tbuckley/cabot-search huggingface dataset:
Effects of BI 655064, an antagonistic anti-CD40 antibody, on clinical and biomarker variables in patients with active rheumatoid arthritis: a randomised, double-blind, placebo-controlled, phase IIa study
Authors: Sudha Visvanathan, Stefan Daniluk, Rafał Ptaszyński, Ulf Müller-Ladner, Meera Ramanujam, Bernd Rosenstock, Anastasia G Eleftheraki, Richard Vinisko, Alena Petříková, Herbert Kellner, Eva Dokoupilova, Brygida Kwiatkowska, Rieke Alten, Christian Schwabe, Patrick Baum, David Joseph, Jay S Fine, Steven J Padula, Jürgen Steffgen
Journal: Annals of the Rheumatic Diseases (2019)

To evaluate the safety, efficacy and therapeutic mechanism of BI 655064, an antagonistic anti-CD40 monoclonal antibody, in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX-IR).In total, 67 patients were randomised to receive weekly subcutaneous doses of 120 mg BI 655064 (n=44) or placebo (n=23) for 12 weeks. The primary endpoint was the proportion of patients who achieved 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Safety was assessed in patients who received at least one dose of study drug.At week 12, the primary endpoint was not met, with 68.2% of patients treated with BI 655064 achieving an ACR20 vs 45.5% with placebo (p=0.064); using Bayesian analysis, the posterior probability of seeing a difference greater than 35% was 42.9%. BI 655064 was associated with greater changes in CD40-CD40L pathway-related markers, including reductions in inflammatory and bone resorption markers (interleukin-6, matrix metalloproteinase-3, receptor activator of nuclear factor-κB ligand), concentration of autoantibodies (immunoglobulin [Ig]G rheumatoid factor [RF], IgM RF, IgA RF) and CD95+ activated B-cell subsets. No serious adverse events (AEs) related to BI 655064 treatment or thromboembolic events occurred; reported AEs were mainly of mild intensity.Although blockade of the CD40-CD40L pathway with BI 655064 in MTX-IR patients with RA resulted in marked changes in clinical and biological parameters, including reductions in activated B-cells, autoantibody production and inflammatory and bone resorption markers, with a favourable safety profile, clinical efficacy was not demonstrated in this small phase IIa study.NCT01751776.
dStruct: identifying differentially reactive regions from RNA structurome profiling data
Authors: Krishna Choudhary, Yu-Hsuan Lai, Elizabeth J. Tran, Sharon Aviran
Journal: Genome biology (2019)

RNA biology is revolutionized by recent developments of diverse high-throughput technologies for transcriptome-wide profiling of molecular RNA structures. RNA structurome profiling data can be used to identify differentially structured regions between groups of samples. Existing methods are limited in scope to specific technologies and/or do not account for biological variation. Here, we present dStruct which is the first broadly applicable method for differential analysis accounting for biological variation in structurome profiling data. dStruct is compatible with diverse profiling technologies, is validated with experimental data and simulations, and outperforms existing methods.
