tbuckley/cabot-search huggingface dataset:
Abstract 3596: How many tumor indications should be initially studied in clinical development of next-generation immunotherapies
Authors: Cong Chen, Qiqi Deng, Linchen He, Devan Mehrotra, Eric H. Rubin, Robert A. Beckman
Journal: Cancer Research (2017)

Abstract An experimental oncology immunotherapy may have the potential to be effective in a large number of tumor indications. Once a recommended Phase II dose (RP2D) is determined, under resource constraint, a natural strategy is to conduct Phase II proof-of-concept (POC) trials in two waves. A cohort of potential tumor indications is selected for the first wave investigation and the second wave investigation in a different cohort of tumor indications is initiated only after the drug has been demonstrated to be effective in the first wave. Immunotherapy development is a dynamic environment with rapidly evolving mechanistic understanding, constant flow of new data and frequent changes in the competitive landscape. How many tumor indications should be investigated in the first wave given the uncertainties? We attempt to answer this question by maximizing a benefit-cost ratio, defined to be the expected number of effective tumor indications correctly identified in the two waves divided by the expected total sample size for the POC trials in the two waves and the total sample size for the Phase III trials triggered by those with a positive outcome in the first wave. It is found that the optimal number of the first wave POC trials is in a range of approximately three to six, which may vary with the resource constraint but is otherwise robust to the key factors we have considered. A recommendation is made on how much resource should be invested in the first wave. Citation Format: Cong Chen, Qiqi Deng, Linchen He, Devan Mehrotra, Eric H. Rubin, Robert A. Beckman. How many tumor indications should be initially studied in clinical development of next-generation immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3596. doi:10.1158/1538-7445.AM2017-3596
Defects in α-Cell Function in Patients With Diabetes Due to Chronic Pancreatitis Compared With Patients With Type 2 Diabetes and Healthy Individuals
Authors: Lena Mumme, Thomas G.K. Breuer, Stephan Rohrer, Nina Schenker, Björn A. Menge, Jens J. Holst, Michael A. Nauck, Juris J. Meier
Journal: Diabetes Care (2017)

Diabetes frequently develops in patients with chronic pancreatitis. We examined the alterations in the glucagon response to hypoglycemia and to oral glucose administration in patients with diabetes due to chronic pancreatitis.Ten patients with diabetes secondary to chronic pancreatitis were compared with 13 patients with type 2 diabetes and 10 healthy control subjects. A stepwise hypoglycemic clamp and an oral glucose tolerance test (OGTT) were performed.Glucose levels during the OGTT were higher in patients with diabetes and chronic pancreatitis and lower in control subjects (P < 0.0001). Insulin and C-peptide levels were reduced, and the glucose-induced suppression of glucagon was impaired in both groups with diabetes (all P < 0.0001 vs. control subjects). During hypoglycemia, glucagon concentrations were reduced in patients with chronic pancreatitis and with type 2 diabetes (P < 0.05). The increase in glucagon during the clamp was inversely related to the glucose-induced glucagon suppression and positively related to β-cell function. Growth hormone responses to hypoglycemia were lower in patients with type 2 diabetes (P = 0.0002) but not in patients with chronic pancreatitis.α-Cell responses to oral glucose ingestion and to hypoglycemia are disturbed in patients with diabetes and chronic pancreatitis and in patients with type 2 diabetes. The similarities between these defects suggest a common etiology.
Abstract 4310: SH003 induces apoptosis of DU145 prostate cancer cells by inhibiting ERK-involved pathway
Authors: Yu-Jeong Choi, Myeong-Sun Kim, Soo-Yeon Kang, Kangwook Lee, Jin Mo Ku, Se Hyang Hong, Hyo In Kim, Chunhoo Cheon, Youme Ko, Huang Ching Wen, Yui Sasaki, Sohyeon Kang, Tai Young Kim, Ji Hye Kim, Yong Cheol Shin, Seong-Gyu Ko
Journal: Cancer Research (2017)

