tbuckley/cabot-search huggingface dataset:
Abstract 4977: Dynamic transcriptional programs controlling single NK cell killing dynamics
Authors: Matthew S. Hall, Joseph T. Decker, Emanuelle I. Grody, Rachel B. Blaisdell, Jacqueline S. Jeruss, Lonnie D. Shea
Journal: Cancer Research (2019)

Abstract NK cells have a vast heterogeneity in function and phenotype in vivo and their healthy function is critical in the prevention of nascent cancers. NK cell-based immunotherapies, such as adoptive NK cell therapy, are emerging and greater insights into the mechanism of NK cell activation could increase their efficacy. In vitro cytotoxicity assays have revealed that a small subset of NK cells kill the majority of cancer target cells, yet little is known about the dynamic state or triggers of these highly cytotoxic cells. Here, we present methodology for discovery of the molecular precursors and drivers of single NK cell killing events. We study the NK-92 cell line both as a model of primary NK cells and to gain direct insights for improving NK-92 based adoptive cell therapies. In our method, we first performed single cell RNA sequencing on NK-92 cells seeded sparsely on a monolayer of HeLa cancer cells along with a control NK-92 cell population. Clustering cells by principal component analysis revealed groups of NK cells that upregulated genes associated with NK cell cytotoxicity in the HeLa cell activated sample that are absent in the control group. Landmark genes associated with the cytotoxic NK cell clusters included PRF1, GZMK, and ITGB2. Utilizing live cell imaging, we identified categories of dynamic functional phenotypes in NK-92 cells exposed to a HeLa cell monolayer including non-motile and non-killing, highly motile but non-killing, single killing, serial killing, and exhausted. In order to link the systems-level single cell gene expression data to functional NK cell behaviors, we next performed high content live cell imaging of NK-92 cells bearing cas9-based endogenous genetic reporters as they surveilled and killed HeLa cells. Utilizing a custom analysis algorithm, we tracked the motility and killing activity of individual NK-92 cells, and correlated this activity to the dynamic gene expression. Next, we aim to identify the causality and sequence of transcriptional changes associated with NK cell killing and extend our results to the analysis of the critical transcription factor networks governing dynamic NK cell functional phenotypes. We note that the single cell functional discovery strategy that we have shown can be applied more broadly to other model systems of the cancer microenvironment. Citation Format: Matthew S. Hall, Joseph T. Decker, Emanuelle I. Grody, Rachel B. Blaisdell, Jacqueline S. Jeruss, Lonnie D. Shea. Dynamic transcriptional programs controlling single NK cell killing dynamics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4977.
Abstract 2236: Development and validation of urine cfDNA preservative kit for detection of genomic alterations in cancer
Authors: Zheng Li, Haoran Tang, Tiantian Zhang, Chunxiao Liu, Shengnan Zhu, Ying Zhang, Binggang Xiang, Zhixin Zhao
Journal: Cancer Research (2019)

Abstract Introduction: cfDNA (circulating cell-free DNA), short DNA fragments shredded from dying normal and tumor cells, has been proved capable of serving as molecular biomarkers for clinical decision making, including but not limit to tumor diagnosis, treatment and monitoring. Urine, by its non-invasive nature and unique biological characteristics, is far superior comparing to other liquid biopsy specimens, such as blood and cerebrospinal fluid, and has broad clinical implications for genitourinary cancers. The challenge for urine cfDNA test, is the instability of cfDNA, caused by nuclease, high content of urea, and contamination from genomic DNA released from nucleated cells and microbials in urine. Here, we have developed a robust and user friendly urine preservative collection Kit to maintain integrity of cfDNA in urine and to facilitate transportation of urinary samples to clinical laboratory. Methods: Urine samples from 5 donors collected using the developed urine collection kit were tested after incubation under 4°C and 37°C, mimicking extreme storage or transporting environments, and were compared to untreated urine and treated urine by another commercial preserve buffer. cfDNA was extracted after incubation of 0, 4, 7 days and then quantified by ddPCR with 3 markers: EGFR as an endogenous DNA marker, PSA (synthetic oligos containing intron-deleted sequence, pre-incubation spike-in) as an exogenous DNA marker, ARv7 (synthetic oligos containing intron-deleted sequence, post-incubation spike-in) as an inner control for the extraction and detection assays. Results While untreated urine showed significant decrease after incubation under 37°C, cfDNA derived from urine stored in developed urine collection tubes remained stable till day 7. There is no significant change on normalized copies of EGFR and PSA in the treated urine samples under 4°C for up to 7 days. Conclusion: the developed Urine Collection Kit demonstrated great urine cfDNA preserving capacity under different temperatures for at least 7 days, on par with commercially available preserve buffer and even outperforming it under certain circumstances. The developed kit provides an easy-to-use solution of obtaining stable urine cfDNA for clinical use. Citation Format: Zheng Li, Haoran Tang, Tiantian Zhang, Chunxiao Liu, Shengnan Zhu, Ying Zhang, Binggang Xiang, Zhixin Zhao. Development and validation of urine cfDNA preservative kit for detection of genomic alterations in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2236.
Abstract 4384: Role of EIF4G1 in non-small cell lung cancer pathogenesis and targeted therapy
Authors: Zhiqiang Qin, Lu Dai, Luis Del Valle
Journal: Cancer Research (2019)

