tbuckley/cabot-search huggingface dataset:
Abstract 3301: Using a novel single-cell lineage-tracing technique to uncover the mechanisms driving nongenetic cancer relapse
Authors: Yaara Oren, Aviv Regev, Joan Brugge
Journal: Cancer Research (2018)

Abstract Despite favorable initial response to platinum chemotherapy, the majority of patients with ovarian cancer will develop recurrent disease and succumb to it within 5 years of diagnosis. Initial recurrence is frequently platinum-sensitive and women can respond to multiple lines of platinum-based chemotherapy before eventually developing platinum-refractory disease. The observation that the tumor cells that survive the initial therapy give rise to a chemosensitive progeny is inconsistent with a simple Darwinian model of selection of genetically resistant clones. Tumor dormancy, stochastic cell state shifts and stem cell-like populations are among the mechanisms hypothesized to mediate re-emergence of platinum-sensitive ovarian cancer. However, given the lack of high-throughput methods to simultaneously track cell state and lineage, it is not currently feasible to distinguish the relative contribution of each of these factors. To address this need, we generated a new lentiviral barcode library, termed Watermelon. Unlike existing barcoding libraries that enable the tracking of multiple cancer cells solely at the DNA level, the Watermelon library encodes transcribed barcodes, which allows one to map the lineage to the transcriptional profile of each individual cell. This unique barcoding scheme, which is coupled with a genetic H2B retention system, enables simultaneous tracing of lineage as well as the transcriptional and proliferative states of each cell in the population during drug treatment. We have established and characterized an in vitro platinum-sensitive relapse model and are applying the Watermelon system together with time-lapse imaging to study the mechanisms underlying time-to-relapse variation and cell-fate decisions. By broadening our knowledge of the cellular and molecular pathways that affect noninherited drug resistance, our work will facilitate the future development of novel therapies that delay or even prevent the emergence of platinum-refractory ovarian cancer. Citation Format: Yaara Oren, Aviv Regev, Joan Brugge. Using a novel single-cell lineage-tracing technique to uncover the mechanisms driving nongenetic cancer relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3301.
Abstract 3219: Sensitizing hypoxic small cell lung cancer cells to radiation and hydrogen peroxide-producing agents using CuATSM
Authors: Sebastian Sciegienka, Samuel Rodman, Ann Tomanek-Chalkley, Kelly C. Falls, Douglas R. Spitz, Melissa A. Fath
Journal: Cancer Research (2018)

Abstract Cancer cells have increased steady state levels of reactive oxygen species (ROS; O2•- and H2O2) compared to normal cells. It has been proposed that using redox active agents that further increase ROS levels will result is selective cancer cell death. This metabolic frailty can be targeted using drugs deemed safe for human use, ascorbate (ASC) and disulfiram (DSF), via a mechanism of H2O2 production. CuATSM is a drug being used in clinical trials to treat ALS disease. Imaging studies have shown that CuATSM preferentially concentrates in hypoxic tissues, releasing its Cu after entering cells. Copper (Cu) can participate in oxidation reactions that result in highly toxic hydroxyl radicals. Tumors often have areas of hypoxic tissue that exhibit resistance to ionizing radiation (IR). Our hypothesis is that CuATSM can be used to sensitize hypoxic regions of tumors to IR, ASC and/or DSF. Method: H2O2 flux after addition of ASC or DSF was measured in small cell lung cancer (SCLC) cells DMS53 using the 3-aminotriazole method. The Cu uptake of these cells was measured in normoxia and hypoxia after treatment with CuATSM. DMS53 and DMS273 (SCLC lines) were treated with ASC, CuATSM, and/or DSF+CuSO4 at varying oxygen tensions with and without IR and clonogenic assays were performed. Results: Pharmacologically relevant dosing of DSF and ASC resulted in significantly higher fluxes of H2O2 compared to control. Both DSF and ASC enhanced IR clonogenic cell death in SCLC lines. Treatment with CuATSM resulted in increased intracellular Cu and enhanced cell death from ASC and IR in hypoxic conditions. Conclusion: These observations support the hypothesis that the differences in steady-state level of ROS in small cell lung cancer cells can be exploited to develop effective therapies using ASC and DSF. Furthermore CuATSM can enhance responses in hypoxic tumor tissues to both IR and ASC. (Supported by P50 CA174521, T32 CA078586, P30 CA086862 and Carver Research Program of Excellence in Redox Biology and Medicine.) Citation Format: Sebastian Sciegienka, Samuel Rodman, Ann Tomanek-Chalkley, Kelly C. Falls, Douglas R. Spitz, Melissa A. Fath. Sensitizing hypoxic small cell lung cancer cells to radiation and hydrogen peroxide-producing agents using CuATSM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3219.
Abstract 271: Diterpenoid pseudolaric acid B induces M-phase arrest and apoptosis primarily through JNK stress signaling in LNCaP prostate cancer cells
Authors: Kartick C. Pramanik, Nehal Gupta, Min Ye, Junxuan Lu, Cheng Jiang
Journal: Cancer Research (2018)