Abstract Herbal medicines have been used in cancer treatment, with many exhibiting favorable side effect and toxicity profiles compared with conventional chemotherapeutic agents. SH003 is a novel extract from Astragalus membranaceus, Angelica gigas, and Trichosanthes Kirilowii Maximowicz combined at a 1:1:1 ratio that impairs the growth of breast cancer cells. Our data demonstrate that SH003 induced apoptosis in DU145 prostate cancer cells by inhibiting ERK signaling. SH003 induced apoptosis of prostate cancer cells in dose-dependent manner, which was independent of androgen dependency. SH003 also increased intracellular ROS levels but this is not associated with its pro-apoptotic effects. SH003 inhibited phosphorylation of Ras/Raf1/MEK/ERK/p90RSK in androgen-independent DU145 cells, but not androgen-dependent LNCaP and PC-3 cells. Moreover, ERK2 overexpression rescued SH003-induced apoptosis in DU145 cells. Thus, our data conclude that SH003 induces apoptotic cell death of DU145 prostate cancer cells by inhibiting ERK-mediated pathway. Citation Format: Yu-Jeong Choi, Myeong-Sun Kim, Soo-Yeon Kang, Kangwook Lee, Jin Mo Ku, Se Hyang Hong, Hyo In Kim, Chunhoo Cheon, Youme Ko, Huang Ching Wen, Yui Sasaki, Sohyeon Kang, Tai Young Kim, Ji Hye Kim, Yong Cheol Shin, Seong-Gyu Ko. SH003 induces apoptosis of DU145 prostate cancer cells by inhibiting ERK-involved pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4310. doi:10.1158/1538-7445.AM2017-4310
Multitudes are adaptable magnitudes in the estimation of number
Authors: Frank H. Durgin
Journal: Behavioral and Brain Sciences (2017)

Visual number comparison does not require participants to choose a unit, whereas units are fundamental to the definition of number. Studies using magnitude estimation rather than comparison show that number perception is compressed dramatically past about 20 units. Even estimates of 5-20 items are increasingly susceptible to effects of visual adaptation, suggesting a rather narrow range in which subitizing-like categorization processes blend into greater reliance on adaptable magnitude information.
Abstract 3762: Superior T cell activity of a membrane-proximal binding antibody when targeting Glypican-3 with an antibody-coupled T-cell receptor (ACTR) armed T cell
Authors: Greg Motz, John Shin, Kathleen Whiteman, Birgit Schultes, Tapasya Pai, Lori Westendorf, Seth Ettenberg, Travis Biechele, Django Sussman, Heather Huet
Journal: Cancer Research (2017)

Abstract Glypican-3 (GPC3) is a GPI-anchored member of the heparan sulfate proteoglycan family. GPC3 is an oncofetal antigen expressed transiently during fetal development with re-expression during malignant transformation. GPC3 is an ideal tumor target as expression has been found in numerous epithelial malignancies, with highest expression in hepatocellular carcinoma (HCC) and non-small cell lung carcinoma (NSCLC), and normal tissue expression is highly restricted (Baumhoer D., Am J Clin Pathol, 2008.). Adoptive T-cell therapy with single-chain variable fragment (scFv)-derived chimeric antigen receptors (CARs) has transformed cancer therapy, but the broad applicability of this approach has been limited in part by safety concerns due the constitutive expression of a biologically active targeting receptor. The Antibody-Coupled T-cell Receptor (ACTR) platform is a universal, engineered T-cell therapy designed to engage the Fc domain of therapeutic antibodies opsonized to tumor cells to mediate anti-tumor activity. ACTR activity is therefore both regulatable and flexible, providing enhanced therapeutic control and improved safety of the T cell therapy. Using both HCC and NSCLC tumor cell lines, we tested a panel of wild-type and afucosylated antibodies with similar binding affinities that bound to regions spanning the GPC3 protein across unique epitopes. We found that for GPC3 targeting antibodies, the greatest activity in a Jurkat-NFAT reporter assay was observed for the afucosylated antibody that bound GPC3 most proximal to the membrane. Further, the antibody that bound membrane proximal also had the most potent activity in primary ACTR T cell cytotoxicity and cytokine release assays. The physical distance between T cells and tumor targets has been previously determined to impact T cell activation for both peptide-MHC and CAR-T interactions. Similarly, our results demonstrate a potential relationship between spatial distance of tumor targets and T cells in determining the activity ACTR transduced T cells when targeting GPC3. Our data demonstrate that ACTR T cell activity is antibody-specific and dose-titratable, highlighting both efficacy and improved safety of the ACTR T cell platform when targeting GPC3+ solid tumor malignancies. Citation Format: Greg Motz, John Shin, Kathleen Whiteman, Birgit Schultes, Tapasya Pai, Lori Westendorf, Seth Ettenberg, Travis Biechele, Django Sussman, Heather Huet. Superior T cell activity of a membrane-proximal binding antibody when targeting Glypican-3 with an antibody-coupled T-cell receptor (ACTR) armed T cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3762. doi:10.1158/1538-7445.AM2017-3762
Abstract 3523: Arginyltransferase1 as a novel suppressor of prostate cancer metastasis
Authors: Michael Birnbaum, Akhilesh Kumar, William Morgan, Fangliang Zhang
Journal: Cancer Research (2017)