Abstract Non-small cell lung cancer (NSCLC) accounts for about 85-90% of lung cancer cases, which represents the number one killer among cancers in US. The majority of lung cancer patients doesn't respond well to conventional chemo-/radio-therapeutic regimens and have a dismal 5-year survival rate of ~15%. The recent introduction of targeted therapy and immunotherapy gives new hopes to NSCLC patients, but their outcome/prognosis is far from satisfactory. The translation initiation EIF4F complex has been shown to play important roles in cancer progression. As an important component of the EIF4F complex, EIF4G1 serves as a scaffold and interacts with several other initiation factors such as EIF4E and EIF4A, and help to initiate cap-dependent translation in mammalian cells. EIF4G1 is overexpressed in a variety of cancers, but its functional role, clinical relevance and potential role as a therapeutic target in NSCLC remain largely unknown. Our recent data demonstrate that EIF4G1 expression level is much higher in NSCLC primary tumors than in paired adjacent normal tissues as well as in NSCLC cell lines than in the normal bronchial epithelial cells. Directly targeting EIF4G1 by RNAi or selective small-molecule inhibitors significantly reduce NSCLC cell proliferation, anchorage-independent growth in vitro as well as tumor progression in vivo. Our recent protein array and proteomics analyses indicate that EIF4G1: 1) has a complex interactome network in NSCLC cells; 2) appears to control the expression of a unique subset of the cellular proteome when compared to normal cells, which are closely related to NSCLC cells survival. Taken together, our data support that EIF4G1 plays a critical role in NSCLC survival, oncogenesis and tumor progression, and may serve as a novel and promising therapeutic target for improving NSCLC treatment. Citation Format: Zhiqiang Qin, Lu Dai, Luis Del Valle. Role of EIF4G1 in non-small cell lung cancer pathogenesis and targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4384.
Abstract 12946: Reduced Aortic Distensibility is Associated With Higher Aorto-Carotid Wave Transmission and Ambulatory Blood Pressure in Young Adults After Coarctation Repair
Authors: Remi R Kowalski, Melissa G Lee, Lex W Doyle, Jeanie L Cheong, Joseph J Smolich, Yves d’Udekem, Jonathan P Mynard, Michael M Cheung
Journal: Circulation (2018)

Introduction: The long-term prognosis of coarctation repair is characterized by high rates of cardiovascular and cerebrovascular disease related to hypertension, the mechanism for which remains unc...
Clinical, Genomic Profile and Recurrent Somatic Mutations in 205 Chronic Lymphocytic Leukemia Treatment-Naive Patients
Authors: Blanca Ferrer, Alicia Serrano, Victoria Adam, Blanca Navarro, Carmen Ivorra, Angeles Medina, Margarita Fernandez, Alicia Rodriguez, Vanesa Martin, Maria Soledad Duran, Eduardo Ríos Herranz, Carmen Benet, Maria Angeles Ruiz, Mario Montagud, Isabel Navarro, Miguel Fernandez, Ana Isabel Teruel, Macarena Ortiz, Rafael Andreu, Paula Amat, Carlos Solano, Javier F Chaves, Maria Jose Terol
Journal: Blood (2017)
<i>Three Identical Strangers</i> and <i>The Twinning Reaction</i>—Clarifying History and Lessons for Today From Peter Neubauer’s Twins Study
Authors: Leon Hoffman, Lois Oppenheim
Journal: JAMA (2019)

