tbuckley/cabot-search huggingface dataset:
Abstract 4975: A small molecule pan Id protein antagonist shows strong antitumor activity
Authors: Paulina M. Wojnarowicz, Bina Desai, Yvette Chin, Sang Bae Lee, Marta Garcia-Cao, Ouathek Ouerfelli, Guangli Yang, Sijia Xu, Yehuda Goldgur, Meredith A. Miller, Jaideep Chaudhary, William A. Garland, Steven K. Albanese, Rajesh Soni, John Philip, Larry Norton, Neal Rosen, Ronald C. Hendrickson, Xi Kathy Zhou, Antonio Iavarone, Andrew J. Dannenberg, John D. Chodera, Nikola Pavletich, Anna Lasorella, Robert Benezra
Journal: Cancer Research (2017)

Abstract The Id family of helix-loop-helix (HLH) proteins, Id1, Id2, Id3 and Id4, play a critical role in inhibiting differentiation during mammalian embryogenesis. They function in part by sequestering ubiquitously expressed E protein bHLH transcription factors via direct protein-protein interactions. Various Id proteins are re-expressed in adults in a number of pathologic states including cancer and diseases of the vasculature, where their activity has been shown to be essential for disease progression. The present study describes the solving of the Id1-E47 dimer crystal structure and subsequent development and characterization of a small molecule antagonist of the Id protein family, AGX51. AGX51 was identified in an in silico screen for compounds that could bind a hydrophobic crevice adjacent to the loop region of Id1, highly conserved in the Id family. AGX51 inhibits the endogenous Id1-E protein interaction leading to the degradation of Id1 via ubiquitin-mediated proteolysis. The stability of all four members of the Id family are antagonized by AGX51 leading to a G0-G1 arrest and profound inhibition of viability with no acquired resistance observed in multiple cell lines after continuous exposure to the compound. Administration of AGX51 is well tolerated in mice and phenocopies genetic loss of Id expression analyses: suppression of breast cancer metastases to the lung associated with a reduced mesenchymal-to-epithelial transition, perturbation of the vasculature within the primary tumor, and growth regression of paclitaxel resistant breast tumors in combination with paclitaxel therapy. These studies identify a novel, first-in-class compound capable of antagonizing the activity of a protein family formerly considered undruggable and point to the possible utility of AGX51 in the management of multiple disease processes in patients. Citation Format: Paulina M. Wojnarowicz, Bina Desai, Yvette Chin, Sang Bae Lee, Marta Garcia-Cao, Ouathek Ouerfelli, Guangli Yang, Sijia Xu, Yehuda Goldgur, Meredith A. Miller, Jaideep Chaudhary, William A. Garland, Steven K. Albanese, Rajesh Soni, John Philip, Larry Norton, Neal Rosen, Ronald C. Hendrickson, Xi Kathy Zhou, Antonio Iavarone, Andrew J. Dannenberg, John D. Chodera, Nikola Pavletich, Anna Lasorella, Robert Benezra. A small molecule pan Id protein antagonist shows strong antitumor activity [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 4975. doi:10.1158/1538-7445.AM2017-4975
Abstract 2200: Dual carfilzomib and doxorubicin carrying nanoparticles for synergistic efficacy in multiple myeloma
Authors: Basar Bilgicer, Tanyel Kiziltepe, David Omstead
Journal: Cancer Research (2017)

Abstract We describe the synthesis and analysis of dual carfilzomib and doxorubicin loaded nanoparticles in their ability to deliver both drugs to multiple myeloma tumor cells at their optimal synergistic ratio. First, to identify the optimal synergistic ratio, various molar ratios of carfilzomib to doxorubicin were screened against multiple myeloma cell lines using the Chou-Talalay method. Both therapeutic agents were then incorporated into liposomes at the identified optimal synergistic ratio of 1:1 to achieve dual drug loaded nanoparticles with a narrow size distribution of ~100 nm and with high reproducibility. Our results established that the dual drug loaded nanoparticles exhibited synergy in vitro and were more efficacious in inhibiting tumor growth in vivo than a combination of free drugs, while at the same time reducing systemic toxicity. In conclusion, this study achieved the preclinical evaluation of dual drug loaded liposomes containing carfilzomib and doxorubicin for enhanced therapeutic efficacy to improve patient outcome in multiple myeloma. Citation Format: Basar Bilgicer, Tanyel Kiziltepe, David Omstead. Dual carfilzomib and doxorubicin carrying nanoparticles for synergistic efficacy in multiple myeloma [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 2200. doi:10.1158/1538-7445.AM2017-2200
Deferred treatment as a viable option for selected patients with mantle cell lymphoma.
Authors: Oscar Calzada, Jeffrey M. Switchenko, Joseph J. Maly, Kristie A. Blum, Natalie Sophia Grover, Stephanie Mathews, Steven I. Park, Max J Gordon, Alexey Valeryevich Danilov, Christopher Flowers, Jonathon Brett Cohen
Journal: Journal of Clinical Oncology (2016)

