tbuckley/cabot-search huggingface dataset:
Molecular subtypes and outcomes in regorafenib-treated patients with metastatic colorectal cancer (mCRC) enrolled in the CORRECT trial.
Authors: Michael Teufel, Susanne Schwenke, Henrik Seidel, Georg Beckmann, Joachim Reischl, Richardus Vonk, Heinz-Josef Lenz, Josep Tabernero, Salvatore Siena, Axel Grothey, Eric Van Cutsem, Michael Jeffers, Scott Wilhelm, Andrea Wagner, Dirk Laurent, Svetlana Kobina, Mark Daniel Rutstein, Pratyaksha Wirapati, Justin Guinney, Sabine Tejpar
Journal: Journal of Clinical Oncology (2015)

3558 Background: In the CORRECT Ph3 trial (NCT01103323), regorafenib improved overall survival (OS) and progression-free survival (PFS) vs placebo in patients with mCRC who progressed on standard therapies (Grothey 2013). Initial biomarker analyses suggested that regorafenib provides a clinical benefit in various mutational subgroups (Jeffers 2013). Here we present additional exploratory analyses to evaluate clinical benefit in CRC subgroups defined by gene expression. Methods: Gene expression analysis (Affymetrix ST1.0 array) was conducted on archival tumor tissue from 281 of the 760 patients (37%) enrolled in CORRECT. Next-generation sequencing (NGS) was done on 239 specimens (FoundationONE). Gene expression data were subjected to hierarchical molecular tumor classification (Marisa 2013). Cox proportional hazards models were used to identify potential prognostic or predictive biomarkers. Results: The distribution of the 6 different CRC subtypes characterized by gene expression clusters originally defined by Marisa and the classification of the 281 patients from CORRECT are shown in the table. The six Marisa subtypes derived a similar OS benefit from regorafenib. Although the numbers of patients in the subgroups are small, a greater PFS benefit for regorafenib was seen in patients in the 'high-risk' subgroup (C4 +C6, n = 26; HR = 0.10; 95%CI 0.02 - 0.35; p = 0.0009) than the 'low-risk' subgroup (C1+C2+C3+C5, n = 255; HR = 0.58; 95%CI 0.44 - 0.77; p = 0.002). NGS analyses suggested that the chromosomal instability group (CIN) was the predominant subgroup in CORRECT. Conclusions: Molecular characterization by gene expression analysis may allow the identification of CRC subgroups that correlate with regorafenib clinical benefit. Data suggest this does not depend on the presence of mutations. Additional exploratory analyses, including the use of the recently defined Consensus molecular subtypes (Dienstmann ASCO 2014), to validate these results are ongoing. Clinical trial information: NCT01103323. Subtype CINImmuneDown (C1) dMMR (C2) KRASmutant (C3) CSC (C4) CINWntUp (C5) CINnormL (C6) Marisa (2013) 21% 19% 13% 10% 27% 10% CORRECT (n) 36% (100) 12% (33) 11% (32) 7% (19) 32% (90) 2% (7)
A Phase I Study of Romidepsin, Gemcitabine, Dexamethasone and Cisplatin Combination Therapy in the Treatment of Peripheral T-Cell and Diffuse Large B-Cell Lymphoma: Canadian Cancer Trials Group Study LY.15
Authors: Tony Reiman, Kerry J. Savage, Michael Crump, Matthew Cheung, David A. MacDonald, Rena Buckstein, Stephen Couban, Eugenia Piliotis, Kevin R Imrie, David Spaner, Sudeep Shivakumar, John Kuruvilla, Diego Villa, Lois E. Shepherd, Tanya Skamene, Chad Winch, Bingshu E Chen, Annette E Hay