Abstract Pseudolaric acid B (PAB) is a major diterpenoid component isolated from the root bark of the traditional Chinese medicinal plant Pseudolarix kaempferi Gordon (Pinaceae). PAB has shown potential as an anticancer agent via inducing cell cycle arrest, apoptosis and DNA damage in several cancer models. To explore potential use of PAB for prostate cancer chemoprevention, we used human LNCaP prostate cancer cells that harbor wild-type p53, functional androgen receptor (AR), and defective PTEN that are characteristic of early stage prostate adenocarcinomas to study cell fates and signaling mechanisms upon PAB exposure in cell culture. Our results show that PAB inhibited LNCaP cell proliferation in a dose- and time-dependent manner (IC50 ~5.4 µM at 24 h and ~ 0.2 µM at 72 h). PAB induced M phase cell cycle arrest as confirmed by increased phosphorylation of histone H3 (p-H3 Ser10). PAB also induced apoptosis evidenced by Annexin V staining and cleavage of the canonical caspase substrate PARP. PAB at lethal exposure concentration decreased AR protein and its best-known target prostate-specific antigen (PSA). Timewise, PAB treatment increased p-H3 (mitosis marker) and the expression of another mitosis/prosurvival protein survivin several hours ahead of PARP cleavage. PAB induced p-H2A.X, which would mark DNA double-strand breaks, and the best-known DNA damage response protein P53 and its target P21Cip1 preceding cPARP. PAB stimulated phosphorylative activation of c-Jun N-terminal kinase (JNK), and the JNK inhibitor SP600125 decreased PAB-induced p-H2A.X, P53/P21Cip1 and cleavage of PARP as well as M phase arrest. Furthermore, PAB significantly increased 2',7'-dichlorofluorescin diacetate (DCF)-reactive oxygen species (DCF-ROS) in LNCaP cells and addition of antioxidant N-acetyl-L-cysteine (NAC) attenuated P53/P21Cip1 cascade and cPARP/apoptosis, but did not affect M phase arrest. Knocking-down of P53 or P21Cip1 by siRNA attenuated cPARP and apoptosis without affecting p-H2A.X. Taken together, these results suggest a rapid induction of M phase arrest by PAB that was primarily mediated by JNK stress signaling, either parallel to or upstream of ROS-DNA damage-driven P53-P21Cip1 apoptosis cascade in LNCaP cells. Citation Format: Kartick C. Pramanik, Nehal Gupta, Min Ye, Junxuan Lu, Cheng Jiang. Diterpenoid pseudolaric acid B induces M-phase arrest and apoptosis primarily through JNK stress signaling in LNCaP prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 271.
Abstract 2507: Axl suppression inhibits cell migration, invasion and survival in breast and prostate cancer cell lines
Authors: Mai Tanaka, Samantha S. Dykes, Dietmar W. Siemann
Journal: Cancer Research (2018)