7567 Background: While mantle cell lymphoma (MCL) has historically been treated at the time of diagnosis, we recently reported a national cohort analysis which identified a subset of patients who can safely defer therapy (Cohen et. al, ASH 2015), validating previously reported single-center findings (Martin et al, JCO 2009). We conducted a multicenter analysis of MCL patients with additional clinical data to better describe the role of deferred therapy in MCL. Methods: Patients ≥ 18 years old who received initial treatment for newly diagnosed MCL between 1995-2015 at one of four academic sites were included. Deferred therapy was defined as receipt of first treatment > 90 days following diagnosis. We identified variables associated with receipt of deferred therapy and evaluated the impact of deferred therapy, demographic factors and MIPI components on progression-free (PFS) and overall survival (OS) in multivariable regression models. Results: Of 356 patients, 71 (20%) received deferred therapy with a median time to treatment for this group of 234 days. Among all patients, the median age at diagnosis was 62 years, 72% were male, 95% were stage III/IV, and 32% presented with B symptoms. Patients receiving deferred therapy were more likely to have an ECOG performance status of 0 (68% vs 49% p = 0.009), lack B symptoms (83% vs 65% p = 0.004) and have normal LDH levels at diagnosis (87% vs 57% p < 0.001). Patients receiving immediate treatment more commonly had bone marrow involvement (84% vs 71% p = 0.016) and splenomegaly (58% vs 41% p = 0.015). In multivariable analysis presence of complex karyotype (CK; ≥ 3 chromosomal abnormalities) was the only significant predictor of inferior OS (HR 3.17, 95% CI 1.69-5.95). Deferred therapy was not associated with differences in OS (HR 0.64: 95% CI 0.30-1.33, p = 0.228), and there was no significant difference in frequency of a CK between the deferred and immediate therapy groups (p = 0.3). Conclusions: This retrospective, multi-center cohort analysis validates prior findings that deferred therapy may be a safe option for a subgroup of MCL patients. Future studies are needed to better identify suitable candidates for deferred therapy.
Letter by Banack et al Regarding Article, “Body Mass Index and Mortality Among Adults Undergoing Cardiac Surgery: A Nationwide Study With a Systematic Review and Meta-Analysis”
Authors: Hailey R. Banack, Steven D. Stovitz, Jay S. Kaufman
Journal: Circulation (2017)

A meta-analysis synthesizes published research on a given topic.In general, it provides high-quality support for a clinical question of interest and is considered the gold standard of evidence under the framework of evidence-based medicine.However, the recent study by Mariscalco and colleagues 1 highlights an important problem with considering meta-analyses the highest level of evidence: if individual studies in the literature are biased, then the summary effect estimate produced by the meta-analysis may reflect the same biased value but with a smaller standard error.Summarizing reduces sampling variability, and therefore 95% confidence intervals, but also incorporates bias from each individual study.No statistical method is available to quantify or adjust for this type of bias.It is conceptually different than issues such as the study heterogeneity or publication bias (assessed by I 2 statistic or Egger's test, respectively).We commend the authors for a comprehensive search strategy identifying 26 cohort studies and including a large population in the meta-analysis, but the study size does nothing to allay our concerns about bias.3][4] We are particularly concerned about the possibility that a form of selection bias, known as collider stratification bias or index event bias, is affecting the results of the studies included in the meta-analysis.This type of bias has been demonstrated to produce attenuated effect estimates (a bias toward the null value) or, in certain situations, to reverse the expected direction of an effect estimate, making a harmful exposure, such as obesity, appear protective.Therefore, we question the value of this meta-analysis.A meta-analysis of biased studies will provide a precise but invalid effect estimate.We have an additional concern about the authors' assertion that their analysis assesses "whether the obesity paradox can be attributed to reverse epidemiology, bias and confounding, or other mechanisms" 1 (p.4).In the Supplemental Material, the authors describe using propensity scores to account for unmeasured confounding and selection bias.However, propensity scores are a tool to adjust for confounding by measured variables.It is impossible to create a propensity score to account for unmeasured confounding.Moreover, propensity scores do not account for selection bias as the authors claim.In fact, none of the impressive statistical methods used in the sensitivity analyses (fractional polynomials, restricted cubic splines, propensity scores) suggests that the results are robust to unmeasured confounding or selection bias.The present study serves as a reminder that, although meta-analyses can be a valuable tool to summarize information, they also can produce misleading results and should not always be considered the gold standard of evidence.
Abstract 2307: The p53/p21 complex is a functional unit that regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins
Authors: Eun Mi Kim, Hong-Duck Um
Journal: Cancer Research (2017)