Abstract 415: Transgenic Expression of Dimethylarginine Dimethylaminohydrolase Attenuates Exercise-induced Fatigue in Duchenne Muscular Dystrophy Carrier Mice
Authors: Joanne F Garbincius, Lauren E Merz, Ashley J Cuttita, Kaitlynn V Bayne, Sara Schrade, Emily A Armstead, Kimber L Converso-Baran, Steven E Whitesall, Louis G D’Alecy, Daniel E Michele
Journal: Circulation Research (2017)

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in dystrophin and characterized by muscle degeneration, cardiomyopathy, and impaired muscle nitric oxide (NO) production that disrupts muscle blood flow regulation and leads to excessive post-exercise fatigue. Interestingly, circulating levels of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) are elevated in dystrophin-deficient subjects. Therefore, we hypothesized that excessive circulating ADMA impairs muscle NO production and thus negatively impacts exercise tolerance in DMD. The objectives of this study were to determine whether increased circulating ADMA is itself sufficient to affect exercise performance, and whether transgenic modulation of ADMA metabolism could improve exercise-induced fatigue in the mdx mouse model of DMD. Although infusion of exogenous ADMA did impair exercise performance in healthy, wild-type mice, transgenic expression of dimethylarginine dimethylaminohydrolase 1 (DDAH), the enzyme that degrades ADMA, did not affect exercise-induced fatigue in dystrophin-deficient male mdx mice. Surprisingly, DDAH transgene expression did attenuate exercise-induced fatigue in dystrophin-heterozygous female mdx carrier mice. This improvement in exercise tolerance was associated with reduced heart weight, improved cardiac contractile function, and improved chronotropic responsiveness to beta-adrenergic stimulation in DDAH-transgenic female mdx carriers. In contrast, DDAH transgene expression did not significantly affect skeletal muscle pathology in female mdx carriers. We conclude that DDAH transgene expression improves exercise tolerance in dystrophin-heterozygous females, possibly by limiting pathological cardiac remodeling and helping to maintain heart performance. These findings emphasize the importance of methylated arginines to the development of cardiomyopathy in female DMD carriers, and have interesting implications for current genetic therapies that may only partially restore dystrophin expression in the hearts of male DMD patients.
Inhibition of miR-328–3p Impairs Cancer Stem Cell Function and Prevents Metastasis in Ovarian Cancer
Authors: Amit K. Srivastava, Ananya Banerjee, Tiantian Cui, Chunhua Han, Shurui Cai, Lu Liu, Dayong Wu, Ri Cui, Zaibo Li, Xiaoli Zhang, Guozhen Xie, Karuppaiyah Selvendiran, Srinivas Patnaik, Adam R. Karpf, Jinsong Liu, David E. Cohn, Qi-En Wang
Journal: Cancer Research (2019)

Cancer stem cells (CSC) play a central role in cancer metastasis and development of drug resistance. miRNA are important in regulating CSC properties and are considered potential therapeutic targets. Here we report that miR-328-3p (miR-328) is significantly upregulated in ovarian CSC. High expression of miR-328 maintained CSC properties by directly targeting DNA damage binding protein 2, which has been shown previously to inhibit ovarian CSC. Reduced activity of ERK signaling in ovarian CSC, mainly due to a low level of reactive oxygen species, contributed to the enhanced expression of miR-328 and maintenance of CSC. Inhibition of miR-328 in mouse orthotopic ovarian xenografts impeded tumor growth and prevented tumor metastasis. In summary, our findings provide a novel mechanism underlying maintenance of the CSC population in ovarian cancer and suggest that targeted inhibition of miR-328 could be exploited for the eradication of CSC and aversion of tumor metastasis in ovarian cancer. SIGNIFICANCE: These findings present inhibition of miR-328 as a novel strategy for efficient elimination of CSC to prevent tumor metastasis and recurrence in patients with epithelial ovarian cancer.
CLO19-049: Central Lymph Node Dissection in the Clinically Node-Negative (cN0) Papillary Thyroid Carcinoma: Is it Necessary?
Authors: Girish M. Suresh, C. Ramachandra, Ravi Arjunan, Rajshekar Halkud
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Surgery is the treatment of choice in papillary thyroid cancer (PTC), which is the most common thyroid malignancy and frequently has metastases in the central compartment lymph nodes (CLN). There is debate among surgeons whether removing normal-appearing lymph nodes in the central neck (prophylactic lymph node dissection) is better than removing only the abnormal-appearing lymph nodes. Herein, we review the potential utility of central compartment lymph nodal dissection (CLND) on surgical outcome and disease-free follow-up of PTC and 5-year survival of patients operated on at our center. Methods: A total of 246 patients from February 2009 to March 2012 who were treated for PTC in our Kidwai Cancer Institution was analyzed retrospectively. 135 patients who underwent total thyroidectomy and CLND were assigned to Group A, which was compared with 111 patients who received total thyroidectomy, without CLND, who were assigned to Group B by evaluation of postoperative complications (recurrent laryngeal nerve damage, hoarseness, hypocalcemia, and hemorrhage rates) and recurrence at the time of Iodine 131 treatment and subsequently at 60 months follow-up. Results: In the present study, Mean DFS and OS did not differ in both groups. Male gender and age more than 45 years had statistically significant DFS but without any impact on OS. There was a significant postoperative complication in group A compared to group B ( P ≤.001), with a very minimal recurrence in the central neck. 4 patients (3.6%) had recurrences in CLN. Conclusion: Considering the significant postoperative complication, which outweighs benefit, we conclude that for cN0 PTC, routine CLND is not necessary.
