tbuckley/cabot-search huggingface dataset:
Abstract LB-151: Prophylactic TNFα blockade unplugs toxicity and efficacy in immunotherapy anti-PD-1 + anti-CTLA-4 combinations
Authors: ELISABETH PEREZ-RUIZ, LUNA MINUTE, MARIA CARMEN OCHOA, ARANTXA AZPILICUETA, SARAY GARASA, M E RODRIGUEZ-RUIZ, VIRGINIA BELSUE, CARMEN MOLINA, PEDRO BERRAONDO, IGNACIO MELERO
Journal: Cancer Research (2018)

Abstract The combination of anti-CTLA-4 and anti-PD-1 checkpoint inhibitors ipilimumab and nivolumab (DIT) has improved survival of patients with metastatic melanoma and renal cell carcinoma in exchange for frequent immune-mediated serious side effects (mainly gastrointestinal), leading to treatment cessation in about one third of the patients and the need to reduce doses of these immunotherapy agents when used in combination. Tumor necrosis factor-α (TNF-α) is an important actionable mediator in inflammatory bowel disease (both ulcerative colitis and Crohn's disease) and its blockade with monoclonal antibodies has been recommended to treat steroid-resistant colitis following checkpoint inhibitors. We have studied whether prophylactic TNFα blockade is able to reduce immune toxicity associated with DIT without altering antitumor activity. Experiments were performed in C57BL/6 mice harboring subcutaneous tumors derived from the MC38 and B16OVA cell lines. Acute immune-mediated colitis was induced by exposure to 3% dextran sulfate sodium (DSS) in drinking water for 3 days. For TNFα blockade etanercept (hTNFR2-IgG chimera) or a mouse anti-TNF-α monoclonal antibody were used. Anti-tumor efficacy was tested following individual tumor sizes upon combined treatment with anti-mPD-1 + anti-mCTLA4 mAbs. Severity of DSS colitis was assessed and scored by daily weight, ultrasound evaluation of intestinal wall thickness and histological assessment on day 7. We observed that the antitumoral efficacy of PD-1+CTLA-4 blockade against MC38 of B16OVA established tumors was not reduced with the prophylactic association of TNF-α blockade. Intriguingly, an improvement of antitumor activity was observed in those mice in which DSS colitis was induced. Importantly, in mice suffering DSS-induced colitis that were co-treated with DIT and TNF-α blockade, digestive toxicity ameliorates as shown by body weight, ultrasound examination and histology. Therefore, TNF-α blockade can be prophylactically associated with anti-PD1 + anti-CTLA-4 mAb combination regimens to prevent toxicity without hindrance of anti-tumor efficacy. These results in mouse models warrant a clinical trial testing profilactic etanercept to improve the safety profile of the nivolumab + ipilimumab combination widening its therapeutic window. Citation Format: ELISABETH PEREZ-RUIZ, LUNA MINUTE, MARIA CARMEN OCHOA, ARANTXA AZPILICUETA, SARAY GARASA, M E RODRIGUEZ-RUIZ, VIRGINIA BELSUE, CARMEN MOLINA, PEDRO BERRAONDO, IGNACIO MELERO. Prophylactic TNFα blockade unplugs toxicity and efficacy in immunotherapy anti-PD-1 + anti-CTLA-4 combinations [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 LB-151.
Abstract 4490: Autocrine and paracrine effects of miR-29 in hPSCs and PDAC cells
Authors: Tricia Factora, Elise Briscoe, Jason Kwon, Janaiah Kota
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma (PDAC) continues to be one of the most lethal malignancies worldwide and responds poorly to current therapeutic modalities. Due to its late stage diagnosis and limited response to current treatments, it is imperative to develop novel and effective therapies for PDAC. Dense fibrotic stroma associated with PDAC abrogates drug perfusion into the tumor and activated pancreatic stellate cells (PSCs) are the major stromal cells responsible for stromal reaction. Furthermore, activated PSCs are known to secrete various factors causing autocrine effects to elicit sustained PSC activation and paracrine effects on cancer cells to promote tumor progression. Our previous work has shown that loss of miR-29 is a common phenomenon of both activated PSCs and pancreatic cancer cells, and its restored expression reduces stromal accumulation and cancer growth. In addition, conditioned media from miR-29 overexpressing PSCs reduces cancer cell viability. To extend our work on the role of miR-29 in tumor-stromal interactions, we examined how autocrine and paracrine signaling is affected by miR-29 overexpression in PSCs and cancer cells. We collected the conditioned media from miR-29a overexpressing human PSCs (hPSC-CM) or cancer cells (CC-CM) and cultured nascent PSCs or cancer cells to evaluate autocrine and paracrine effects. hPSCs and PDAC cells cultured in miR-29 hPSC-CM resulted in a significant reduction of cell viability. Likewise, miR-29 overexpressing CC-CM reduced the viability of hPSCs and cancer cells. Additionally, cancer cell migration was reduced when treated with miR-29 overexpressing hPSC- and CC-CM. Taken together, our results demonstrate that conditioned media collected from miR-29 overexpressing hPSCs and cancer cells reduces hPSC/cancer cell viability and cancer cell migration. Moreover, our findings highlight the important role of miR-29 in the autocrine/paracrine interactions between PSCs and cancer cells. In our future studies, we expect to identify the key factors that are regulated by miR-29 in tumor-stromal interactions. Citation Format: Tricia Factora, Elise Briscoe, Jason Kwon, Janaiah Kota. Autocrine and paracrine effects of miR-29 in hPSCs and PDAC 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 4490.
The Genesis of QRS Changes Produced by Selective Coronary Arteriography
Authors: Orlandomaytin, Cesarcastillo, Agustincastellanos
Journal: Circulation (1970)