Abstract Cancer is the second leading cause of death in the United States with approximately 90% of cancer-related deaths resulting from metastatic disease. In tumor cells, upregulation of certain signaling pathways promote metastatic phenotypes characterized by enhanced invasion, migration, survival, proliferation and induction of angiogenesis. One pathway of considerable interest involves the receptor tyrosine kinase Axl that is expressed in a variety of tumor types and is associated with poor prognosis and metastasis. Furthermore, Axl's ligand, Growth arrest specific 6 (Gas6) protein, can activate a number of downstream signaling pathways that promote metastatic phenotypes. The purpose of the current study was to characterize Axl and Gas6 in a number of human tumor cell lines and to determine the effect of Axl suppression on the metastatic phenotypes, specifically cell migration, invasion and survival. A panel of human tumor cell lines, including prostate, breast, colorectal, renal, and osteosarcoma, were characterized for Axl expression by Western blot and qPCR. Gas6 expression was assessed by qPCR and Gas6 secretion was determined in conditioned media by ELISA. Axl was genetically inactivated by shRNA in prostate (DU145) and breast (MDA-MB-231) cancer cell lines. The efficiency of knockdown was determined by Western blot. The effect of Axl knockdown on the migratory and invasive potentials of these cell lines was evaluated by transwell migration and invasion assays. A clonogenic cell survival assay was used to assess the impact of Axl knockdown on tumor cell viability. Axl-expressing tumor cells expressed and secreted its ligand Gas6, suggesting that Axl is co-expressed with Gas6, and may be mediated by autocrine regulation. Genetic inactivation of Axl (shRNA) inhibited cell migration, invasion and reduced clonogenic cell survival in both the MD-MB-231 breast and DU145 prostate cancer cell lines. These findings suggest that Axl may be a novel therapeutic target to inhibit the dissemination of tumor cells. Ongoing experiments are evaluating the impact of the Axl-targeting agent R428 on Axl signaling and metastatic phenotype. Citation Format: Mai Tanaka, Samantha S. Dykes, Dietmar W. Siemann. Axl suppression inhibits cell migration, invasion and survival in breast and prostate cancer cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2507.
The impact of primary surgery on stage IV breast cancer.
Authors: Ella Harris, Malcolm R. Kell, Reem Salman, Maurice Stokes, Tom Gorey
Journal: Journal of Clinical Oncology (2012)

1113 Background: The role of primary surgery in metastatic breast cancer is unclear. Here in we have performed metaanalysis on available data to assess the role of surgery on oncological outcome in patients with stage IV breast cancer. Methods: A comprehensive search for published trials that examined outcome following removal of primary disease in stage IV breast cancer was performed using MEDLINE and cross referencing available data. Reviews of each study were conducted, and data were extracted. Primary outcome was overall survival related to surgical removal of primary disease. Results: We identified 15 relevant studies of which 10 were appropriate for analysis. Data was available on 28,693 patients with stage IV disease, of whom 52.8% underwent removal of the primary carcinoma. Patients undergoing primary surgery in this setting were more likely to be alive at 3 years 40% vs. 22% (OR 2.32 CI 2.08-2.6, p&lt;0.01 (surgery vs. no surgery)). Analysis of subgroups for selection to surgery or not, favoured smaller tumours, fewer comorbidities, fewer metastases (p&lt;0.01). There was no difference between the two groups in location of metastases, grade of tumour or receptor status. Conclusions: Patients undergoing removal of primary carcinoma in the setting of stage IV breast cancer appear to have an improved overall survival. However the available data suggest that these surgical patients probably have better prognosis stage IV disease than those patients not undergoing surgery.
Abstract 15607: Mitochondrial and Biochemical Effects of Repetitive Cycles of Remote Ischemic Conditioning (RIC) in Human Upper and Lower Extremities
Authors: Maia Y Taft, Elizabeth Kenny, Nicholas Krehel, Hannah Airgood, Kate Holquist, Stacey Gerstel, Catherine Corey, Jon Rittenberger, Frank X Guyette, Sruti Shiva, Cameron Dezfulian
Journal: Circulation (2015)