Authors’ response: Prevention of bacterial sexually transmitted infections (STI) in France: a comprehensive approach
Authors: Ndeindo Ndeikoundam Ngangro, Annie Velter, Nathalie Lydie, Florence Lot
Journal: Eurosurveillance (2019)

Preview this article: Authors’ response: Prevention of bacterial sexually transmitted infections (STI) in France: a comprehensive approach, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/24/12/eurosurv-24-12-8-1.gif
Defining Parameters Attributing to the Role of Osteomacs in Regulating Stem Cell Function and the Hematopoietic Niche
Authors: Safa F. Mohamad, Joydeep Ghosh, Andrea M. Gunawan, Rachel Blosser, Malgorzata Kamocka, Chi Zhang, Dunn W Kenneth, Khalid Mohammad, Melissa A Kacena, Edward F. Srour
Journal: Blood (2018)
Adherence to Guideline-Directed Stroke Prevention Therapy for Atrial Fibrillation Is Achievable
Authors: Jonathan P. Piccini, Haolin Xu, Margueritte Cox, Roland A. Matsouaka, Gregg C. Fonarow, Javed Butler, Anne B. Curtis, Nihar Desai, Margaret Fang, Pamela J. McCabe, Robert L. Page II, Mintu Turakhia, Andrea M. Russo, Bradley P. Knight, Mandeep Sidhu, Jodie L. Hurwitz, Kenneth A. Ellenbogen, William R. Lewis
Journal: Circulation (2019)

Background: Efforts to improve prescription of oral anticoagulation (OAC) drugs in patients with atrial fibrillation have had limited success in improving guideline adherence. Methods: We evaluated adherence to the American College of Cardiology/American Heart Association performance measures for OAC in eligible patients with a CHA 2 DS 2 -VASc score ≥2 and trends in prescription over time in the American Heart Association’s Get With The Guidelines–AFIB (atrial fibrillation) registry. Adjusted associations with in-hospital outcomes were also determined. The cohort included 33 235 patients with a CHA 2 DS 2 -VASc score ≥2 who were admitted for atrial fibrillation and were enrolled at 115 sites between January 1, 2013, and September 31, 2017. Results: The median (25th, 75th percentile) age was 73 years (65, 81 years); 51% were female; and the median (25th, 75th percentile) CHA 2 DS 2 -VASc score was 4 (3, 5). At admission, 16 206 (59.5%) of 27 221 patients with a previous diagnosis of atrial fibrillation were taking OAC agents, and OAC drug use at admission was associated with a lower adjusted odds of in-hospital ischemic stroke (odds ratio, 0.38; 95% CI, 0.24–0.59; P &lt;0.0001). At discharge, prescription of OAC in eligible patients (no contraindications) was 93.5% (n=25 499 of 27 270). In a sensitivity analysis, when excluding only strict contraindications (4.6%, n=1497 of 32 806), OAC prescription at discharge was 80.3%. OAC prescription at discharge was higher in those aged ≤75 years, men, those with heart failure, those with previous atrial fibrillation ablation, and those with rhythm control ( P &lt;0.0001 for all). OAC use was lowest in Hispanic patients (90.2%, P &lt;0.0001). Prescription of OAC at discharge in eligible patients improved over time from 79.9% to 96.6% ( P &lt;0.0001). Conclusions: Among hospitals participating in the GWTG-AFIB quality improvement program, OAC prescription at discharge in eligible guideline-indicated patients increased significantly and improved consistently over time. These data confirm that high-level adherence to guideline-recommended stroke prevention is achievable.
