared with control group who were given only cytotoxic chemotherapy.
Histopathological markers at craniotomy and outcome in breast cancer brain metastases.
Authors: Megan Jean McKee, Dimitri G. Trembath, Allison Mary Deal, Kevin Keith, Bentley R. Midkiff, Nana Nikolaishvilli-Feinberg, Amy Garrett, Kimberly L. Blackwell, Jose Pablo Leone, Ronald L. Hamilton, Adam Brufsky, Aki Morikawa, Edi Brogi, Andrew David Seidman, Matthew G. Ewend, Stergios J. Moschos, Carey K. Anders
Journal: Journal of Clinical Oncology (2015)

2027 Background: Brain metastases (BM) are a devastating consequence of advanced breast cancer (BC). Little is known about the clinical significance of histopathological features associated with BM tumor and stroma. Lymphocytic infiltrate (LymInf) has been shown to be predictive of response to therapy in primary BC and prognostic in patients (pts) with triple negative (TN) BC. Increased LymInf has been associated with better prognosis in melanoma BM. In a 3-institution cohort, we report on the association of LymInf and other histopathological markers in BCBM with prognosis. Methods: Under IRB approval, a clinically-annotated tumor bank of 83 BCBM was established from craniotomy tissues. LymInf, hemorrhage, and necrosis (Nec) were assessed on H&E stain (score 0-3); gliosis was scored as present/absent. Primary endpoint was survival from craniotomy. The Kaplan Meier method and Log-rank tests were used to evaluate survival. Results: Median age was 52 yrs. Median follow-up was 2.74 yrs. Hormone receptor (HR) status was 47% HR+ and 53% HR-. Subtype was: 36% (22/61) HR+/Her2-, 23% (14/61) Her2+, and 41% (25/61) TN. Higher Nec (2-3+) was observed more frequently in TN BCBM (76%) compared to HR+/Her2- (32%) or Her2+ (36%) BCBM, p = 0.004. Across all subtypes, higher Nec was associated with inferior survival post-craniotomy compared to low Nec (median 1.0 v 1.8 yrs, p = 0.02); this trend was notable in the HR+ BCBM (1.3 v 2.5 yrs, p = 0.19). LymInf was observed in 60% (48/81) of BCBM. Across all pts, higher LymInf was not associated with post-craniotomy survival (p = 0.3). In the HR- cohort, any LymInf (1-3+ v 0) was associated with longer survival post-craniotomy (0.9 v 0.3 yrs, p = 0.03); this held true for the TN pts (0.9 v 0.5 yrs, p = 0.14). Any LymInf was also associated with longer survival from diagnosis of primary BC in the TN group (4.3 v 3.1 yrs, p = 0.02). Conclusions: Higher necrosis as observed on H&E stain from BCBM at craniotomy is associated with TN subtype and with a negative prognosis. LymInf may be prognostic of an improved outcome, especially in the HR- population. Given that immunotherapy is being used successfully in metastatic melanoma and is being investigated in metastatic BC, evaluation of this approach in patients with BCBM is warranted.
Effect of nivolumab on tumor growth rate (TGR) in metastatic renal cell carcinoma (mRCC).