Abstract Arginylation is a post-translational modification wholly mediated by Arginyltransferase 1 (Ate1). Our studies have shown that Ate1 and arginylation are upregulated during stress conditions. In addition, it was recently shown that Ate1-deficient fibroblasts demonstrate cancer-like characteristics including genomic instability and mutagenesis. While Ate1’s role in cancer is poorly understood, our preliminary studies suggest that Ate1 is an important regulator of metastasis and cancer progression in prostate cancer models. In this study, our data suggests that Ate1 is essential for normal cell stress response in conditions including cellular oxidant, apoptosis inducing drugs, and radiation. Further, we show that a loss of Ate1 in LnCaP prostate cancer cells increases anchorage-independent growth in the soft-agar assay, and that a loss of Ate1 in PC-3 prostate cancer cells increases matrigel invasion in the Boyden chamber assay. To text how Ate1 affects metastasis in vivo, PC-3 cells with Ate1 or control shRNA were orthotopically implanted into the prostates of immunocompromised mice to observe metastasis. While very little metastasis was observed in PC-3 control cells, PC-3 cells with reduced Ate1 achieved much higher levels of metastasis. In conclusion, our data suggests that the loss of Ate1 in prostate cancer promotes cancer progression phenotypes and cell survival. In future studies, we will examine if Ate1 levels in human prostate cancers in prostate cancer prognosis. Citation Format: Michael Birnbaum, Akhilesh Kumar, William Morgan, Fangliang Zhang. Arginyltransferase1 as a novel suppressor of prostate cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3523. doi:10.1158/1538-7445.AM2017-3523
Abstract 5792: Development of cell line derived organoids to evaluate stroma targeted therapies in pancreatic cancer
Authors: Bradley Hall, Bindu Santhamma, Andrew Cannon, Rakesh Bhatia, Sushil Kumar, Chandrakanth Are, Hareesh Nair, Klaus Nickisch, Surinder Batra
Journal: Cancer Research (2017)

Abstract Background: Most solid tumors have extensive stroma that not only facilitates the tumor progression but also impedes the delivery of the chemotherapeutic agents. Due to lack of any in-vitro system, presently it is difficult to evaluate any stroma-targeted therapies. Therefore, we developed an organoid system using labeled pancreatic cancer and stellate cell lines. Methods: Murine (FC 1295 and imPSCc-2) cell lines cultured in different combinations were grown as an organoid system using matrigel. The organoids, starting day four were treated with either gemcitabine or EC359, a novel mifepristone derived steroidal cytotoxic agent that targets tumor stroma, or both in combination. qRT-PCR analysis of activated stroma signature genes was performed on the mRNA isolated from different treatment groups. H&amp;E, immunohistochemistry, and western blot analysis were performed to further validate our findings. Results: Histologically, these cell line derived organoids develop ductal structures surrounded by fibroblast as seen in the pancreatic tumors. Immunohistochemistry demonstrated alpha-SMA staining of imPSCc-2 while FC 1295 cells were stained positive for CK19 and Na/K-ATPase. Gemcitabine treatment of the organoids resulted in 98% relative reduction in GFP fluorescence while EC359 decreased the fluorescence by 46% as compared to control. qRT-PCR demonstrated significant reduction (p&amp;lt;0.01) in the expression of activated stroma associated genes such as COL1A1, POSTN, SPARC, COL3A1, COL5A2 and THBS2. However, there was a significant increase in the expression of COL10A1, suggesting the differential regulation of stroma associated genes to stroma-targeted therapies. Further, western blot analysis demonstrated that EC359 reduced the expression of markers of activated stroma including alpha-SMA, and vimentin. Conclusions: Our novel cell line derived organoid model can be utilized for fast, and inexpensive evaluation of stroma-targeted therapies. Also, our study demonstrates that gemcitabine and a novel mifepristone-derivative can be used as combination therapy to simultaneously target cancer cells and associated stroma for the treatment of pancreatic cancer. Citation Format: Bradley Hall, Bindu Santhamma, Andrew Cannon, Rakesh Bhatia, Sushil Kumar, Chandrakanth Are, Hareesh Nair, Klaus Nickisch, Surinder Batra. Development of cell line derived organoids to evaluate stroma targeted therapies in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5792. doi:10.1158/1538-7445.AM2017-5792
The effect of secukinumab on moderate-to-severe scalp psoriasis: Results of a 24-week, randomized, double-blind, placebo-controlled phase 3b study
Authors: Jerry Bagel, Kristina Callis Duffin, Angela Moore, Laura K. Ferris, Kimberly Siu, Jennifer Steadman, Farid Kianifard, Judit Nyirady, Mark Lebwohl
Journal: Journal of the American Academy of Dermatology (2017)

