tbuckley/cabot-search huggingface dataset:
Abstract P3-03-18: An ex-vivo platform predicts anti-tumor outcome of metabolically-targeted, algorithm-driven combination therapy in triple-negative breast cancer
Authors: A Goldman, B Majumder, A Dhawan, M Kohandel, P Majumder, S Sengupta
Journal: Cancer Research (2017)

Abstract Cancer cells undergo phenotypic cell state transitions in response to chemotherapy as a mechanism that can confer transient resistance. However, such cell state transitions can also unlock unique vulnerabilities that can be exploited using temporally-sequenced combination chemotherapy. Here, utilizing a primary breast cancer ex-vivo functional assay that captures tumor heterogeneity, we report that in response to a chemotherapeutic agent, a subset of cancer cells can mount an acutely-induced phenotypic adaptive resistance to future cytotoxic pressure via the transient acquisition of a unique metabolic state defined by augmented glycolysis together with mitochondrial proficiency. These cells activate two complex, temporally-interdependent pathways that enable a glucose shunt towards the pentose phosphate pathway (PPP), which confers an adaptive cross-tolerance to different chemotherapeutic agents. Mathematically modeling these pathways, and simulating drug schedules, we define a rationally-designed 3-drug combination therapy of metabolic inhibitors and cytotoxic agents, which results in improved cancer survival. Our findings highlight a new bioenergetics-based adaptive resistance mechanism through which cancer cells can survive combinations of chemotherapy. Administration of metabolic inhibitors in rational, temporal sequence with existing chemotherapy can emerge as a new paradigm in the treatment of cancer. Citation Format: Goldman A, Majumder B, Dhawan A, Kohandel M, Majumder P, Sengupta S. An ex-vivo platform predicts anti-tumor outcome of metabolically-targeted, algorithm-driven combination therapy in triple-negative breast cancer [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 P3-03-18.
Genetic Determinants of Response to Guadecitabine (SGI-110) in AML
Authors: Patricia L. Kropf, Woonbok Chung, Andrew D. Kelly, Hagop M. Kantarjian, Gail J. Roboz, Karen W.L. Yee, Pietro Taverna, Sue Naim, Mohammad Azab, Jaroslav Jelinek, Jean-Pierre J. Issa
Journal: Blood (2016)
NPI-2358, a Novel Vascular Disrupting Agent Blocks Growth and Angiogenesis in Multiple Myeloma Cells.
Authors: Dharminder Chauhan, Ajita V. Singh, Madhavi Bandi, Noopur Raje, Robert L Schlossman, G. Kenneth Lloyd, Paul Richardson, Michael A. Palladino, Kenneth C. Anderson
Journal: Blood (2009)
Image Gallery: PELVIS syndrome
Authors: V. Piccolo, E. Moscarella, O. Ametrano, R. Picciocchi, T. Russo
Journal: British Journal of Dermatology (2017)