Long-term efficacy and safety of obeticholic acid for patients with primary biliary cholangitis: 3-year results of an international open-label extension study
Authors: Michael Trauner, Frederik Nevens, Mitchell L Shiffman, Joost P H Drenth, Christopher L Bowlus, Victor Vargas, Pietro Andreone, Gideon M Hirschfield, Richard Pencek, Elizabeth Smoot Malecha, Leigh MacConell, David Shapiro
Journal: The Lancet. Gastroenterology & hepatology (2019)
CLO19-040: The Role of Adjuvant Therapy in Patients With Pathological T2N0 Resected Gastric Adenocarcinoma
Authors: John Khoury, David Macari, Daniel Ezekwudo, Ayoda Werede, Ishmael A. Jaiyesimi
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: There is controversy surrounding the benefit of adjuvant therapy for patients with pT2N0, stage IB gastric adenocarcinoma following surgical resection. Methods: Patients with T2N0 gastric adenocarcinoma (tumor invasion into the muscularis propria) who underwent surgical resection with pathological evaluation of at least 15 lymph nodes were identified from the Surveillance Epidemiology and End Results Registry (SEER) database. Demographics, adjuvant therapy, and survival data were collected and analyzed using SPSS statistical software. Results: A total of 452 cases were identified between 2004 and 2014. Median age at diagnosis was 69. 60.2% of the patients were white, 27.7% Asian, 10.8% black, and 1.3% from other races. Adjuvant therapy was administered to 30.5% of the patients, of which 44.2% received chemoradiation, 48% chemotherapy only, and 7.2% radiation therapy only. After a median follow up of 39 months, the median overall survival (OS) was not reached in the group of patients who received adjuvant therapy versus 100 months in the group that did not receive adjuvant therapy ( P =.005). The 5-year OS rate (5-YOS) was 77% for the adjuvant therapy group versus 62% for those who did not receive adjuvant therapy. Univariate analysis revealed that the hazard ratio for death [adjuvant therapy vs observation] was 0.54; 95% CI, 0.35 to 0.83. Adjuvant therapy showed statistically significant survival benefit in patients younger than 60 years of age (5-YOS, 95% vs 79%) and failed to show survival benefit in patients older than 60 (5-YOS, 63% vs 58%). Multivariate analysis revealed that age was associated with mortality, whereas sex, race, grade, tumor size, and number of lymph nodes examined were not associated with increased mortality. Conclusions: Adjuvant therapy provided survival benefit for pT2N0, stage IB resected gastric adenocarcinoma. Our results suggest that patients younger than 60 year of age may benefit the most from this therapy.