Abstract Although well known as a transcription factor, the p53 tumor suppressor also exists in the cytoplasm (including the mitochondria) of normal and cancer cells. Moreover, nuclear p53 is translocated to the mitochondria upon apoptotic stimulation of cells. The cytoplasmic/mitochondrial p53 can bind pro-survival Bcl-2 family proteins (e.g., Bcl-2, Bcl-XL, and Bcl-w), liberating Bax therefrom. Bax then exerts its pro-apoptotic or anti-invasive function depending on experimental conditions. Given the ability of p53 to interact with p21, we investigated the possible involvement of p21 in these functions. Here, we show that whereas p53 can bind to Bcl-w alone, it requires p21 to liberate Bax from Bcl-w and suppress/promote cell invasion/death, respectively. p21 consistently binds Bcl-w, forming a p53/p21/Bcl-w complex. Only this trifold complex, but not any of the pairings, facilitates the release of Bax from Bcl-w. Accordingly, a p53 derivative incapable of binding p21 fails to mediate radiotherapy-induced tumor retardation and cell death in mice. We further show that Bcl-2 and Bcl-XL also serves as a target of p53/p21 cooperative action. Overall, our findings indicate that the p53/p21 complex rather than p53 itself regulates cell invasion and death by targeting Bcl-2 proteins. We propose that the p53/p21 complex is a functional unit that acts on multiple types of cellular components, providing a new foundation for understanding the tumor-suppressing functions of p53 and p21. Citation Format: Eun Mi Kim, Hong-Duck Um. The p53/p21 complex is a functional unit that regulates cancer cell invasion and apoptosis by targeting Bcl-2 family proteins [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 2307. doi:10.1158/1538-7445.AM2017-2307
Abstract 663: Clinical performance and utilization of 3 PD-L1 immunohistochemical assays
Authors: Steven M. Anderson, Bruce Horten, Bryan McCune, Ronald Paler
Journal: Cancer Research (2017)

Abstract Three different PD-L1 immunohistochemical (IHC) assays have recently been approved to help guide treatment decisions regarding anti-PD-1 (Keytruda®, Opdivo®) and anti-PD-L1 (Tecentriq®) immuno-oncology based therapies. The three assays differ in the primary monoclonal antibodies used, the assay platform (Dako, Ventana), scoring and interpretation criteria, and intended use. Our clinical laboratories currently offer all 3 assays (pharmDx™ 22C3, pharmDx™ 28-8, and SP142) because they are associated with different intended uses, companion and complementary diagnostics for non-small-cell lung cancer (NSCLC), and complementary diagnostic for urothelial carcinomas (UC). In the NSCLC samples evaluated in the first year since the approval of the two pharmDx™ assays, we have noted a higher percentage of positive samples with the pharmDx™ 28-8 assay (50%) compared to the pharmDx™ 22C3 assay (30%). This difference is mainly due to the use of different assay cutoffs associated with the two assays, as there is good correlation between the overall staining patterns, including the distribution of the percentage of tumor cells exhibiting positive staining. For the SP142 assay tested on UC samples, 22% of the cases were considered positive. All 3 assays are robust, with a limited number of samples considered inconclusive (&amp;lt;10%), mainly due to an inadequate number of tumor cells. The companion diagnostic PD-L1 assay (pharmDx™ 22C3) has had the greatest utilization of the 3 assays, as it is required for the use of the Keytruda® in NSCLC samples. The performance features of the 3 different PD-L1 assays in the clinical laboratory setting has shown that all assays are robust and can be readily scored and interpreted by the pathology team. The utilization of the 3 assays correlates with respective intended use, tumor type and companion versus complementary diagnostic application, for each assay. Citation Format: Steven M. Anderson, Bruce Horten, Bryan McCune, Ronald Paler. Clinical performance and utilization of 3 PD-L1 immunohistochemical assays [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 663. doi:10.1158/1538-7445.AM2017-663
The Benefit of Early Preventive Dental Care for Children
Authors: Shulamite S. Huang, Ryan R. Ruff, Richard Niederman
Journal: JAMA Pediatrics (2017)

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Abstract 3590: Somatic variation discovery with GATK4
Authors: Geraldine A. Van der Auwera
Journal: Cancer Research (2017)