Conflicts of interest: none declared. http://orcid.org/0000‐0001‐7798‐4368 Dear Editor, A 4‐month‐old girl presented with a perineal infantile haemangioma.1 It appeared during the second week of life, associated with a large skin tag and two cutaneous orifices in the anogenital and sacral areas (a, b). These were connected through a complex horseshoe fistula detected by fistulogram (c). Spinal magnetic resonance investigation showed a lipomyelomeningocele producing a tethered cord (e). The patient was otherwise normal in terms of development, so on the basis of the clinical and radiological findings a diagnosis of PELVIS syndrome was made. PELVIS is an acronym indicating the association of perineal haemangioma, external genitalia malformations, lipomyelomeningocele, vesicorenal abnormalities, imperforate anus and skin tag.2 Because of the small size of the infantile haemangioma, the patient was given propranolol 1% cream twice daily, with good response after 3 months (d).
Induction and Break of Immune Tolerance to Human FVIII in a HLA-DRB1*1501 Humanized Hemophilic Mouse Model
Authors: Katharina Nora Steinitz, Brigitte Binder, Christian Lubich, Rafi Uddin Ahmad, Markus Weiller, Maurus de la Rosa, Hans Peter Schwarz, Friedrich Scheiflinger, Birgit M Reipert
Journal: Blood (2011)
Abstract B07: Screening of patient-derived carcinoma cells and animal models identifies transcription as target in pancreatic cancer.
Authors: Vladimir Khazak, Natalia Skobeleva, Natalia Beglyarova, Egor Bobrov, Yan Zhou, Sandra A. Jablonski, Louis M. Weiner, Keren Paz, Igor Astsaturov
Journal: Clinical Cancer Research (2016)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals yearly in the US. With almost 90% lethality even when diagnosed prior to metastasis, there is an urgent unmet medical need for new therapies or better matching of existing therapies to patients. To address this emergency, we first had developed a panel of new physiological models for study of PDAC, rapidly expanding surgical PDAC tumor samples in culture with the Rho kinase inhibitor Y-27632, and creating matched patient-derived xenografts (PDX). Using this panel, we evaluated sensitivity to a large panel of existing drugs. Only a small minority of agents were cytotoxic in vitro in a significant number of independent PDAC models. Among these, transcriptional repressors were predominated. From a short list of drugs not previously used in PDAC, triptolide, a covalent inhibitor of the ERCC3, a bifunctional regulator of transcription and DNA repair, was most consistently effective in vitro and highly effective in vivo, causing prolonged complete regression in multiple PDX models. Triptolide is a natural product compound from Chinese medicinal plant Tripterygium wilfordii, and it was found to be the most active agent in the screen. Importantly, triptolide showed superior activity in MYC-amplified PDX models, suggesting a critical role for ERCC3 in this subset. Triptolide elicited rapid and profound depletion of MYC oncoprotein, a transcriptional co-factor for ERCC3. Expression of ERCC3 was MYC-dependent, while resistance to triptolide was associated with elevated ERCC3 and MYC expression. These findings provide preclinical evidences for transcriptional vulnerability in PDAC via ERCC3 targeting and a new mechanistic approach for disruption of MYC-dependent pancreatic cancers. Citation Format: Vladimir Khazak, Natalia Skobeleva, Natalia Beglyarova, Egor Bobrov, Yan Zhou, Sandra A. Jablonski, Louis M. Weiner, Keren Paz, Igor Astsaturov. Screening of patient-derived carcinoma cells and animal models identifies transcription as target in pancreatic cancer.. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B07.
NHS breast screening programme
Authors: H. Goodare, M. King, M. Baum, A. Johnson, J. Shekhdar, N E Day, R. Boer, H. de Koning, A. Threlfall, C. Woodman, A. Street, E. Friedman
Journal: BMJ (1999)

editor 1 is a very sad event for editorial freedom in general and for medical journals world wide in particular.This disgraceful incident has shown that neither size nor success gives any guarantee for editorial freedomnot even the two combined.
ABCA3 Expression Predicts Response to Gemtuzumab Ozogamicin in AML
Authors: Antony Ceraulo, Aminetou Mint-Mohamed, Delphine Maucort-Boulch, Etienne Paubelle, Xavier Thomas, Lea Herpe, Olivier Nibourel, Claude Preudhomme, Sylvie Castaigne, Hervé Dombret, Eric Wattel
Journal: Blood (2016)
Abstract A36: Assessment of effectiveness and molecular markers of CDK4/6 inhibitor Palbociclib in Pancreatic Ductal Adenocarcinomas
Authors: Beatriz Salvador, Pedro P. López-Casas, Camino Menéndez, Natalia Baños, Francesca Sarno, Yin Min-Jean, Peter Olson, Todd VanArsdale, David J. Shields, Manuel Hidalgo
Journal: Clinical Cancer Research (2016)