HSR19-091: Incidence of Adverse Events Following Use of Different PARP Inhibitors: Systematic Review and Meta-Analysis
Authors: Thanh Ho, Irbaz Bin Riaz, Maheen Akhter, Saad Ullah Malik, Anum Riaz, Muhammad Zain Farooq, Safi U. Khan, Zhen Wang, M. Hassan Murad, Andrea Wahner Hendrickson
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Poly (ADP-ribose) polymerases (PARPs) are a highly conserved family of enzymes whose main function is to preserve genomic integrity following DNA damage. PARP inhibitors (PARPi) are increasingly used in cancers with deficiencies in homologous recombination. Clinical trials in breast and ovarian cancers have led to several FDA approvals in recent years, and their use in clinical practice is continuing to rise. It is thus necessary to assess their adverse event (AE) profile. Method: Literature search was performed using Ovid MEDLINE, EMBASE, CENTRAL, and Scopus (inception through October 26, 2018). Eligible studies were phase 3, randomized, controlled trials that compared single agent PARPi to placebo or standard treatment. Number of patients treated and AEs reported were recorded. Observed incidence of AE was reported with 95% CI. Heterogeneity was evaluated using Cochran Q statistic and I2 statistics quantified the proportion of heterogeneity not due to chance. Results: Databases revealed 869 references. Of these, 6 were eligible: 2 in breast cancer (OlympiAD, EMBRACA) and 4 in ovarian cancer (NOVA, ARIEL3, SOLO1, SOLO2). PARPi included niraparib (NOVA), olaparib (OlympiAD, SOLO1, SOLO2), rucaparib (ARIEL3), and talazoparib (EMBRACA). Of 1,685 patients who received PARPi, incidence of any AE, regardless of grade, was 98.5% (95% CI, 97.2–99.2%). Common AEs were: nausea (incidence rate, 68.9% and 95% CI, 58.7%–77.5%), fatigue (56.3%, 45.3%–66.8%), anemia (46.3%, 37.2%–55.8%), vomiting (33.7%, 29.5%–38.3%), neutropenia (24.7%, 15.3%–37.4%), headache (23.9%, 19.9%–28.4%), and reduced appetite (21.7%, 19.3%–24.3%). Myeloid neoplasms were rare (1.2%, 0.7%–1.9%). Incidence of grade 3 or higher AE was 44.3% (30.2%–59.5%) and often related to myelosuppression, specifically anemia (24.7%, 15.3%–37.4%), neutropenia (10.7%, 6.6%–16.9%), and thrombocytopenia (5.0%, 1.7%–14.0%). Incidence of serious AE was 24.3% (19.4%–29.9%); dose interruption occurred in 53.3% (41.2%–65.0%) and dose reduction occurred in 39.2% (23.6%–57.4%). 10% (7.4%–13.6%) of patients discontinued therapy due to AE. Death due to AE was rare; less than 1% (0.4%, 0.2%–0.8%) in all trials. Conclusion : Myelosuppression and gastrointestinal toxicities were the most commonly reported AE in 6 randomized phase 3 trials of PARPi for breast and ovarian cancers. Therapy was rarely discontinued due to AE. It remains to be seen whether these results will be reflected in clinical practice.
VEGFR-3 mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels
Authors: Yulong He, Iiro Rajantie, Katri Pajusola, Seppo Yla-Herttuala, Thomas C. Harding, Karin Jooss, Takashi Takahashi, Kari Alitalo
Journal: Cancer Research (2005)

2024  A number of signaling pathways regulate expression of and response to pro-angiogenic factors. Because the protein tyrosine kinase, Src has been implicated in both of these processes, we hypothesized that Src is a critical mediator of angiogenesis induced by colorectal carcinoma cells. To examine Src-mediated angiogenic properties, temperature-sensitive SV40 Tag immortalized endothelial cells from both the colon (CEC) and liver (HEC) were stimulated with conditioned media from HT29 human colorectal carcinoma cells previously treated with a selective Src kinase inhibitor, PP2, or DMSO control. Endothelial proliferation was determined by MTT; migration was determined by modified Boyden chamber assay. To asses the ability of Src to regulate growth factor-induced endothelial activation, the above assays were repeated in the presence of 1) 2% FBS, 2) EGF, 3) bFGF, 4) VEGF-A or 5) HGF either in the presence or absence of a selective Src inhibitor. For protein analysis, HEC pretreated with PP2 or DMSO were stimulated with EGF and lysed at various time points. Total and phosphorylated forms of Akt, Erk, and Src were assessed by western blotting and densitometry. Conditioned media from HT29 colorectal carcinoma cells induced a ∼2-fold increase in proliferation and migration in the CEC and >3-fold increase in proliferation and migration HEC respectively. The conditioned media from the Src-inhibited colorectal carcinoma cells failed to induce significant proliferation or migration in either cell line. Likewise, EGF, bFGF, VEGF, and HGF induced a 5.0-, 3.7-, 4.4-, and 3.9-fold increase in migration in HEC respectively and a 3.3-, 2.4-, 2.7- and 4.0-fold increase in migration in CEC respectively. In contrast, while EGF and bFGF caused ∼2-fold increase in proliferation in both HEC and CEC, VEGF failed to increase proliferation above control values. HGF induced a 1.5-fold increase in CEC proliferation, but failed to induce proliferation in HEC. Pretreatment with the selective Src inhibitor abrogated endothelial proliferation and migration induced by all factors. EGF treatment of HEC induced a 2-fold increase in Src kinase activity, a >5-fold increase in phosphorylated Erk and ∼3 fold increase in phosphorylated Akt, all of which were effectively blocked by Src inhibition. We therefore conclude that angiogenesis induced by colorectal carcinoma cells is regulated by Src kinase and that heterogeneous endothelial cells from distinct anatomic sites may be differentially activated by colorectal carcinoma cells.