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TRIM67 Activates p53 to Suppress Colorectal Cancer Initiation and Progression
Authors: Shiyan Wang, Yanquan Zhang, Junzhe Huang, Chi Chun Wong, Jianning Zhai, Chuangen Li, Guifeng Wei, Liuyang Zhao, Guoping Wang, Hong Wei, Zengren Zhao, Jun Yu
Journal: Cancer Research (2019)

Tripartite motif (TRIM) family proteins participate in a variety of important cellular processes, including apoptosis, cell-cycle arrest, DNA repair, and senescence. In this study, we demonstrated that a novel TRIM family member, TRIM67, was commonly silenced in colorectal cancer and its downregulation was associated with poor survival. Trim67 knockout in ApcMin/+ mice increased the incidence, multiplicity, and burden of colorectal tumors. Similarly, colon-specific knockout of Trim67 significantly accelerated azoxymethane-induced colorectal cancer in mice. RNA sequencing revealed that the antitumor effect of TRIM67 was mediated by activation of the p53 signaling pathway. TRIM67 interacted directly with the C-terminus of p53, inhibiting p53 degradation by its ubiquitin ligase MDM2. TRIM67 was also a transcriptional target of p53; upon cellular stress, p53 bound to the TRIM67 promoter and induced significant upregulation of TRIM67, thereby forming a TRIM67/p53 self-amplifying loop that boosts p53-induced cell growth inhibition and apoptosis. Consequently, loss of this p53-positive regulatory program profoundly compromised p53-mediated responses to chemotherapy-induced DNA damage. Dampened p53 response was also observed in tumors of Trim67 knockout mice and Trim67 knockout embryonic fibroblasts. TRIM67 reactivation restored p53 activation and sensitized colorectal cancer cells to chemotherapy in vitro and in vivo. TRIM67 thus functions as a pivotal tumor suppressor in colorectal cancer and is a potential target for improving chemotherapy responsiveness. SIGNIFICANCE: The TRIM67/p53 axis represents a novel therapeutic target that could be harnessed to improve chemotherapy efficacy in colorectal cancer expressing wild-type p53 but with repressed p53 signaling.
BMA sexism: Doctors at annual meeting hear fresh allegations of harassment
Authors: Abi Rimmer
Journal: BMJ (2019)

BMA members have expressed their support for a review into alleged sexism in the organisation and have called for its findings to be published quickly as possible. Doctors at the BMA’s annual representative meeting in Belfast on 26 June voted in favour of a motion (box 1) that also raised concerns over the association’s handling of allegations of sexism and harassment. Box 1 ### Full wording of the ARM motion That this meeting: 1. Believes the current BMA in-house complaints procedure is not fit for purpose 2. Believes that BMA members with valid complaints are actively discouraged from raising a concern due to the current complaint system 3. Believes that sexism and harassment are not seriously addressed by the BMA 4. Welcomes the announcement of an independent external investigation into recent complaints of sexism and harassment within the BMA, as long as the investigator has the confidence of the complainants 5. Expects the findings of the external investigation into complaints of sexism and harassment within … RETURN TO TEXT
IL2-STAT5 immune signatures to predict responses to PD-1 inhibition and azacitidine treatment in acute myeloid leukemia (AML): A subset analysis of a phase 2 study.
Authors: Hussein Abbas, Mansour Alfayez, Guillermo Garcia-Manero, Farhad Ravandi, Tapan M. Kadia, Courtney Denton Dinardo, Jairo Mathews, Wilmer Flores, Michael Andreeff, Steven Mitchell Kornblau, Marina Konopleva, Jorge E. Cortes, Sattva Swarup Neelapu, Hagop M. Kantarjian, Richard Eric Davis, Naval Guastad Daver
Journal: Journal of Clinical Oncology (2019)