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) continues to be the deadliest human cancer with a 5-year survival rate of 7%. One of the current standards of care for advanced PDAC is gemcitabine plus nab-paclitaxel, a regimen our group helped develop. Finding new agents to combine with this regimen remains necessary, particularly using drug targeting strategies. At the molecular level, genetic and genomic profiling identified CDKN2A as a very frequently disrupted gene in PDAC (&amp;lt;90%). This gene encodes the tumor suppressor p16, a cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor, that controls cell cycle progression. Recently, the selective CDK4/6 inhibitor palbociclib was approved by the FDA for certain types of breast cancer patients. Whether palbociclib can also benefit patients with PDAC is unknown. In the current study, we aimed to evaluate the effectiveness of palbociclib monotherapy and in combination with nab-paclitaxel and gemcitabine/nab-paclitaxel in a cohort of PDACs patient derived xenograft (PDX) models. PDX models obtained from late stage PDAC patients were treated with palbociclib alone and in combination with gemcitabine/nab-paclitaxel. The majority of models displayed &amp;gt;50% tumor growth inhibition (TGI) following treatment with single agent palbociclib. Treatment with palbociclib plus nab-paclitaxel or palbociclib plus gemcitabine/nab-paclitaxel increased TGI to a greater degree than the gemcitabine/nab-paclitaxel combination and also increased the duration of response as compared to the standard of care therapy. Moving forward, the palbociclib/nab-paclitaxel combination will be evaluated in a clinical trial for PDAC patients. We are currently expanding our analyses to a larger cohort of PDX models and performing molecular characterization of these models in order to gain insights on biomarkers and mechanism of action of the drug combinations in PDAC. Citation Format: Beatriz Salvador, Pedro P. López-Casas, Camino Menéndez, Natalia Baños, Francesca Sarno, Yin Min-Jean, Peter Olson, Todd VanArsdale, David J. Shields, Manuel Hidalgo. Assessment of effectiveness and molecular markers of CDK4/6 inhibitor Palbociclib in Pancreatic Ductal Adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A36.
Sex and Gender Reporting in Research
Authors: Carl G. Streed, Harvey J. Makadon
Journal: JAMA (2017)

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Effect of inhibition of Src and insulin/insulin-like growth factor-1 receptor (IR/IGF-1R) on tumor activity and bone turnover in prostate cancer (PCa) models in vivo relative to inhibition of either kinase alone.
Authors: Farshid Dayyani, John C. Araujo, Joan M. Carboni, Marco M. Gottardis, Geralyn Carol Trudel, Christopher Logothetis, Gary E. Gallick
Journal: Journal of Clinical Oncology (2012)

e15151 Background: Growth of prostate cancer (PCa) metastases relies on bidirectional interactions between the tumor and microenvironment.The Src family kinases (SFK) and insulin-like growth factor-1 receptor (IGF-1R) signaling axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are small molecule inhibitors that target SFK and IGF-1R/IR, respectively. This study examined the in vitro and in vivo effects of BMS-754807 and dasatinib on PCa growth. Methods: Antitumor effects of both reagents were tested alone and in combination in vitro in PC3 and LNCaP cells, using proliferation and apoptosis assays. Signaling pathways were interrogated by western blots. Tumor growth in vivo was assessed by orthotopic and intratibial injection of PC3 cells and subcutaneous growth of primary human xenograft PCa-133b. Serum markers were measured by ELISA. Results: In vitro, dasatinib decreased proliferation and migration of PCa cells whereas BMS-754807 induced apoptosis. All observed anti-tumor effects were enhanced when dual blockade was used. IGF-1 induced phosphorylation of Akt1, but not Akt2, was partially inhibited by either drug alone and almost completely abrogated by the combination. Dasatinib and BMS-754807 inhibited in vivo orthotopic and intratibial tumor growth of PC3 cells more potently than either as a single agent alone with a corresponding decrease in bone turnover markers. Both drugs also exhibited synergism in primary human xenograft tumors. Potent target inhibition (p-Src, p-IGF-1R, p-Akt) by the drug combination was also demonstrated in xenografts. Conclusions: The combination of dasatinib and BMS-754807 may be a rational therapeutic approach in PCa by blocking both independent and complementary processes critical to tumor growth.
Correction: Elp3 drives Wnt-dependent tumor initiation and regeneration in the intestine
Authors: Aurélie Ladang, Francesca Rapino, Lukas C. Heukamp, Lars Tharun, Kateryna Shostak, Damien Hermand, Sylvain Delaunay, Iva Klevernic, Zheshen Jiang, Nicolas Jacques, Diane Jamart, Valérie Migeot, Alexandra Florin, Serkan Göktuna, Brigitte Malgrange, Owen J. Sansom, Laurent Nguyen, Reinhard Büttner, Pierre Close, Alain Chariot
Journal: The Journal of Experimental Medicine (2017)
Abstract P5-07-12: RAD51AP1 is a novel prognostic marker and therapeutic target for breast cancer
Authors: M Thangaraju, RB Kolhe, R Pathania
Journal: Cancer Research (2017)