Introduction: RIC is protective against heart and brain ischemia. The mechanisms are still debated as are dose effects of repetitive cycles using the upper or lower extremity. Increases in reactive hyperemia (RH), plasma nitrite and reactive oxygen species (ROS) may underlie protective signaling. Hypothesis: Repetitive cycles of RIC will be more effective in thigh than forearm increasing plasma nitrite and inhibiting mitochondrial function with small increases in ROS. Methods: Ten healthy individuals were subjected to 4 cycles of 5 min of limb ischemia, delivered by blood pressure cuff occlusion, and 5 min reperfusion (RIC). Subjects were randomized to right forearm or right thigh RIC first, then crossed over to the other extremity 2 weeks later. Blood flow and perfusion were monitored using laser speckle contrast imaging and by tissue oximetry on the ipsilateral and contralateral foot or hand. Blood was obtained at baseline and after each cycle and 24 h later for determination of platelet nitrite levels (chemiluminescence), mitochondrial function (Seahorse) and superoxide (ROS) generation (mitoSOX flow cytometry) and plasma nitrite. Results: RH, nitrite levels, mitochondrial oximetry and ROS were similar in arm (presented below) and thigh(p&gt;0.2). RH (178% increased blood flow, 17% increased oximetry; p&lt;0.0001) occurred after each RIC cycle with no difference between cycles 1-4. Plasma nitrite significantly increased (23%; p=0.033) after four cycles RIC and returned to baseline 24h later. The platelet rich plasma (PRP) nitrite was highest after cycle 1 (76% increase; p=0.002) with steady reduction after each cycle (15% over baseline by cycle 4; p=0.001). With each cycle platelet mitochondrial respiration declined (24% max by cycle 4) whereas superoxide generation increased (27% max by cycle 4; p&lt;0.05). Conclusions: RIC using arm or leg produce similar physiologic and biochemical effects. RH of similar degree occurs with each cycle whereas nitrite production peaks after the first cycle and is consumed with subsequent cycles coincident with gradual mitochondrial inhibition and superoxide generation. These biochemical responses have been suggested in pre-clinical work to underlie protective signaling and differ little based on extremity used.
Association of <i>p53 Arg72Pro</i> polymorphism and HPV status with the initiation, progression, and development of cervical cancer (CC): A meta-analysis.
Authors: Steven Habbous, Vincent Pang, Lawson Eng, Helen Mackay, Eitan Amir, Geoffrey Liu
Journal: Journal of Clinical Oncology (2012)

1597 Background: CC develops through progression from normal cervical epithelium through squamous intra-epithelial lesions (SILs) to cancer. CC is classically associated with oncogenic human papillomavirus (HPV). Yet, not all CC patients demonstrate HPV infection at diagnosis. HPV+ and HPV– subsets of CC patients may thus represent distinct entities. HPV binds to P53, promoting its degradation; the Arg variant of p53 Arg72Pro binds more ardently to HPV than the Pro variant. Although there have been meta-analyses of Arg72Pro in CC risk, none has evaluated the relationship between Arg72Pro and HPV status together. We hypothesize that p53 Arg72Pro modifies aspects of the carcinogenic process in HPV+ (but not HPV-) subsets of CC. Methods: Pubmed/Embase databases identified 1494 potential studies; 51 were eligible and included. Separate analyses were performed to evaluate CC risk (CC vs normal), initiation of cancer (SIL vs normal), and progression towards cancer (CC vs SIL), by HPV status. Pooled odds ratios (pOR) were generated using RevMan 5.1 software. Results: p53 Arg72Pro was not associated with CC risk in either HPV+ or HPV- patient subsets (pORs 0.92; 95%CI, 0.6-1.3 and pORs 1.07; 95%CI, 0.7-1.7, respectively). Similarly, there was no association with the initiation of disease (SIL vs normal): pORs 0.96; 95%CI, 0.7-1.3 (HPV+ subset); 1.11; 95%CI, 0.9-1.4 (HPV- subset). There was no association with disease progression from SIL to CC in the HPV- subset (pOR, 0.98; 95%CI, 0.7-1.4). However, in the HPV+ subset, comparing the progression from SIL through to CC, there was strong and significant association: pOR, 1.37; 95%CI, 1.2-1.6 (p=4.0x10E-4), with no evidence of heterogeneity (I 2 = 0%) or bias (by funnel plot). Sensitivity analyses demonstrated similarly significant results, even after taking into account differing quality of methodological designs and type of biological sample analyzed (tumour vs. blood) of the underlying studies. Associations were mainly restricted to Caucasian studies. Conclusions: In this meta-analysis, the Arg variant of p53 Arg72Pro was associated with progression of SIL to CC only in HPV+ subsets, but not to disease initiation or risk of CC.
Abstract 5179: Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing PRPF4B as a metastasis driver
Authors: Bob van de Water, Erik Danen, Esmee Koedoot, Maria Rogkoti, Michiel Fokkelman, Sylvia Le Devedec, John Martens, Peter Stoilov, John Foekens
Journal: Cancer Research (2018)