Journal: Blood (2016)
Abstract P2-01-19: SentiNot: A way to avoid sentinel node biopsy (SNB) in patients with a preoperative diagnosis of ductal cancer in situ (DCIS)
Authors: A Karakatsanis, HM Olofsson, S Eriksson, Y Andersson, LÅ Bergkvist, I Mohammed, M Sundqvist, S Abdsaleh, R Olofsson Bagge, M Sund, F Wärnberg
Journal: Cancer Research (2017)

Abstract Background The risk for node metastasis in preoperative diagnosis of DCIS is low. ASCO guidelines suggest that SNB could be performed when mastectomy is planned or in those cases where the probability of upgrading to invasive cancer postoperatively is high. Despite that, SNB is performed almost in 54% of DCIS procedures in the Uppsala-Örebro Region. Thus, morbidity and resources have to be balanced against the risk of a reoperation. Methods Patients with a preoperative diagnosis of DCIS grade 3, grade 2 ≥20mm or planned for a mastectomy will be included. Sienna+ is injected in the breast at the first operation. If the specimen contains invasive cancer, a SNB is performed in another session. Sienna+ can be detected in the axilla at least four weeks after the injection. Endpoints of the trial are the feasibility of detection of the SN as well as how many SNBs are avoided. Results In the first 34 cases, six had invasive breast cancer. On reoperation (median 29 days, iqr 10) SNB was successful in four cases with SPIO, one with Tc99 and three cases with blue dye. Totally, the combination of SPIO and blue dye was successful in all cases. No metastases were found. Patient characteristics Total cohort (N=34)Group with IBC (n=6)Age (yrs)58.6 (54.9, 62.9)60.2 (47.4, 72.9)Size (mm)40.0 (31.2, 62.9)57.7 (27.2, 88.1)DCIS grade29 (26.5%)2 (33.3%) 323 (67.6%)4 (66.7%) na2 (5.9%)0PalpableYes30 (88.2%)1 (16.7%) No4 (11.8%)5 (83.3%)BCSYes22 (64.7%)3 (50%) No12 (35.3%)3 (50%)Transcutaneous counts at the end of the operation266 (196,336)300 (126,474) Conclusion It is possible to load the SN with SPIO and reoperate within 4 weeks from the first operation. A rough 83,4% of all patients with DCIS who would have undergone SNB avoided it. Our preliminary results show that 5,6 SNB was avoided for each patient that was operated. SN was detected in all cases with a combination of SPIO and blue dye, but only in 66,7% SPIO. It seems that increased experience with SPIO will increase the effectivity of this procedure. Citation Format: Karakatsanis A, Olofsson HM, Eriksson S, Andersson Y, Bergkvist LÅ, Mohammed I, Sundqvist M, Abdsaleh S, Olofsson Bagge R, Sund M, Wärnberg F. SentiNot: A way to avoid sentinel node biopsy (SNB) in patients with a preoperative diagnosis of ductal cancer in situ (DCIS) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-01-19.
The CD40/CD40 Ligand (CD40L) Pathway Plays a Role in Primary Hemostasis and Platelet Function.
Authors: Florian Langer, Susan B. Ingersoll, Ali Amirkhosravi, Todd V. Meyer, Farooq A. Siddiqui, Steve Rocca, Sarfraz Ahmad, Jamie M. Walker, Mildred Amaya, Hina Desai, John L. Francis
Journal: Blood (2004)
Increased Microparticle-Linked Procoagulant Activity In Patients with Primary Immune Thrombocytopenia.