Abstract Background: Ionizing radiation is one of the most effective therapeutic strategies for the treatment of breast cancer and is considered as a more appropriate therapy for patients with high-risk of recurrence. Despite substantial benefits are achievable with this treatment, especially for ductal carcinoma and early invasive cancer, the critical barrier in using this treatment strategy is that tumor cells develop radioresistance, which in turn progress into advanced invasive cancer. Breast cancer stem cells (BCSCs), a subpopulation of cells within the tumor with a characteristic feature of self-renewal, play a critical role radioresistance and treatment failure. BCSCs exhibit increased DNA repair activity by increasing RAD51AP1 for their prolonged survival and to evade from the radiation therapy. We explored the expression profile of RAD51AP1 in BCSCs, human normal and various subtypes of breast tumor tissues and cell lines and response to chemo- and radiation- therapy. Methods: Gene expression (RNA and protein) profile was assessed using semi-quantitative and real-time PCR (qPCR) and western blot analyses. RAD51AP1 expression and its prognostic value in large cohort of human samples were analyzed by TCGA, GOBO, and Kaplan-Meier plotter integrative bioinformatics interface analyses. Breast cancer stem cell (BCSC) status was analyzed by FACS using CD24 and CD49f cell surface marker. Cell death was analyzed by propidium iodide (PI) stained cell cycle analysis. Results: We found that tumor propagating CD49f+CD24+ cells activate RAD51AP1 more promptly than non-tumorigenic CD49f-CD24- cells and confer chemo- and radiation- therapy resistance. RAD51AP1 inactivation facilitates chemo- and radiation- therapy response by depleting CD49f+CD24+ cells with significant activation of apoptotic cell death signaling. RAD51AP1 expression was significantly higher in BC, especially in the basal triple-negative and HER2-positive BC subtype, than in normal mammary tissue. Further, RAD51AP1 expression is highest in grade III histological tumor types and negatively associated to overall disease-free survival. RAD51AP1 levels across different BC cell lines showed that triple-negative breast cancer (TNBC) cell lines expressed highest level of this gene than other sub types. Conclusion:Overall, our findings provide evidence that BCSCs utilize DNA repair signaling for their self-renewal and RAD51AP1 play a critical role in BCSC self-renewal and maintenance. Further, RAD51AP1 expression profile can be used as a prognostic marker to monitor disease progression and chemotherapy response. Citation Format: Thangaraju M, Kolhe RB, Pathania R. RAD51AP1 is a novel prognostic marker and therapeutic target for breast cancer [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 P5-07-12.
Next Generation Sequencing (NGS) Based Minimal Residual Disease (MRD) Testing Is Highly Predictive of Overall and Progression Free Survival in the Total Therapy Trials and Shows Different Prognostic Implications in High Vs Standard Risk Multiple Myeloma
Authors: Carolina Schinke, Shayu Deshpande, Hongwei Wang, Victoria Carlton, Katherine A. Kong, Martin Moorhead, Tom Willis, Purvi Patel, Sharmilan Thanendrarajan, Meera Mohan, Pankaj Mathur, Sandra Susanibar, Shadiqul Hoque, Muthukumar Radhakrishnan, Ruslana Tytarenko, Owen W Stephens, Leo Rasche, Frits van Rhee, Maurizio Zangari, Nathan Petty, Daisy V. Alapat, Sarah K. Johnson, Joshua Epstein, Bart Barlogie, Faith E Davies, Antje Hoering, Niels Weinhold, Gareth J Morgan
Journal: Blood (2016)
Abstract B16: Activation of NRF2 and adaptive resistance to chemotherapy
Authors: Sarah A. Clinton, Karen W. Barbour, Franklin G. Berger
Journal: Cancer Research (2017)

