tbuckley/cabot-search huggingface dataset:
A Functional In Vivo RNAi screen Involving Jumonji C Domain Containing Candidates Unravels Kdm5b As a Negative Modulator of Hematopoietic Stem Cell Self-Renewal
Authors: Sonia Cellot, Kristin J Hope, Martin Sauvageau, Jalila Chagraoui, Eric Deneault, Tara MacRae, Nadine Mayotte, Guy Sauvageau
Journal: Blood (2011)
Autologous Transplantation of Non-Cryopreserved Bone Marrow for the Treatment of High-Risk Adult Acute Lymphoblastic Leukemia in First Complete Remission.
Authors: Jerzy Holowiecki, Sebastian Giebel, Malgorzata Krawczyk-Kulis, Maria Sadus-Wojciechowska, Lucja Kachel, Jerzy Wojnar, Beata Stella-Holowiecka, Sebastian Grosicki
Journal: Blood (2005)
Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer
Authors: Longchuan Bai, Bing Zhou, Chao-Yie Yang, Jiao Ji, Donna McEachern, Sally Przybranowski, Hui Jiang, Jiantao Hu, Fuming Xu, Yujun Zhao, Liu Liu, Ester Fernandez-Salas, Jing Xu, Yali Dou, Bo Wen, Duxin Sun, Jennifer Meagher, Jeanne Stuckey, Daniel F. Hayes, Shunqiang Li, Matthew J. Ellis, Shaomeng Wang
Journal: Cancer Research (2017)

Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET protein degrader, BETd-246, which exhibits superior selectivity, potency, and antitumor activity. In human TNBC cells, BETd-246 induced degradation of BET proteins at low nanomolar concentrations within 1 hour of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211. RNA-seq analysis revealed predominant downregulation of a large number of genes involved in proliferation and apoptosis in cells treated with BETd-246, as compared with BETi-211 treatment that upregulated and downregulated a similar number of genes. Functional investigations identified the MCL1 gene as a critical downstream effector for BET degraders, which synergized with small-molecule inhibitors of BCL-xL in triggering apoptosis. In multiple murine xenograft models of human breast cancer, BETd-246 and a further optimized analogue BETd-260 effectively depleted BET proteins in tumors and exhibited strong antitumor activities at well-tolerated dosing schedules. Overall, our findings show that targeting BET proteins for degradation represents an effective therapeutic strategy for TNBC treatment. Cancer Res; 77(9); 2476-87. ©2017 AACR.
DRES-12. PROFILING OF DIFFERENT GBM CELL POPULATIONS WITH VARYING APOPTOTIC THRESHOLDS IDENTIFIES IGFBP-2 AS A NOVEL MEDIATOR OF TRAIL RESISTANCE
Authors: Ahmet Cingoz, Zeynep Hulya Gumus, Mehmet Gonen, Tugba Bagci-Onder
Journal: Neuro-Oncology (2016)

Glioblastoma Multiforme (GBM) is most common and aggressive primary brain tumor. Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) causes apoptosis of target cells through extrinsic apoptotic pathway and can selectively induce apoptosis in tumor cells. However, many cancer cell lines are resistant to TRAIL, and mechanisms regulating this resistance are not well understood. In this study, we generated TRAIL-resistant cell line models. We selected TRAIL-resistant subpopulations of a GBM cell line, which displays partial TRAIL sensitivity. U87MG cells were treated with different, but fixed concentrations of TRAIL for several weeks, after which the surviving cell fractions were expanded in TRAIL-free conditions. Cell viability and caspase assays revealed that these cells exhibited sustained TRAIL-resistance. Tumor generation capacities of control and resistant sub-populations as tested in orthotopic brain xenograft models were similar. To examine the molecular differences, we examined the expression of apoptosis-related genes with qPCR and observed that Bcl-xL was significantly upregulated in TRAIL-resistant populations. We also conducted genome wide RNA sequencing for further understanding the gene expression changes and observed upregulation of IGFBP-2 gene as our top gene in resistant cell subpopulations. As IGFBP2 is a novel gene associated with resistance, we performed computational analyses of available TCGA data in glioma samples and showed that high IGFBP-2 expression levels were significantly correlated with poor patient survival in both low grade glioma (LGG) and GBM patients. To understand the role of IGFBP-2 in TRAIL resistance, we overexpressed IGFBP2 in sensitive cells and observed that GBM cells acquired partial TRAIL resistance in the presence of IGFBP-2 overexpression or IGFBP2 recombinant protein. Our future efforts are directed at understanding the role of IGFBP-2 gene for resistance mechanisms and effects of signaling pathways. Our results will provide further understanding of molecular mechanisms of tumor heterogeneity in GBM cells, and help with the novel treatment strategies.