Authors: Camille Mazza, Julia Arfi-Rouche, Serge Koscielny, Caroline Caramella, Jihene Lahmar, Bernard J. Escudier, Laurence Albiges
Journal: Journal of Clinical Oncology (2017)

481 Background: Response assessment under immune checkpoint inhibitors is a challenge that RECIST criteria may not adequately reflect. TGR takes into account the pretreatment kinetics and allows dynamic assessments. How TGR varies under nivolumab remains unknown. We aim at describing the pattern of TGR changes during nivolumab treatment. Methods: We performed a central radiological review of all consecutive patients treated with nivolumab at Gustave Roussy within the GETUG-AFU 26 NIVOREN (EudraCT 2015-004117). Tumor response was assessed at week 8 and every 8-12 weeks subsequently using RECIST 1.1. TGR was computed for the pre nivolumab treatment (TGR pre) and at first (TGR N1) and second assessment (TGR N2) under nivolumab. Results: A total of 45 patients treated with nivolumab between Feb and Jul 2016 were reviewed. Median age at nivolumab start was 60 years-old, 74 % were male. Median number of prior lines of systemic therapies was 2. Median follow-up from nivolumab start was 6 months. TGR pre and TGR N1 were available in 39 patients. Overall, mean decrease in TGR N1 compared to TGR pre was 26%. Among 39 evaluable patients, 23 (59%) patients had a decrease in TGR N1 compared with TGR pre; while an increase was described in 16 (41%) patients. Only one patient out of 39 (2.5%) had a major increase of more than 50% in TGR N1 compared with TGR pre, and could be defined as a hyper-progressor. Consecutive TGR N1 and TGR N2 were available in 24 patients. There was a high correlation between TGR N1 and TGR N2 (r=0.7), suggesting that first evaluation of tumor kinetics adequately reflects subsequent response to nivolumab. However, 4/24 patients (17%) had an initial increase in TGR N1 with subsequent decrease in TGR N2, defining potentially the pseudo-progressors. Conversely, 6/24 patients (25%) had an initial decrease in TGR N1 before a rebound in TGR N2 suggesting a prompt acquired resistance to nivolumab. Conclusions: We report the first TGR assessment of mRCC patients under nivolumab. Overall, 59 % of patients had a decrease in TGR under nivolumab compared to pre nivolumab. TGR in patients with mRCC might provide early information about tumor response to nivolumab. Analysis extended to the entire study population and correlation with PFS and OS will be reported.
Microarray Functional Comparison of CD34+ and Megakaryocytic Cell Transcriptomes in Myeloid Metaplasia with Myelofibrosis.
Authors: Marie-Caroline Le Bousse-Kerdiles, Christophe Desterke, Carole Tonetti, Philippe Dessen, Hugues Ripoche, Vladimir Lazar, Bernadette Guerton, Denis Clay, William Vainchenker, Stephane Giraudier
Journal: Blood (2005)
A presurgical study of oral silybin-phosphatidylcholine in patients with early breast cancer.
Authors: Matteo Lazzeroni, Aliana Guerrieri-Gonzaga, Sara Gandini, Harriet Ann Johansson, Davide Serrano, Serena Mora, Pietro Caldarella, Gianmatteo Pagani, Alberto Luini, Giancarlo Pruneri, Valentina Aristarco, Antonella Puccio, Antonella Riva, Giovanna Petrangolini, Walter Cabri, Paolo Morazzoni, Andrea De Censi, Bernardo Bonanni
Journal: Journal of Clinical Oncology (2014)

2580 Background: Silybin-phosphatidylcholine (Siliphos) is an orally bioavailable complex of silybin, a poorly absorbable polyphenolic flavonolignan derived from milk thistle and endowed with potential anticancer activity in preclinical models. The purpose of the window of opportunity trial (code n. R621-IEO661/511) was to determine the tissue distribution of silybin-phosphatidylcholineand its effect on cell proliferation and other biomarkers in breast cancer (BC) patients. Methods: Twelve BC patients received silybin-phosphatidylcholine, 2.8 g daily for 4 weeks prior to surgery. Silybin levels were measured before (SIL) and after (TOT SIL) enzymatic hydrolysis by HPLC-MS/MS in biological samples (plasma, urine, BC tissue and surrounding normal tissue). Fasting blood samples were taken at baseline, before the last administration (end) and 2 hours after. Results: All patients were fully compliant and completed the treatment program. No toxicity was observed. SIL and TOT-SIL were undetectable in baseline samples. Median SIL and TOT-SIL concentrations after supplementation are shown in the table. Median TOT-SIL concentration was higher in the tumor as compared to the adjacent normal tissue (P=0.018). Despite a high between-subject variability, plasma SIL levels significantly correlated with the low concentration in normal tissue (Spearman coefficient=0.690, P=0.027). Conclusions: We show for the first time that oral silybin-phosphatidylcholine can attain biologically relevant breast tumor tissue levels and high blood concentrations of silybin. These results provide the basis for future clinical studies of Siliphos in breast carcinogenesis prevention. Circulating and tissue biomarkers of activity will be presented at the conference. Median (Q1-Q3) concentrations after supplementation. Urine*-final ng/mL Plasma-end ng/mL Plasma-end-2h ng/mL Breast-K ng/g Breast-N ng/g TOT-SIL 6,676 (3,766-14,515) 901 (651-1,481) 14,538 (13,147-16,828) 131 (35-869) 11 (0-34) SIL 144 (62-349) 69 (13-59) 5,847 (4,526-6,454) 33 (4-58) 0 (0-4) * Creatinine normalization; end: before the last administration; end-2h: 2 hours after the last administration; K: cancer tissue; N: normal tissue.