BackgroundModerate-to-severe scalp psoriasis has not been evaluated in prospective trials of patients without moderate-to-severe body psoriasis.ObjectiveEvaluate the efficacy and safety of secukinumab in moderate-to-severe scalp psoriasis.MethodsIn this 24-week, double-blind, phase 3b study, 102 patients were randomized 1:1 to subcutaneous secukinumab 300 mg or placebo at baseline, weeks 1, 2, and 3, and then every 4 weeks from week 4 to 20. The primary efficacy variable was 90% improvement of Psoriasis Scalp Severity Index (PSSI 90) score from baseline to week 12.ResultsAt week 12, PSSI 90 (secukinumab 300 mg vs placebo, 52.9% vs 2.0%) and Investigator's Global Assessment modified 2011 scalp responses of 0 or 1 (secukinumab 300 mg vs placebo, 56.9% vs 5.9%) were significantly greater with secukinumab 300 mg than placebo (P < .001 for both). In addition, significantly more patients achieved complete clearance of scalp psoriasis at week 12 with secukinumab 300 mg than placebo (35.3% vs 0%; P < .001). The median time to 50% reduction in PSSI score was 3.29 weeks with secukinumab 300 mg. The safety profile of secukinumab was consistent with previous phase 3 studies.LimitationsThere was no active comparator arm.ConclusionSecukinumab is efficacious and well-tolerated for patients with extensive moderate-to-severe scalp psoriasis.
Effectiveness and safety of standardised shorter regimens for multidrug-resistant tuberculosis: individual patient data and aggregate data meta-analyses
Authors: Faiz Ahmad Khan, M.A. Hamid Salim, Philipp du Cros, Esther C. Casas, Atajan Khamraev, Welile Sikhondze, Andrea Benedetti, Mayara Bastos, Zhiyi Lan, Ernesto Jaramillo, Dennis Falzon, Dick Menzies
Journal: European Respiratory Journal (2017)

We assessed the effectiveness and safety of standardised, shorter multidrug-resistant tuberculosis (MDR-TB) regimens by pooling data from observational studies. Published studies were identified from medical databases; unpublished studies were identified from expert consultation. We conducted aggregate data meta-analyses to estimate pooled proportions of treatment outcomes and individual patient data (IPD) meta-regression to identify risk factors for unsuccessful treatment in patients treated with 9- to 12-month MDR-TB regimens composed of a second-line injectable, gatifloxacin/moxifloxacin, prothionamide, clofazimine, isoniazid, pyrazinamide and ethambutol. We included five studies in which 796 out of 1279 (62.2%) individuals with confirmed MDR-TB (98.4%) or rifampin-resistant TB (1.6%), and not previously exposed to second-line drugs, were eligible for shorter regimens. 669 out of 796 participants were successfully treated (83.0%, 95% CI 71.9–90.3%). In IPD meta-regression (three studies, n=497), failure/relapse was associated with fluoroquinolone resistance (crude OR 46, 95% CI 8–273), pyrazinamide resistance (OR 8, 95% CI 2–38) and no culture conversion by month 2 of treatment (OR 7, 95% CI 3–202). Two participants acquired extensive drug resistance. Four studies reported grade 3 or 4 adverse events in 55 out of 304 (18.1%) participants. Shorter regimens were effective in treating MDR-TB; however, there is uncertainty surrounding the generalisability of the high rate of treatment success to less selected populations, to programmatic settings and in the absence of drug susceptibility tests to key component drugs.
Abstract 536: Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis
Authors: Jinah Park, Junil Kim, Poul H. Sorensen, Seong-Jin Kim
Journal: Cancer Research (2017)