Multicentric prospective study of validation of angiogenesis polymorphisms in HCC patients treated with sorafenib. INNOVATE study
Authors: A. Casadei Gardini, L. Faloppi, B. Daniele, S. Cascinu, S. Lonardi, G. Masi, F. Negri, D. Santini, N. Silvestris, V. Zagonel, M. Scartozzi
Journal: Annals of Oncology (2016)
DDIS-12. A FACILE, ROBUST AND PREDICTIVE IN VITRO BLOOD-BRAIN-BARRIER MODEL FOR HIGH-THROUGHPUT SCREENING AND DISCOVERY OF BRAIN-PENETRATING AGENTS
Authors: Choi-Fong Cho, Justin Wolfe, Colin Fazden, Kalvis Hornburg, E. Antonio Chiocca, Bradley Pentelute, Sean E. Lawler
Journal: Neuro-Oncology (2016)

The inability of most systemically delivered therapeutics to cross the blood-brain-barrier (BBB) contributes a major barrier to effective brain cancer treatment. The tumor neovasculature in malignant glioma is known to be leaky, however invasive cells remain protected behind an intact BBB, and continue to thrive within the brain, ultimately leading to tumor regrowth and patient death. This leaves us with an urgent unmet need for the development of next-generation therapeutics with improved brain delivery. For the first time, we describe here the utility of 3D multicellular BBB spheroids made of human brain endothelial cells (ECs), pericytes and astrocytes as a screening tool for brain-penetrating agents. We show that the outer surface of the spheroids, composed primarily of ECs and pericytes, form a tight barrier which is permeabilized in the presence of VEGF. The barrier is characterized by the presence of intact tight junctions and efflux-pump activity (i.e., P-glycoprotein). Furthermore, we have used this model to successfully demonstrate the transport of angiopep-2 (a well-known brain delivery vector) and its conjugates (containing cargoes of various sizes such as peptide, protein and affibody), thereby highlighting the versatility of this model to screen and study a wide range of therapeutic agents. We demonstrate that this model is superior to the conventional transwell model in maintaining essential BBB characteristics (i.e., tight/adherens junctions and P-glycoprotein expression) and as a drug-screening tool. We have utilized the spheroid model to screen a panel of cell-penetrating peptides (CPPs) to identify several candidates with high brain-penetration potential. We then verified the ability of the top 4 candidate CPPs to cross the BBB in mice. This high-throughput in vitro model can lead to better design and analysis of first-in-class glioma therapeutics, and improve prediction of drug penetration in a living model, paving the way for breakthrough discoveries in brain cancer.