7041 Background: Combining PD-1/PD-L1 blockade with hypomethylating agents (HMA) shows encouraging preliminary efficacy in AML, but immune features predictive of response are lacking. Methods: We treated 11 relapsed/refractory (R/R) AML patients with azacitidine (AZA) and nivolumab (Nivo) in a phase 2 clinical trial ( Daver N et al Cancer Discovery 2018). Patient characteristics: median (med) age 65 years (47-73), 63% adverse cytogenetics, 27% TP53 mutated. Pretreatment bone marrow aspirates had immune-phenotypic 17-color flow analysis and NanoString RNA quantification of 1469 immune-relevant genes. Results were correlated with clinical, pathological and molecular data. Results: The median courses of AZA+Nivo administered was 3 (range 1-17). The CR/CRi rate was 45% (including 2 CR, 1 CRi, 1 CRN and 1 CRP), with a median time to response of 1.8 months (range 0.8-4.9 months). The median overall survival was 13 months with 27% patients alive at 1 year. We found significant positive correlations between proportions of T-effector cells at baseline, and CD3+, CD8+, and T-regulatory cells at end of cycle (EOC) 1 (r &gt; 0.75, p &lt; 0.01 for all). At EOC2, these correlations were no longer significant. However, there was a significant positive correlation between T-effector cells at baseline and T-regulatory cells (r = 1, p &lt; 0.001) at EOC4. Using NanoString analysis, we found 105 differentially expressed genes (fold change = 1.5, p &lt; 0.05) between responders (5/11) and non-responders (6/11) at pretreatment. IL2-STAT5, TP53 and TNF Hallmark pathways and immune response from GO gene sets were highly enriched (q &lt; 5x10 -4 ) in responders. We then utilized z-score distribution analysis to quantify the degree of activation of known immunologic pathways. We found that signatures highly specific to neutrophils, NK cells, T-cells and eosinophils were significantly (p &lt; 0.05) upregulated in patients with CR compared to non-responders at pretreatment. Conclusions: Our data demonstrates that a signature suggestive of lymphocyte activation in the pretreatment BM may be associated with augmented clinical response to PD-1 based therapies. Similar underlying pathways that have consistently predicted for responses to PD-1 inhibition in solid cancers, primarily IL2-STAT5 genes, may have predictive relevance in AML. Such pretreatment flow and NanoString signatures may help select AML patients most likely to benefit from PD-1 blockade plus HMA, further enhancing the benefit-risk ratio with such therapies.
Abstract 899: Selective clearance of cells undergoing therapy-induced senescence in a model of triple negative breast cancer
Authors: Liliya Tyutyunyk, Tareq Saleh, David A. Gewirtz
Journal: Cancer Research (2019)

Abstract Despite the ability of chemotherapy (and/or radiation) to eliminate the majority of tumor cells, some residual surviving cells may be able to escape cell death by entering into a prolonged senescence-based growth arrest. In addition to apoptosis, the majority of anti-cancer therapies induce senescence that has long been considered to be a favorable outcome of treatment due to its perceived irreversibility. However, accumulating studies in the literature demonstrate that therapy induced senescence may reflect one form of tumor dormancy and disease recurrence, when senescent cells are able to regain proliferative capacity. Tumor cells that escape dormancy often demonstrate an aggressive phenotype and are refractory to further treatment. Senescent cells are characterized by a specific (though often heterogeneous) secretory profile (Senescence Associated Secretory Phenotype or SASP), some components of which have been shown to promote tumorigenesis and may assist in neoplastic escape after therapy. In the current work, we evaluated the capacity of the BCL protein family inhibitor, ABT 263, to selectively clear breast tumor cells induced into senescence by doxorubicin. MDA-MB231-231 human breast cancer cells (a model of triple negative breast cancer) were induced into senescence upon exposure to a clinical concentration of the chemotherapeutic agent, doxorubicin (Dox). While a fraction of the MDA-MB-231 cell population underwent cell death, a large subpopulation entered into a state of prolonged growth arrest that lasted for several days, after which time the cells recovered proliferative capacity and formed colonies. At the time points when cells were arrested, prominent Senescence Associated β-Galactosidase staining marker indicative of senescence. In addition, tumor tissue collected from mice that received injections of Dox also were positive for β-Galactosidase staining. Cells induced into senescence and treated with ABT263 for 18 hours showed a significant increase in apoptosis and did not regain colony forming capabilities. We therefore postulate that senescence and escape from senescence may represent a form of tumor dormancy and disease recurrence, respectively. Consequently, if Therapy Induced Senescence is a deleterious outcome of treatment, it is of importance to identify strategies that might prevent senescent cells from neoplastic escape and induce cell death in order to completely eliminate residual tumors and thereby interfere with disease recurrence. Citation Format: Liliya Tyutyunyk, Tareq Saleh, David A. Gewirtz. Selective clearance of cells undergoing therapy-induced senescence in a model of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 899.
Image Gallery: Fournier gangrene in a patient with severe hidradenitis suppurativa
Authors: J. Magdaleno‐Tapial, C. Valenzuela‐Oñate, A. Martínez‐Doménech, J.L. Sánchez‐Carazo, A. Pérez‐Ferriols
Journal: British Journal of Dermatology (2019)
Abstract PO-059: SOX2-mediated 5hmC dysregulation in GBM Stem Cells
Authors: Hernando Lopez-Bertoni
Journal: Cancer Research (2020)