Abstract 18804: Chronic Pressure Overload Impairs Cardiac Microvascular Endothelial Cell Metabolism and Angiogenic Potential in Aortic Stenosis Patients
Authors: Sander Trenson, Arief Wibowo, Hadewich Hermans, Sandra Schoors, Pauline de Zeeuw, Maarten Vanhaverbeke, Sander Craps, Hilde Gillijns, Ellen Caluwé, Jozef Bartunek, Paul Herijgers, Marie-Christine Herregods, Peter Carmeliet, Aernout Luttun, Stefan Janssens
Journal: Circulation (2016)

Introduction:  Chronic myocardial pressure overload leads to interstitial fibrosis and capillary rarefaction. We previously showed that transverse aortic constriction upregulates Transforming Growth Factor s (TGFs)-dependent fibrosis-related genes, including Cartilage Intermediate Layer Protein (CILP), in murine cardiac microvascular endothelial cells (MiVEC).   Hypothesis:  In aortic stenosis patients (AS), chronic pressure overload induces a phenotypic switch in cardiac MiVEC that impairs EC function and metabolism.   Methods:  We culture-expanded CD31+ MiVEC after MACS isolation from right atrium (RA, low pressure) and left ventricular outflow tract (LVOT, pressure overload) surgical biopsies of AS and exposed them to TGFs and the TGFs-1 receptor inhibitor, SD208 for 48h. At p4, MiVEC angiogenic potential was determined using 2D tube formation and 3D spheroid sprouting. Glycolytic and oxidative metabolic fluxes were assessed using  3 H-5-Glucose and  3 H-9,10-palmitic acid.   Results:  In AS, CILP expression in LVOT positively correlated with LA dilation and pulmonary artery pressure (n=19, Pearson, P 300-fold in the presence of TGF-s (p=0.01) via activation of the SD208-inhibitable TGFs-1 receptor. LVOT MiVEC showed less sprouts/spheroid (12.84±2.01  vs  23.17±1.38 in RA MiVEC, P vs  30.55±3.57/cm 2 , P=0.03), less nodes (188.07±53.15  vs  273.14±62.76/cm 2 , P=0.03) and reduced total network length (7.95±1.34  vs  10.39±1.21 mm/mm 2 , P=0.02) compared to RA (n=6). Glycolytic flux was comparable (P=0.38), but palmitic acid flux was higher in LVOT-derived MiVEC (7.46±2.3  vs  3.54±1.10 nmol/h/mg protein in RA MiVEC, P   Conclusions:  Chronic pressure overload induces a molecular and metabolic switch in human cardiac MiVEC, characterized by TGFs-dependent CILP-upregulation, loss of angiogenic potential in vitro and increased fatty acid oxidation. These data, for the first time, identify human cardiac MiVEC as a critical target to reverse fibrosis and capillary rarefaction in pressure overloaded hearts.