EXTH-36. SCREENING COMPOUNDS THAT TARGET THE DNA DAMAGE RESPONSE FOR BLOOD-BRAIN-BARRIER PERMEABILITY
Authors: Nimita Dave, Harlan Shannon, Anthony Sinn, Tiaishia Spragins, Barbara Bailey, Courtney Hemenway, Jixin Ding, Mohammad Saadatzadeh, David Jones, Aaron Cohen-Gadol, Karen Pollok
Journal: Neuro-Oncology (2016)

For glioblastoma (GBM), development of strategies that stabilize disease progression and ultimately achieve a cure will require comprehensive approaches towards target selection and design of therapies. Activation of the DNA damage response (DDR) by temozolomide and irradiation induces signaling pathways with actionable therapeutic targets (Akt, Chk1, and Mdm2), providing fertile ground to develop novel anti-GBM combination therapies. Using pediatric and adult GBM cells with clinically relevant molecular profiles, isobologram analyses indicated that combinations of small molecule inhibitors to these DDR-induced targets can synergistically block in vitro cell growth and decrease resistance of GBM cells to temozolomide. Knowing the degree of blood-brain-barrier (BBB) permeability is particularly important in the selection of therapeutic compounds for the treatment of GBM. To this end, we adapted the Mouse Brain Uptake Assay (MBUA), which determines the BBB apparent permeability (Papp, nm/sec) for drugs across an intact BBB with the assumption that uptake rate is an important contributor to brain concentrations. When Papp is plotted as a function of cLogD and compared with calibration compounds, specific mechanistic interpretation is possible. Optimal BBB Papp values fall within the region of brain uptake limited only by cerebral blood flow, and not limited by low passive permeability or active efflux. Inhibitors of interest have been analyzed using the MBUA. BBB permeability, as measured by Papp, was in the order RG7388>RG7112>nutlin3a for MDM2 inhibitors and CHIR124>AZD7762 for Chk1 inhibitors. Survival in an intracranial GBM xenograft model indicated that an intermittent dosing regimen of temozolomide with Akt (GDC0068) and Mdm2 (RG7112) inhibitors exhibiting moderate BBB permeability significantly reduced GBM growth with minimal toxicity. Studies are in progress to determine if the next-generation Mdm2 inhibitor RG7388 with a more favorable BBB Papp can further improve efficacy of combination therapy and offer new therapeutic options for GBM.
PDTB-28. TARGETING MEDULLOBLASTOMA WITH BENZODIAZAPINES DELIVERED USING TUNABLE BIODEGRADABLE HYDROGELS
Authors: Laura Kallay, Daniel Pomeranz Krummel, Kashi Reddy Methuku, Zhaobin Zhang, James Cook, Jeffrey Olson, Daniel Brat, Tobey MacDonald, Stefanie Sydlik, Soma Sengupta
Journal: Neuro-Oncology (2016)

Medulloblastoma (MB) is a common pediatric malignant primary brain tumor originating in the posterior fossa. MB is generally classified into one of four molecular subgroups: Wnt, Shh, Group 3, and Group 4. Subgroup 3 is the most clinically aggressive of the four and exhibits a molecular signature that includes over expression of the GABRA5 receptor. Previously, we reported on use of a novel microdevice to screen a broad range of benzodiazepine compounds that functioned as GABRA5 agonists (Jonas et al., 2016). This study identified a new benzodiazepine compound (KRM-II-08) that was particularly efficacious and thus an attractive candidate as a therapeutic against Group 3 medulloblastoma. The Cook laboratory have now synthesized a new series of benzodiazepine derived allosteric modulators. These compounds will initially be tested in tissue culture, those that are efficacious will be tested in the nude mouse tumor xenograft model. While the microdevice used previously provided a superb platform to screen a number of compounds in the same tumor, it is not a satisfactory system to bring forward into the clinic for brain tumor treatment. We are therefore exploring use of biodegradable hydrogels where the compounds are chemically “clicked” onto a modified chondroitan sulfate or hyaluronic acid (HA). Importantly, the hydrogels being employed have mechanical properties and covalent modifications to allow for the tunable release of the benzodiazepines in targeting medulloblastoma tumors. We will report on the progress in characterizing the new benzodiazepine compounds under study and the design of and observations regarding use of hydrogel formulations employed. Reference: Jonas O., Calligaris D., Muthuku K.R. et al. (2016) J. Biomed. Nanotech. 12: 1-6.
Safety and activity of the pan–fibroblast growth factor receptor (FGFR) inhibitor erdafitinib in phase 1 study patients with advanced urothelial carcinoma
Authors: J.-C. Soria, A. Italiano, A. Cervantes, J. Tabernero, J. Infante, P.N. Lara, A. Spira, E. Calvo, V. Moreno, J.-Y. Blay, R. Lauer, N. Chan, B. Zhong, A. Ademi Santiago-Walker, J. Bussolari, F.R. Luo, H. Xie, P. Hammerman
Journal: Annals of Oncology (2016)
Epigenetic Priming with Decitabine Prior to Standard Induction Chemotherapy in Less-Than-Favorable Risk Acute Myelogenous Leukemia (AML).
Authors: Joseph M. Scandura, Gail J. Roboz, Michelle Moh, Jahar R Bose, Usama S Gergis, Sebastian A Mayer, Cindy Ippoliti, Curcio J Tania, Ellen K Ritchie, Eric J. Feldman
Journal: Blood (2009)
A Novel Method of Isolation of Mesenchymal Stem Cells from Human Umbilical Cord Tisssues.