Authors: Elena G. Arias Salgado, Ihosvany Fernández Bello, Mayte Álvarez Román, Isabel Rivas, Mónica Martín Salces, Ana Rodríguez de la Rúa, Víctor Jiménez-Yuste, Nora V. Butta
Journal: Blood (2010)
PP28. THERAPEUTIC COMPOUND DISCOVERY AND VALIDATION OF DRUGS TARGETING A RECURRENT GLIOBLASTOMA (GBM) PHENOTYPE USING LINCS COMPOUNDS VIA QUADRATIC ANALYSES
Authors: Dr Shahnaz Al Rashid, Dr Paul O’Reilly, Dr philip dunne, Mr Matthew Alderdice, Dr Thomas Flannery, Prof Kevin Prise, Dr Shu-Dong Zhang, Dr Darragh McArt
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is the most prevalent and aggressive of malignant primary brain tumours. Despite multi-modal therapy, including surgical resection, radiotherapy and chemotherapy, GBM continues to be uniformly lethal, with a median survival of 12–18 months from the time of diagnosis. The resistance to therapy and ultimate recurrence is thought to originate from a sub-population of cells residing in the initial tumour, identified as glioma-initiating or glioma-stem cells (GSC). These GSC have been shown to be intrinsically more invasive, with enhanced repair and drug-efflux pathways mediating resistance to chemo-radiation therapies. The purpose of this study was to use and validate a novel connectivity mapping procedure to identify candidate compounds targeting therapy-resistant and recurrent GBM. This procedure was developed by O’Reilly and colleagues (“QUADrATiC: A Scalable Approach to Repurposing FDA-approved therapeutics”, under review in Bioinformatics), and in this study, was performed on publicly available NCBI GEO microarray datasets. Based on the cancer stem cell theory whereby the resistant GSCs repopulate and are enriched in recurrent tumours, primary and recurrent GBM gene expression profiles were compared and the connections between the identified gene lists and drug responses were mapped. To validate that this connectivity mapping procedure is reliable at identifying effective treatments to target therapeutic resistance and recurrence, we tested one of the top ten compounds identified, rosiglitazone (rosi), a ligand of the peroxisome proliferator activated receptor gamma (PPARγ). The efficacy of rosi alone and in combination with the current standard of care therapies, temozolomide and radiation, at killing GSC was assessed in vitro using the clonogenic survival assay. Our data indicated that rosi significantly reduced survival of both non-stem glioma cells and GSC, alone and in combination with radiation and temozolomide. The p53 pathway was identified as a pathway by which rosi may induce permanent cell cycle arrest and cell death. Further work is ongoing to fully elucidate the downstream mechanisms of cell death. This work is proof-of-principle that the current connectivity mapping procedure can be instrumental in identifying more targeted therapeutic interventions for GBM resistance and prevent recurrence.
Antimicrobial and Immunomodulatory Surface‐Functionalized Electrospun Membranes for Bone Regeneration
Authors: Asha Mathew, Cedryck Vaquette, Saeed Hashimi, Irani Rathnayake, Flavia Huygens, Dietmar W. Hutmacher, Saso Ivanovski
Journal: Advanced Healthcare Materials (2017)

Guided bone regeneration (GBR) is a surgical procedure utilizing occlusive membranes for providing space maintenance and enabling selective repopulation of the damaged area. While this technique is effective in regenerating bone, bacterial infiltration occurs frequently and can compromise the regenerative outcome. In this study, the authors describe the development and characterization of a GBR membrane made of medical grade polycaprolactone (mPCL) electrospun fibers with antibacterial and immunomodulatory properties. This is achieved by the immobilization of the antibiotic azithromycin into the membrane via a solvent evaporation technique leading to a sustained release of the drug over 14 d. In vitro testing shows that this controlled release of azithromycin is proficient at inhibiting the growth of Staphylococcus aureus for 14 d. Implantation of azithromycin loaded mPCL membrane in a rodent calvarial defect induces macrophage polarization toward the M 2 phenotype after one week and results in significantly more bone regeneration eight weeks post‐surgery. The results suggest that this antibacterial membrane should be effective at preventing infection and also impacts on the macrophage polarization enhancing bone regeneration. The drug loading technique developed in this study is simple, effective with a strong potential for clinical translation and can be applied to different types of scaffolds and implants for applications in craniofacial and orthopedics applications.