Abstract Nuclear factor-erythroid-2-related factor 2 (NRF2), a member of the cap ‘n’ collar family of bZIP transcription factors, confers protection against oxidative and electrophilic stress. NRF2 is of great interest in cancer research, due to its role in response to chemotherapy, including the class of drugs targeting thymidylate synthase (TYMS). It has long been known that inhibition of TYMS leads to depletion of thymidine levels and the onset of programmed cell death, deriving from the enzyme's function as the sole de novo source of thymidine for DNA replication and repair. Exposing cells to TYMS inhibitors such as fluoropyrimidine antimetabolites (5-fluorouracil, or FUra; 5'-fluoro-2'-deoxyuridine, or FdUrd), as well as anti-folate analogs (raltitrexed, or RTX), induce intracellular concentrations of reactive oxygen species, which are a primary cause of drug-mediated toxicity. This prompted our focus on assessing the impact of NRF2 on cellular response to TYMS inhibitors. Using human colon tumor-derived cell line HCT116, we have shown by gene expression profiling that drug exposure induces expression of a number of genes that are modulated by NRF2. Quantitative PCR assays of several colon tumor cell lines verified that FUra, FdUrd, and RTX induce transcription of several genes known to be NRF2-targets, including AKR1B10, ALDH3A1, HSPB8, HMOX1, and SERPINE1, among others. Such induction mirrors that in response to the known NRF2 activator tert-butylhydroquinone (tBHQ). NRF2 protein concentration and nuclear localization are increased by FdUrd treatment, though not to the same extent as with tBHQ. Reporter gene constructs were used to show that both FdUrd and tBHQ induce transcription mediated by the NRF2-binding antioxidant response element (ARE). Furthermore, chromatin-immunoprecipitation experiments revealed that TYMS inhibitors promote occupancy of the ARE regions of several genes by NRF2; again, tBHQ had a much greater effect. Further analysis showed an association between gene induction by TYMS inhibitors and patterns of histone acetylation within the NRF2-binding ARE regions. Finally, we observed that increases in the apoptotic index following exposure to TYMS inhibitors were greater in cells in which the transcription factor was subjected to siRNA-mediated “knockdown” or CRISPR/Cas9-mediated “knockout”, indicating that reduced NRF2 expression sensitizes cells to TYMS inhibitors. Overall, we conclude that TYMS inhibitors activate NRF2 and its downstream target genes, thereby constraining drug response. Reducing such activation of NRF2 or its consequences may be an effective strategy to sensitizing tumor cells to chemotherapy. Citation Format: Sarah A. Clinton, Karen W. Barbour, Franklin G. Berger. Activation of NRF2 and adaptive resistance to chemotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B16.
Regulation of Apoptosis and Oxidative Stress by LMP1 Oncoprotein of Epstein-Barr Virus in Patients with Low Grade B-Cell Leukemic Lymphomas
Authors: Panagiotis Theodorou Diamantopoulos, Katerina Polonyfi, Nikolaos Spanakis, Athanassios Galanopoulos, Georgia Diamantopoulou, Efthymia Bazanis, Angeliki-Maria Saridaki, Maria K. Angelopoulou, Christos Poziopoulos, Eleni Variami, Marina Mantzourani, Theodoros P. Vassilakopoulos, Marina Siakantaris, Nikolaos Anagnostopoulos, Despoina Perrea, Panagoula Kollia, John Meletis, Nora-Athina Viniou
Journal: Blood (2011)
Abstract BS2-2: PTEN loss by exosomal microRNA primes brain metastasis outgrowth
Authors: D Yu
Journal: Cancer Research (2017)

Abstract Of 1.6 million newly diagnosed breast cancer patients per year, about 10-16% will develop brain metastases. Among the different subtypes of breast cancer, HER2-overexpressing (HER2+) and triple-negative breast cancers (TNBC) have the highest incidence of brain metastasis. Recently, advances in targeted therapies for breast cancer (e.g., trastuzumab, T-DM1, and lapatinib) have prolonged patient survival through better control of the systemic disease. However, when patients have disease recurrence, their brain metastasis incidence doubles, which represents an imposing challenge. Current treatment options are limited and merely palliative for those patients with brain-metastatic breast cancer, and their one year survival is less than 20%. To develop effective treatments for brain metastasis, we strived to gain global understanding of the mechanisms of brain metastasis to guide rapid development of novel and clinically applicable targeted therapies. We recently found that the brain astrocytes secrete exosomes that contain PTEN-targeting miR-19a, among other biomolecules. After brain metastatic tumor cells uptake these astrocytes-derived exosomes, miR-19a reversibly downregulates PTEN expression in metastatic tumor cells, thereby increasing Akt and NF-kB signaling, leading to an increased secretion of CCL2 cytokine. CCL2 then recruits CCR2 positive and Iba1 positive myeloid cells that promote proliferation and inhibit apoptosis of brain metastatic tumor cells and facilitate metastatic tumor outgrowth to symptomatic brain metastasis. Importantly, inhibition of exosome secretion or stable ablation of CCL2 inhibits brain metastasis outgrowth in vivo, demonstrating the potential of exosome- and CCL2-targeting for therapeutic intervention of life-threatening brain metastases (Nature, 11/2015). Currently, we are exploring the clinical potential by systematic preclinical testing in animal models. Citation Format: Yu D. PTEN loss by exosomal microRNA primes brain metastasis outgrowth [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 BS2-2.