BPI19-021: Medical Oncologist Perspectives of the Veterans Affairs National Precision Oncology Program
Authors: Vishal Vashistha, Pradeep J. Poonnen, Vimla L. Patel, Halcyon G. Skinner, Jane L. Snowdon, Victoria McCaffrey, Neil L. Spector, Bradley Hintze, Jill E. Duffy, Gretchen P. Jackson, Michael J. Kelley
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Genomic sequencing of tumor samples is often considered for patients diagnosed with metastatic malignancies. In July 2016, the Veterans Health Administration (VHA) created the VA National Precision Oncology Program (NPOP) to offer next generation sequencing (NGS) multigene panels for veterans with advanced solid tumors. We sought to assess the perceptions of NPOP among medical oncologists across VHA. Methods: Semi-structured interviews were designed to evaluate the following concepts: expectations for NGS testing, required workflow to conduct testing, applicability of testing results, and summative views of genomic sequencing. VHA medical oncologists who had previously sent at least one sample for testing through NPOP were solicited to participate for an in-person or telephonic conversation. Interviews were analyzed by an inductive narrative approach to code responses, which was then followed by thematic analysis for key findings that emerged. Results: 17 medical oncologists were interviewed from 16 different VA medical centers (VAMCs) in 12 states. 16 (94.1%) oncologists reported sending at least 5 samples for NGS testing; 4 (23.5%) oncologists practiced at VAMCs that sent over 100 samples. Clinicians collectively expected that testing would determine all clinically relevant genomic alterations in a reasonable time. Testing was expedited for oncologists who maintained a collaborative relationship with their local pathologists and proceduralists. 8 (47.1%) oncologists felt that testing reports should provide greater insight into the clinical significance of uncommon gene variants. 6 (35.3%) respondents expressed that educational efforts are warranted to describe optimal sample processing, indications for testing, and/or relevance of rare mutations. Twelve (70.6%) respondents felt strongly that NGS testing would improve outcomes for their patients, while 3 (17.6%) oncologists were wary that the current number of actionable mutations is too limited to offer widespread benefit. Conclusions: VHA medical oncologists opined that NGS testing through VA NPOP improved outcomes. The testing process is expedited with multidisciplinary involvement. Designed approaches to semi-algorithmically report testing results may improve efficiency of clinical decision-making. More education is warranted to detail the procedural requirements to conduct testing, indications for test ordering, and interpretation of results.
The worldwide assessment of separation of patients from ventilatory assistance (WEAN SAFE) ERS Clinical Research Collaboration
Authors: Leo Heunks, Giacomo Bellani, Tài Pham, Laurent Brochard, John G. Laffey
Journal: European Respiratory Journal (2019)

<b>The worldwide assessment of separation of patients from ventilatory assistance (WEAN SAFE) Clinical Research Collaboration is addressing key issues related to weaning from mechanical ventilation</b>http://ow.ly/lggq30nRSWG