β <sub>2</sub> -Glycoprotein I/IgA Immune Complexes
Authors: Manuel Serrano, José A. Martínez-Flores, Dolores Pérez, Florencio García, Oscar Cabrera, Daniel Pleguezuelo, Estela Paz-Artal, José M. Morales, Esther González, Antonio Serrano
Journal: Circulation (2017)

Background: Antiphospholipid syndrome is characterized by recurrent thrombosis and gestational morbidity in patients with antiphospholipid autoantibodies (aPLs). Predictive value of the presence of aPLs is low, and new markers are necessary to identify aPL carriers at higher risk and take preventive measures on them. The presence of circulating immune complexes of IgA bound to β 2 -glycoprotein I (B2A-CIC) has been associated with occurrence of acute thrombotic events. In this work we study its possible predictive value for the appearance of acute thrombotic events in patients who are going to undergo transplant surgery, a well-known trigger of acute thrombotic events in aPL carriers. Methods: We performed a follow-up study based on the Magnum 12+12 Cohort of patients who received a kidney transplant (n=1339). Three groups were established: group 1 patients who were positive for IgA anti-β 2 -glycoprotein I (aB2GP1) and B2A-CIC (n=125); group 2 patients who were positive only for IgA aB2GP1 (n=240); and control group, patients who were negative for IgA aB2GP1 (n=974). Levels of autoantibodies and B2A-CIC were quantified immediately before the transplant surgery and patients were followed up for 6 months. Results: In group 1, 46.4% of patients experienced any type of thrombosis versus 10.4% in group 2 ( P &lt;0.001) and 8.6% in the control group ( P &lt;0.001). The incidence of graft thrombosis in group 1 (31.2%) was significantly higher than that observed in group 2 (3.3%, P &lt;0.001) and the control group (2.6%, P &lt;0.001). In a multivariate analysis, the presence of B2A-CIC was an independent variable to experience any type of posttransplant thrombosis (hazard ratio, 6.72; 95% confidence interval, 4.81–9.37) and, prominently, for graft thrombosis (hazard ratio, 14.75; 95% confidence interval, 9.11–23.89). No significant differences were found between B2A-CIC–negative and control group patients. Conclusions: The presence of B2A-CIC is a predictor of acute thrombotic events. Patients who were positive for IgA aB2GP1 only are at risk of experiencing thrombosis if they are B2A-CIC positive. If they are B2A-CIC–negative patients, they have the same risk as the control group. Treatments to prevent acute thrombotic events should focus on B2A-CIC–positive patients.
A Model Estimating Indirect Costs of Premature Death Associated with Severe Hepatic Veno-Occlusive Disease (sVOD) Among Hematopoietic Stem Cell Transplant (HSCT) Patients in the United States (U.S.)
Authors: Tiffany P. Quock, Zheng-Yi Zhou, Byran Dai, Wenxi Tang, Kathleen F. Villa
Journal: Blood (2015)
CD25 Enables Oncogenic BCR Signaling and Represents a Therapeutic Target in Refractory B Cell Malignancies
Authors: Jae-Woong Lee, Huimin Geng, Zhengshan Chen, Lars Klemm, Kadriye Nehir Cosgun, Gang Xiao, Behzad Masouleh, Christian Hurtz, Samir Parekh, Steven M. Kornblau, Ari Melnick, Abul Abbas, Elisabeth Paietta, Markus Müschen
Journal: Blood (2016)
A Phase I Study of 90Y-Ibritumomab-Tiuxetan (90Y-It) in Children with Recurrent/Refractory CD20 Positive Lymphoma: A Cog Phase I Consortium Study.
Authors: Mitchell S. Cairo, Erin Cooney, Mark Krailo, Richard Belanger, Sherrie L. Perkins, Rashid Fawwaz, Anne Angiolillo, Peter Adamson
Journal: Blood (2005)
Clinical Significance of Serum Th1-, Th2- and Regulatory T Cells-Associated Cytokines in Adult T-Cell Leukemia/Lymphoma: High Interleukin-5 and -10 Levels Are Significant Unfavorable Prognostic Factors.
Authors: Atsushi Inagaki, Takashi Ishida, Toshihiko Ishii, Hirokazu Komatsu, Shinsuke Iida, Kentaro Yonekura, Shogo Takeuchi, Yoshifusa Takatsuka, Atae Utsunomiya, Ryuzo Ueda
Journal: Blood (2005)
Serial early post-IMRT undetectable plasma EBV DNA to predict outcomes in non-metastatic nasopharyngeal cancer.