Abstract The Genome Analysis Toolkit or GATK, developed at the Broad Institute, is currently one of the most widely used software toolkits for germline short variant discovery and genotyping in whole genome and exome data. GATK4 is the next generation of GATK; it runs faster and covers more ground, adding somatic SNVs, Indels and CNVs to its variant discovery portfolio. Given the breathtaking increase in the amount of genomic data produced in recent years, GATK development has come to tackle multiple challenges: a) reflect the cutting-edge of science in terms of depth as well as breadth of analyses offered, b) scale to petabytes of data and c) provide a way to navigate the tradeoff between turn-around-time and cost of analyses. GATK4 addresses all of these challenges through a complete redesign and reimplementation of the original GATK software. This new version greatly expands the toolkit's scope of action within the variant discovery space by improving somatic mutation calling and adding copy number, structural variant and tumor-heterogeneity analysis tools. For the established tools and algorithms composing the GATK Best Practices pipelines for short variant discovery (including MuTect2, the next generation of the DREAM challenge-winning somatic SNV caller MuTect, developed originally in the Cancer Genome Analysis group at the Broad Institute), GATK4 is a substantial upgrade that streamlines the tools' operation, providing functionally equivalent results in a much faster timeframe through greatly increased efficiency and leaner engineering. Designed with cloud infrastructure in mind (although it still runs on local infrastructure), GATK4 is implemented with support for Apache Spark, makes key operations hundreds of times faster than previous generations of GATK and comes with end-to-end pipeline implementations that run out of the box on select cloud platforms. Citation Format: Geraldine A. Van der Auwera. Somatic variation discovery with GATK4 [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 3590. doi:10.1158/1538-7445.AM2017-3590
Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study
Authors: Shyamala C. Navada, Guillermo Garcia-Manero, Katherine P. Hearn, Rosalie Odchimar-Reissig, Erin P. Demakos, Yesid Alvarado, Naval Daver, Courtney D DiNardo, Marina Konopleva, Gautam Borthakur, Pierre Fenaux, Michael E. Petrone, Patrick Simon Zbyszewski, Steven M. Fruchtman, Lewis R. Silverman
Journal: Blood (2016)
Abstract LB-062: Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles
Authors: Tambet Teesalu, Hunt Hedi, Lorena Simón-Gracia, Allan Tobi, Kazuki N. Sugahara, Shweta Sharma, Erkki Ruoslahti
Journal: Cancer Research (2017)

Abstract Gastrointestinal and gynecological malignancies disseminate loco-regionally in the peritoneal cavity - a condition known as peritoneal carcinomatosis (PC). Intraperitoneal (IP) administration can be used to improve therapeutic index of anticancer drugs used for PC treatment. Activity of IP anticancer drugs can be further potentiated by encapsulation in nanocarriers and/or affinity targeting with tumor-specific affinity ligands, such as tumor homing peptides. Here we evaluated a novel tumor penetrating peptide, linTT1 (AKRGARSTA), as a PC targeting ligand for nanoparticles. We first demonstrated that the primary homing receptor for linTT1, p32 (or gC1qR), is expressed on the cell surface of peritoneal carcinoma cell lines of gastric (MKN-45P), ovarian (SKOV-3), and colon (CT-26) origin, and that peritoneal tumors in mice and clinical peritoneal carcinoma explants express p32 protein accessible from the IP space. Iron oxide nanoworms (NWs) functionalized with the linTT1 peptide were taken up and routed to mitochondria in cultured PC cells. NWs functionalized with linTT1 peptide in tandem with a pro-apoptotic [D(KLAKLAK)2] peptide showed p32-dependent cytotoxicity in MKN-45P, SKOV-3, and CT-26 cells. Upon IP administration in mice bearing MKN-45P, SKOV-3, and CT-26 tumors, linTT1-functionalized NWs showed robust homing and penetration into malignant lesions, whereas only a background accumulation was seen in control tissues. In tumors, the linTT1-NW accumulation was seen predominantly in CD31-positive blood vessels, in LYVE-1-positive lymphatic structures, and in CD11b-positive tumor macrophages. Experimental therapy of mice bearing peritoneal MKN-45P xenografts and CT-26 syngeneic tumors with IP linTT1- D(KLAKLAK)2-NWs resulted in significant reduction of weight of peritoneal tumors and significant decrease in the number of metastatic tumor nodules, whereas treatment with untargeted D(KLAKLAK)2-NWs had no effect. Our data show that targeting of p32 with linTT1 tumor-penetrating peptide improves tumor selectivity and antitumor efficacy of IP pro-apoptotic NWs. P32-directed intraperitoneal targeting of other anticancer agents and nanoparticles using peptides and other affinity ligands may represent a general strategy to increase their therapeutic index. Citation Format: Tambet Teesalu, Hunt Hedi, Lorena Simón-Gracia, Allan Tobi, Kazuki N. Sugahara, Shweta Sharma, Erkki Ruoslahti. Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles [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 LB-062. doi:10.1158/1538-7445.AM2017-LB-062