Authors: Lulu Lu, Yong-jun Liu, Zhen-shu Xu, Cun-gang Fan, Han Wang, Wei Gong, Zhi-bo Han, Yong-xin Lu, Delong Liu, Zhi-zhe Chen, Zhong-chao Han
Journal: Blood (2005)
In Vivo Effects of Notch Signaling Inhibitor on Tumor Growth and Its Mechanism of Action.
Authors: Shigeo Masuda, Suk-Young Lee, Keiki Kumano, Mamiko Sakata-Yanagimoto, Kyoko Haraguchi, Takahiro Suzuki, Takeshi Iwatsubo, Hideaki Natsugari, Seishi Ogawa, Mineo Kurokawa, Shigeru Chiba
Journal: Blood (2006)
supportive care Influence of concomitant clopidogrel consumption on development of paclitaxel-associated toxicity: A pharmacoepidemiological study
Authors: K. Agergaard, M. Mau-Sørensen, T.B. Stage, T.L. Jørgensen, R.E. Hassel, K.D. Steffensen, J.W. Pedersen, M.L.H. Milo, S.H. Poulsen, A. Pottegård, J. Hallas, K. Brøsen, T.K. Bergmann
Journal: Annals of Oncology (2016)
METB-02. EXPRESSION LEVEL OF GLUTAMINASE 2 IS ASSOCIATED WITH REGIONAL HETEROGENEITY OF 5-AMINOLEVULINIC ACID FLUORESCENCE IN GLIOBLASTOMA
Authors: Chul-kee Park, So Jin Kim, Ja Eun Kim, Yong Hwy Kim, Taeyoung Hwang, Jung Ho Han, Ki-Jeong Kim, Soon-Tae Lee, Tae Min Kim, Seung Hong Choi, Sunghyouk Park, Se-Hoon Lee
Journal: Neuro-Oncology (2016)

Fluorescence-guided surgery using 5-aminolevulinic acid (5-ALA) is a widely used for glioblastoma (GBM) treatment. However, there is intratumoral heterogeneity of fluorescence intensity which may reflect different onco-metabolic program. We investigated the genes that is responsible for the 5-ALA fluorescence intensity in GBM tissue. We have developed the in-house system of fluorescence quantification in tumor tissues. Using this system, we collected 3 classes of GBM tissues in each of 5 patients according to the fluorescence intensity such as strong, weak, and none, during the 5-ALA fluorescence-guided surgery. After RNA extraction from all 15 samples, gene expression profiles were analyzed by RNA-sequencing. We identified 77 genes of proportional relation and 509 genes of inverse relation between gene expression and fluorescence intensity. Gene set enrichment analysis was performed with the identified differentially expressed genes, and we focused on glutaminase 2 (GLS2) gene, because it was derived in multiple significant gene sets of cell metabolism. Higher expression of GLS2 is related lower 5-ALA fluorescence. We validated the effect of GLS2 on 5-ALA fluorescence in multiple GBM cell lines. After transduction of GLS2 gene into U87MG and T98 cell lines, we could observe significant reduction of intracellular protoporphyrinogen IX level after 5-ALA treatment. We discovered an inverse relationship between 5-ALA fluorescence and GLS2 expression in GBM, which can be a metabolic surrogate marker for the degree of malignancy in the realm of intratumoral heterogeneity.