Authors: Victor HF Lee, Dora Lai Wan Kwong, To-Wai Leung, Cheuk-Wai Choi, Sherry CY Ng, Ka-On Lam, Chun-Kin Sze, Chi-Chung Tong, Patty PY Ho, Wendy WL Chan, Lai-San Wong, Dennis KC Leung, Ann SY Chan, Fong-Ting Chan, Kin-Sang Lau
Journal: Journal of Clinical Oncology (2015)

6007 Background: The relationship between early undetectable plasma EBV DNA after intensity-modulated radiation therapy (IMRT) for NPC and long-term survival remains unclear. Early post-IMRT undetectable plasma EBV DNA is a proposed efficacy endpoint which warrants investigation as a predictor of long-term survival. We prospectively explored the predictive power of post-IMRT 8th week and 6th month undetectable plasma EBV DNA for 3-year survival outcomes in patients with non-metastatic NPC. Methods: Two hundred and sixty patients with non-metastatic NPC were treated with IMRT +/- concurrent /induction/adjuvant platinum-based chemotherapy. Plasma EBV DNA was taken at diagnosis and then 8 weeks and 6 months after IMRT. Time-dependent Receiver-Operating Characteristics (TD-ROC) were used to obtain Cτ indices. Cox regression models identified interaction between undetectable post-IMRT 8th week and 6th month plasma EBV DNA and outcomes including progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: A strong relationship was shown between post-IMRT 8th week and 6th month undetectable plasma EBV DNA with PFS, CSS and OS (TD-ROC revealing higher Cτ indices for stage IVA–B compared to stage I–III). Cox regression showed that post-IMRT 8th week and 6th month undetectable plasma EBV DNA were prognostic of PFS (p < 0.001 and p < 0.001, respectively), CSS (p = 0.006 and p = 0.004, respectively) and OS (p = 0.039 and p = 0.012, respectively). Baseline plasma EBV DNA was not prognostic of any survival outcome. Conclusions: Our study showed a strong relationship between post-IMRT 8th week and 6th month undetectable plasma EBV DNA and 3-year survival outcomes. This suggested the use of early plasma EBV DNA as a predictor of survival in this setting. Post-IMRT 8th week plasma EBV DNA Post-IMRT 6th month plasma EBV DNA Cτ 95% CI Cτ 95% CI PFS stage I–III 0.651 0.504 – 0.799 0.601 0.463 – 0.738 stage IVA–B 0.670 0.531 – 0.810 0.826 0.715 – 0.937 p value < 0.001 < 0.001 CSS stage I–III 0.679 0.471 – 0.886 0.517 0.502 – 0.532 stage IVA–B 0.694 0.447 – 0.940 0.771 0.498 – 1.044 p value 0.0048 < 0.001 OS stage I–III 0.584 0.462 – 0.707 0.517 0.502 – 0.533 stage IVA–B 0.694 0.447 – 0.940 0.771 0.498 – 1.044 p value < 0.001 < 0.001
Imatinib Changed Everything
Authors: Dan L. Longo
Journal: New England Journal of Medicine (2017)

The initial successes of combination chemotherapy were stunning. Childhood acute leukemia, several forms of lymphoma, and testicular cancer all became largely curable malignant conditions. Adjuvant chemotherapy led to dramatically longer survival among persons with breast cancer. The fundamental principle of chemotherapy was to target dividing cells, because it was assumed that more rapid proliferation than “normal” was an underlying common defect in cancer. The effective agents generally attacked DNA or the mitotic spindle. Some tumors, such as breast cancer and prostate cancer, were susceptible to hormonal manipulation because of growth regulation of their normal-tissue counterparts.Gradually data emerged that, except . . .