Abstract Primary brain tumors are among the most devastating forms of cancer and glioblastoma (GBM) represents the most aggressive and lethal form of the disease. We now know that GBM contain small subsets of cells that display tumor-propagating stem-like phenotypes (i.e. glioma stem cells or GSCs) that act as critical determinants of GBM resistance to current treatments and tumor recurrence for which there is no proven therapy. Altered patterns of DNA methylation are widely reported in human GBM. However, substantial knowledge gaps remain in our understanding of the molecular mechanisms responsible for this epigenetic dysregulation, its downstream consequences and role in the GBM tumor propagating phenotype. Understanding and ultimately targeting the epigenetic mechanisms that induce and maintain these tumor-propagating cell subsets is critical to improving GBM therapy and patient outcomes. DNA methylation generally occurs in cytosine-guanine (CpG) sequences and is established by DNMTs, which catalyze the conversion of cytosine to 5-methylcytosine (5mC). DNA methylation is a reversible process and is partially mediated by the ten-eleven translocation (TET) family of enzymes which function as deoxygenases to catalyze the conversion of 5mC to 5-hydroxymethylcytosine (5hmC). Levels of 5hmC closely track with the differentiation state of cells with terminally differentiated cells containing high levels of 5hmC and less differentiated cells having very low levels. Multiple studies found negative correlations between 5hmC levels and glioma grade and loss of 5hmC correlates with poor prognosis of GBM patients, strongly suggesting that these enzymes activate tumor suppressing mechanisms. Our preliminary data shows that exogenous SOX2 represses the TET2 demethylase and decreases 5hmC, the enzymatic product catalyzed by TET proteins, in GSCs. TET2 repression using 2 independent shRNA hairpins efficiently decreases 5hmc levels and significantly enhanced self-renewal capacity and tumor growth capacity of low-passage GSC isolates. We also show that SOX2 induces expression of miR-10b-5p, a known onco-miR predicted to target TET2, and inhibiting this miRNA partially rescues the reduction in 5hmC expression observed in GSCs expressing transgenic SOX2, thus implicating miR-10b-5p as a critical mediator of SOX2-induced onco-methylation, GSC induction and glioma malignancy. Our preliminary results support a mechanism in which SOX2 represses TET2 leading to 5hmC loss by directly activating miR-10b-5p transcription and predicts that targeting this novel mechanism of epigenetic dysregulation by inhibiting miR-10b-5p in vivo will can lead to pre-clinical GBM therapeutics. Citation Format: Hernando Lopez-Bertoni. SOX2-mediated 5hmC dysregulation in GBM Stem Cells [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-059.
Abstract 12132: Impact of Primary Coronary Angioplasty Delay on Microvascular Obstruction as Assessed by Coronary Flow Velocity Measurements and Left Ventricular Dilatation in ST-Segment Elevation Myocardial Infarction
Authors: Atsushi Yamamuro, Koichi Tamita, Shuichiro Kaji, Takeshi Kitai, Junichi Yoshikawa
Journal: Circulation (2012)

Background: The impact of total ischemic time on microvascular obstruction as assessed by coronary flow velocity measurements (MVO-CFV) and left ventricular (LV) dilatation has been insufficiently ...