Analysis of circulating cell-free DNA in plasma shows a higher detection rate of EGFR mutations in patients with extrathoracic disease progression
Authors: Y. Seki, Y. Fujiwara, T. Kohno, Y. Goto, H. Horinouchi, S. Kanda, H. Nokihara, N. Yamamoto, K. Kuwano, Y. Ohe
Journal: Annals of Oncology (2016)
Subset Analysis of Response to Treatment of Chronic Phase CML in a Phase 1 Study of Ponatinib in Refractory Hematologic Malignancies
Authors: Jorge E. Cortes, Hagop M. Kantarjian, Neil Shah, Dale Bixby, Michael J. Mauro, Ian W. Flinn, Thomas O'Hare, Simin Hu, Tim Clackson, Victor M. Rivera, Christopher D. Turner, Frank Haluska, Brian J. Druker, Michael W. Deininger, Moshe Talpaz
Journal: Blood (2011)
Injury rates in recreational tennis players do not differ between different playing surfaces
Authors: Babette M Pluim, Benjamin Clarsen, Evert Verhagen
Journal: British Journal of Sports Medicine (2017)

Objective The aim of this study was to determine whether there is a difference in the prevalence of tennis injuries between the four most common court surfaces in the Netherlands, including hard court, clay, sand-fill artificial grass and red-sand-fill artificial grass. Natural grass was not included in this study. Methods This was a repeated cross-sectional study over 6 months, involving members of the Royal Netherlands Lawn Tennis Association (KNLTB). A monthly questionnaire was sent to a random sample of 20 000 KNLTB members, stratified by their club’s playing surface. The questionnaire included questions on court surface, tennis exposure and physical complaints, using the Oslo Sports Trauma Research Centre questionnaire on health problems. Results A total of 3656 (18%) of the 20 000 invited members completed at least one of the monthly questionnaires [mean age 49 years (15)]. A total of 4047 injuries were reported by 1957 respondents. Of these injuries, 3246 (80%) were overuse and 801 (20%) were acute. There were no statistically significant differences in injury prevalence between groups who played primarily on any one of the four court surfaces. However, players who played on multiple surfaces had a higher injury prevalence, particularly of overuse injuries, than those who primarily played on one court surface. Compared with the other court surfaces, there was a higher prevalence of lower limb overuse injuries when playing on hard court. Conclusion There is no significant difference in the overall prevalence of injury on clay, hard court, sand-fill artificial grass and red-sand-fill artificial grass.
Next Generation XPO1 Inhibitor KPT-8602 for the Treatment of Drug-Resistant Multiple Myeloma
Authors: Joel G Turner, Jana L Dawson, Christopher L Cubitt, Erkan Baluglo, Steven Grant, Yun Dai, Kenneth H Shain, William S. Dalton, Sharon Shacham, William Senapedis, Daniel M Sullivan
Journal: Blood (2015)
REPLACE-BG: A Randomized Trial Comparing Continuous Glucose Monitoring With and Without Routine Blood Glucose Monitoring in Adults With Well-Controlled Type 1 Diabetes
Authors: Grazia Aleppo, Katrina J. Ruedy, Tonya D. Riddlesworth, Davida F. Kruger, Anne L. Peters, Irl Hirsch, Richard M. Bergenstal, Elena Toschi, Andrew J. Ahmann, Viral N. Shah, Michael R. Rickels, Bruce W. Bode, Athena Philis-Tsimikas, Rodica Pop-Busui, Henry Rodriguez, Emily Eyth, Anuj Bhargava, Craig Kollman, Roy W. Beck
Journal: Diabetes Care (2017)

To determine whether the use of continuous glucose monitoring (CGM) without confirmatory blood glucose monitoring (BGM) measurements is as safe and effective as using CGM adjunctive to BGM in adults with well-controlled type 1 diabetes (T1D).A randomized noninferiority clinical trial was conducted at 14 sites in the T1D Exchange Clinic Network. Participants were ≥18 years of age (mean 44 ± 14 years), had T1D for ≥1 year (mean duration 24 ± 12 years), used an insulin pump, and had an HbA1c ≤9.0% (≤75 mmol/mL) (mean 7.0 ± 0.7% [53 ± 7.7 mmol/mol]); prestudy, 47% were CGM users. Participants were randomly assigned 2:1 to the CGM-only (n = 149) or CGM+BGM (n = 77) group. The primary outcome was time in range (70-180 mg/dL) over the 26-week trial, with a prespecified noninferiority limit of 7.5%.CGM use averaged 6.7 ± 0.5 and 6.8 ± 0.4 days/week in the CGM-only and CGM+BGM groups, respectively, over the 26-week trial. BGM tests per day (including the two required daily for CGM calibration) averaged 2.8 ± 0.9 and 5.4 ± 1.4 in the two groups, respectively (P < 0.001). Mean time in 70-180 mg/dL was 63 ± 13% at both baseline and 26 weeks in the CGM-only group and 65 ± 13% and 65 ± 11% in the CGM+BGM group (adjusted difference 0%; one-sided 95% CI -2%). No severe hypoglycemic events occurred in the CGM-only group, and one occurred in the CGM+BGM group.Use of CGM without regular use of confirmatory BGM is as safe and effective as using CGM with BGM in adults with well-controlled T1D at low risk for severe hypoglycemia.