A multicentre validation of the 1-min sit-to-stand test in patients with COPD
Authors: Sarah Crook, Gilbert Büsching, Konrad Schultz, Nicola Lehbert, Danijel Jelusic, Stephan Keusch, Michael Wittmann, Michael Schuler, Thomas Radtke, Martin Frey, Alexander Turk, Milo A. Puhan, Anja Frei
Journal: European Respiratory Journal (2017)

Our aim was to comprehensively validate the 1-min sit-to-stand (STS) test in chronic obstructive pulmonary disease (COPD) patients and explore the physiological response to the test. We used data from two longitudinal studies of COPD patients who completed inpatient pulmonary rehabilitation programmes. We collected 1-min STS test, 6-min walk test (6MWT), health-related quality of life, dyspnoea and exercise cardiorespiratory data at admission and discharge. We assessed the learning effect, test–retest reliability, construct validity, responsiveness and minimal important difference of the 1-min STS test. In both studies (n=52 and n=203) the 1-min STS test was strongly correlated with the 6MWT at admission (r=0.59 and 0.64, respectively) and discharge (r=0.67 and 0.68, respectively). Intraclass correlation coefficients (95% CI) between 1-min STS tests were 0.93 (0.83–0.97) for learning effect and 0.99 (0.97–1.00) for reliability. Standardised response means (95% CI) were 0.87 (0.58–1.16) and 0.91 (0.78–1.07). The estimated minimal important difference was three repetitions. End-exercise oxygen consumption, carbon dioxide output, ventilation, breathing frequency and heart rate were similar in the 1-min STS test and 6MWT. The 1-min STS test is a reliable, valid and responsive test for measuring functional exercise capacity in COPD patients and elicited a physiological response comparable to that of the 6MWT.
Stability and solubility improvement of Sompoi ( Acacia concinna Linn.) pod extract by topical microemulsion
Authors: Worrapan Poomanee, Wantida Chaiyana, R. Randall Wickett, Pimporn Leelapornpisid
Journal: Asian Journal of Pharmaceutical Sciences (2017)

The aim of this study was to enhance the solubility and stability of Acacia concinna extract by loading in a microemulsion for topical application. Both physical appearance and biological activities of the extract-loaded microemulsion were determined in comparison with the extract solution. Pseudoternary phase diagrams of three oil types including tea seed oil, grape seed oil, and sesame oil, together with polysorbate 85 or the mixture of polysorbate 85 and sorbitan oleate as surfactants, and absolute ethanol as a co-surfactant were constructed to optimize the microemulsion area. The selected microemulsion was then characterized for droplet size, polydispersity index, and viscosity. Tea seed oil exhibited the highest microemulsion area in the phase diagram because it had the highest unsaturated fatty acid content. The microemulsion composed of tea seed oil (5%), polysorbate 85 (40%), ethanol (20%), and water (35%) exhibited Newtonian flow behavior with the droplet size and polydispersity index of 68.03 ± 1.09 nm and 0.44 ± 0.04, respectively. After 4% w/w of the extract was incorporated into the microemulsion, larger droplets size was observed (239.77 ± 12.69 nm) with a lower polydispersity index (0.37 ± 0.02). After storage in various conditions, both physical appearances and the stability of biological activity of the extract-loaded microemulsion were improved compared to the solution. Therefore, the A. concinna loaded microemulsion may be a promising carrier for further development into a topical formulation and clinical trials for pharmaceutical and cosmeceutical applications are also suggested.
The T Cell Cytolytic Molecules Fas Ligand and TRAIL, the Trafficking Molecules CCR9, β7 Integrin and PSGL-1, and the Immune Modulating Molecules OX40, CEACAM1, and CTLA4 Are Required for Thymic Graft-Versus-Host Disease
Authors: Il-Kang Na, Sydney X. Lu, Gabrielle L. Goldberg, Daniel Daniel Hirschhorn-Cymerman, Christopher G. King, Odette M. Smith, David Suh, Uttam Rao, Nury Yim, Amanda M. Holland, Olaf Penack, Robert R. Jenq, Arnab Ghosh, Laura Teisch, Simon Meykler, Janine Lin, Alejandro Sepulveda, Taha Merghoub, Alan Houghton, Marcel R. M. van den Brink
Journal: Blood (2008)
B Cell Lymphoma In Association with Multiple Myeloma: Analysis of the Biologic Relationship
Authors: Anuj K. Mahindra, Aliyah R. Sohani, Christiana E. Toomey, James S. Michaelson, Jeffrey A. Barnes, Jeremy S. Abramson, Ronald Takvorian, Noopur S. Raje, Ephraim P. Hochberg
Journal: Blood (2011)