Abstract Metastasis is the major cause of death in cancer patients and migration of cancer cells from the primary tumor to distant sites is the prerequisite of metastasis formation. Here we applied an imaging-based RNAi phenotypic cell migration screen uing two highly migratory basal breast cancer cell lines (Hs578T and MDA-MB-231 to provide a repository of candidate metastasis drug targets. We screened ~4,200 individual target genes covering most cell signaling components. We discovered 133 and 113 migratory modulators of Hs578T and MDA-MB-231, respectively, of which 45 genes were common denominators of cell migration. Interaction networks of candidate migratory modulators were in common with networks of different clinical breast cancer prognostic and metastasis classifiers. The splicing factors PRPF4B and BUD31 and the transcription factor BPTF were amplified in human primary breast tumors and the expression was associated with metastasis-free survival. Depletion of PRPF4B, BUD31 and BPTF caused primarily downregulation of genes involved in focal adhesion and ECM-interaction pathways. PRPF4B was essential for TNBC cell migration and critical for breast cancer metastasis formation in vivo, making PRPF4B a candidate for further drug development. Our systematic phenotypic screen provides an important repository for signaling determinants that functionally drive cancer cell migration. Citation Format: Bob van de Water, Erik Danen, Esmee Koedoot, Maria Rogkoti, Michiel Fokkelman, Sylvia Le Devedec, John Martens, Peter Stoilov, John Foekens. Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing PRPF4B as a metastasis driver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5179.
Fibroblastic reticular cells initiate immune responses in visceral adipose tissues and secure peritoneal immunity
Authors: Christian Perez-Shibayama, Cristina Gil-Cruz, Hung-Wei Cheng, Lucas Onder, Andrea Printz, Urs Mörbe, Mario Novkovic, Conglei Li, Constantino Lopez-Macias, Matthew B. Buechler, Shannon J. Turley, Matthias Mack, Charlotte Soneson, Mark D. Robinson, Elke Scandella, Jennifer Gommerman, Burkhard Ludewig
Journal: Science Immunology (2018)

MYD88 signaling in fibroblastic reticular cells drives the initiation of immune responses in fat-associated lymphoid clusters.
Abstract 2243: Cell-phone radiofrequency enhances angiogenesis and stimulates cell invasion of human head and neck cancer cells
Authors: Ala-Eddin Al Moustafa
Journal: Cancer Research (2018)

Abstract Today, cell-phone is the most widespread technology globally. It has been suggested that cell-phone radiofrequency (RF) use may increase the risk of human brain and probably head cancers. However, the outcome of cell phone RF on head and neck (HN) cancer progression has not been explored yet. Thus, first we examined the outcome of cell-phone RF on angiogenesis using the chorioallantoic membrane (CAM) of the chicken embryo as a model. Then we investigated the effect of cell-phone RF on cell invasion and colony formation in soft agar of two human HN cancer cell lines. Our data revealed that cell-phone RF promotes angiogenesis of the CAM. In addition, cell-phone RF enhances cell invasion and colony formation of human HN cancer cells; this is accompanied by a down-regulation of E-cadherin expression. Regarding the mechanism of cell-phone RF on angiogenesis, cell invasion and colony formation, we found that cell-phone RF activates Erk1 and Erk2 in our experimental models which could be the main pathway behind these events. These data suggest that cell-phone RF enhances HN cancer progression by stimulating angiogenesis, cell invasion and tumor formation via Erk1 and Erk2. Citation Format: Ala-Eddin Al Moustafa. Cell-phone radiofrequency enhances angiogenesis and stimulates cell invasion of human head and neck cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2243.
Response to Letter Regarding Article, “Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of Acute Myocardial Infarction”
Authors: TobiasReichlin, MihaelPotocki, ChristianMueller, AffanIrfan, RaphaelTwerenbold, MiriamReiter, WillibaldHochholzer, HannaCrettol, FedericoPeter, JuliaMeissner, PhilipHaaf, BeatriceDrexler, StefanoBassetti, StephanSteuer, KatrinWinkler, StefanOsswald
Journal: Circulation (2012)