Abstract Chromosomal rearrangements that facilitate tumor formation and progression through activation of oncogenic tyrosine kinase are frequently observed in cancer. The ETV6-NTRK3 (EN) fusion has been implicated in various cancers, including infantile fibrosarcoma, secretory breast carcinoma and acute myeloblastic leukemia, and has exhibited in vivo and in vitro transforming ability. In the present study, we analyzed transcriptome alterations using RNA-Seq in EN-transduced NIH3T3 fibroblasts to identify the mechanisms that are involved in EN-mediated tumorigenesis. Through functional profile assessment of EN-regulated transcriptome alterations, we found that EN up-regulated genes mainly associated with cell motion, membrane invagination, and cell proliferation, while down-regulated genes are involved in cell adhesion, which described the transforming potential and increased proliferation in EN-transduced cells. Notably, KEGG pathway analysis identified the JAK-STAT signaling pathway with the highest statistical significance. Moreover, Ingenuity Pathway Analysis and gene regulatory network analysis identified the Stat1 transcription factor and its target genes as top EN-regulated molecules. We further demonstrated that EN enhanced STAT1 phosphorylation but attenuated STAT1 acetylation, thereby inhibiting the interaction between NF-κB p65 and acetylated STAT1. Consequently, nuclear translocation of NF-κB p65 and subsequent anti-apoptotic NF-κB activity were increased by EN. Taken together, here we report, for the first time, STAT1 as a significantly EN-regulated transcription factor and a crucial mediator of EN-induced tumorigenesis. [This work was supported by a National Research Foundation grant of Korea (NRF-2014M3A9B5073918) funded by the Korea government.] Citation Format: Jinah Park, Junil Kim, Poul H. Sorensen, Seong-Jin Kim. Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 536. doi:10.1158/1538-7445.AM2017-536
Novel Mutations in NOTCH and Altered Wnt/β-Catenin Pathway Indicate a Role of Embryonic Signals in the Pathogenesis of T-Cell Prolymphocytic Leukemia
Authors: Henan Zhang, Shulan Tian, Esteban Braggio, Andrew L Feldman, Rhett P. Ketterling, Rong He, Timothy G. Call, Thomas E. Witzig, Sameer A. Parikh, Yi Lin, Charla R Secreto, Emma I Andersson, Satu Mustjoki, Alexandra Schrader, Marco Herling, Huihuang Yan, Wei Ding
Journal: Blood (2016)
Abstract 112: Identifying drugs that target ovarian cancer tumor initiating cells
Authors: Michelle K. Ozaki, Carrie D. House, Christina M. Annunziata
Journal: Cancer Research (2017)

Abstract Ovarian cancer is the most lethal gynecological cancer, with overall five-year survival for women with advanced disease being at only 25%. The current standard of care is treatment with a platinum-based chemotherapy drug. Unfortunately, a subpopulation of tumor cells often persists, contributing to platinum-based chemotherapy resistance and disease recurrence. In this study we investigated drugs to target these putative tumor-initiating cells (TICs), and explored the pathways of these drugs in both adherent proliferative cell culture conditions and non-adherent TIC-enriched cultures. We conducted a drug screen under both growth conditions, in order to identify compounds that are able to inhibit growth of TICs. Of the drugs identified, we focused further efforts on those involved with inhibiting the NF-kappaB pathway because prior studies have linked NF-kappaB activity with drug resistance and poor survival. Cell viability assays done with the four drugs, bardoxolone methyl, salinomycin, disulfiram, and elesclomol, show these drugs inhibit the growth of ovarian cancer cell lines both as TICs and in corresponding adherent cultures. Disulfiram showed preferential killing of TICs in some of the cell lines tested. All drugs showed some evidence for inhibiting NF-kappaB on Western blot, and ability to decrease CD133/ALDH double-positive TICs on flow cytometry. Carboplatin is known to kill proliferative ovarian cancer cells, and increase the relative percentage of CD133/ALDH positive TICs. Our ongoing studies will address combination of each drug with carboplatin, with the hypothesis that these drugs will increase in vivo efficacy by suppressing TICs, and thereby decrease recurrence of platinum-resistant ovarian cancer. Citation Format: Michelle K. Ozaki, Carrie D. House, Christina M. Annunziata. Identifying drugs that target ovarian cancer tumor initiating cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 112. doi:10.1158/1538-7445.AM2017-112