Antibody-Drug Conjugates with Uncleavable Linkers for the Treatment of Non-Hodgkin Lymphoma.
Authors: Andrew G. Polson, Suzanna Clark, Changchun Du, Dan Eaton, Kristi Elkins, Reina N. Fuji, Mary Ann, Alane Gray, Tom Januario, Hartmut Koeppen, Jeffery Lau, Will Leach, Elena McDorman, Kathleen McKeever, Saileta Prabhu, Suzie J. Scales, Dionysos Slaga, Susan Spencer, Marna Williams, David Xie, Shang-Fan Yu, Bing Zheng, Allen Ebens
Journal: Blood (2007)
Can skin compression with prophylactic drugs for CIPN lead to better anticancer effects?
Authors: Tsuyoshi Ohno, Naomi Kaneko, Shigetoshi Matsuo, Takashi Azuma, Yukio Kamohara, Satoshi Inoue, Mio Fujii, Takayuki Miyoshi, Tomayoshi Hayashi, Kosho Yamanouchi, Susumu Eguchi
Journal: Annals of Oncology (2016)
Ki67, tumor stage (TS) and axillary node metastases (ANMs): a complex relationship
Authors: G. Galli, G. Bregni, E. Meneghini, S. Cavalieri, F. Di Salvo, H. Amash, B. Paolini, F. de Braud, M.C. De Santis, M. Sant, S. Di Cosimo
Journal: Annals of Oncology (2016)
T-Cell-Independent Re-Stimulation of FVIII-Specific Memory B Cells Requires Help from Activated Plasmacytoid Dendritic Cells.
Authors: Aniko Ginta Pordes, Christina Hausl, Peter Allacher, Rafi U. Ahmad, Bernhard Baumgartner, Hans Peter Schwarz, Hartmut Ehrlich, Birgit M. Reipert
Journal: Blood (2007)
The Death of Animals in Medical School
Authors: Daren J. Simkin, Jeremy A. Greene, Julianna Jung, Bethany C. Sacks, Henry E. Fessler
Journal: New England Journal of Medicine (2017)

Although live animals had been used in medical education for millennia, with recent changes at Johns Hopkins and the University of Tennessee, every core U.S. medical school curriculum has now ceased this practice. It is worth considering the causes and implications of this milestone.
MiR-31-3p is a predictive biomarker of cetuximab response in FIRE3 clinical trial
Authors: P. Laurent-Puig, M.-L. Grisoni, V. Heinemann, K. Fontaine, C. Vazart, V. Decaulne, F. Rousseau, B. Courtieu, F. Lieabert, A. Jung, D. Neureiter, R. Thiébaut, S. Stintzing
Journal: Annals of Oncology (2016)
GENT-09. QUANTITATIVE IMAGING BIOMARKER FOR PREDICTING GENOMIC PROFILES IN GLIOBLASTOMA
Authors: Do-Hyun Nam, Ho Jun Seol
Journal: Neuro-Oncology (2016)

We postulated that radio phenotype of glioblastoma (GBM) represents their own genomic characteristics. From May 2012 to June 2014 we retrospectively identified 65 treatment-naïve or recurrent GBM patients with available clinical information from the Samsung Medical Center data registry. Using NordicICE, we performed quantitative imaging analysis and collected the dataset composing of radio phenotypic parameters. We found these radio phenotypic dataset was composed of three clusters through louvain clustering methods. Each clusters represented each own gene expression profiles, such as classical type, pro neural and neural types, and mesenchymal types of GBM. Additionally, we investigated their copy number variations and somatic mutation patterns and found radio phenotype represented genomic characteristics in GBM. These radio phenotypes also reflected the clinical outcome of the patients with GBM. Noninvasive radiological imaging together with integrative radiogenomic analysis can provide an important tool in helping to advance personalized therapy for subset of GBM.