Selective coronary arteriography produces characteristic ST-T changes associated with significant axis shifts. In patients with normal control AQRS (mean, +88.6°; sd ± 12.2°) left coronary injections induced an important leftward deviation of the AQRS: mean, +8.2°; sd, ±49.1° (P < 0.001). Right coronary artery opacification changed the AQRS from a control mean of +66.5°; sd, ±17.2° to a mean of 89.3°; sd, ±16.7° (P < 0.001). Left axis shifts after left coronary artery injections were significantly more marked than right axis deviation after right coronary injections. Important increases (beyond 0.02 sec) in ventricular activation time were not observed. These electrocardiographic abnormalities were attributed to the transient ischemic or toxic effect produced by the bolus of dye. This could result in different degrees of complete or incomplete block in the divisions of the left branch or in an extensive peripheral block affecting large areas of the subendocardial regions of the heart.
Abstract SY07-02: Epigenetic regulation of T-cell exhaustion: Implications for cancer immunotherapy
Authors: Benjamin A. Youngblood, Hazem Ghoniem, Ardiana Moustaki, Hossam Abdelsamed, Yiping Fan, Paul Thomas, Elizabeth Stewart, Sara Federico
Journal: Cancer Research (2018)

Abstract Immune checkpoint blockade (ICB)-mediated rejuvenation of CD8 T-cell effector functions has emerged as one of the most promising frontiers for treating cancer and chronic infections. However, antigen-specific T cells that have experienced prolonged antigen exposure are often terminally differentiated, and have a limited capacity to mount an effector response during ICB treatment. Such exhaustion of effector potential is a major impediment of current T cell-based immunotherapy efforts. Using in vivo mouse models of tumor and chronic viral infection, we assessed the role of de novo epigenetic programming in establishing ICB-refractory exhausted T cells. We observed that genetic deletion of the de novo DNA methyltransferase, Dnmt3a, in T cells at the effector stage of an immune response to chronic lymphocytic choriomeningitis virus (LCMV) infection allowed antigen-specific T cells to remain highly functional despite expressing high levels of PD-1 and having prolonged exposure to antigen. Quite strikingly, PD-1 blockade treatment of chronically infected animals resulted in massive expansion of PD-1+ Dnmt3a-deficient antigen-specific T cells. Whole-genome methylation profiling of WT and Dnmt3a-deficient LCMV-specific CD8 T cells identified de novo DNA methylation programs that are coupled to development of ICB-nonresponsive virus and tumor-specific T cells. Building upon these findings, we have identified de novo epigenetic programs acquired in human tumor-associated PD-1hi CD8 T cells. Collectively, these data establish Dnmt3a-mediated de novo DNA methylation programming as a key regulator in establishing ICB-refractory exhausted CD8 T cells and highlight epigenetic reprogramming of T cells as a novel approach to enhance T cell-based cancer therapies. Citation Format: Benjamin A. Youngblood, Hazem Ghoniem, Ardiana Moustaki, Hossam Abdelsamed, Yiping Fan, Paul Thomas, Elizabeth Stewart, Sara Federico. Epigenetic regulation of T-cell exhaustion: Implications for cancer immunotherapy [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 SY07-02.
Abstract 15934: Higher Midlife Serum Levels of Kidney-injury Molecule-1 (KIM-1) are Associated With Incident Fatal CHD Over Very Long-term Follow-up Among Men
Authors: Rachel H Mackey, Greg G Grandits, Lewis H Kuller, Joel Estis, John A Todd, Malli R Yerramilli, James Neaton
Journal: Circulation (2015)

Introduction: Higher levels of kidney-injury molecule-1 (KIM-1) measured in urine are associated with presence and progression of acute renal disease. A recent study reported similar results for KIM-1 measured in blood. Hypothesis: We hypothesized that KIM-1 measured in stored serum from middle-aged men who participated in the Multiple Risk Factor Intervention Trial (MRFIT) would differentiate very long-term risk of fatal CHD vs. survival to a mean age of 80 over approximately 30 year follow-up. Methods: We conducted a nested case-control study within MRFIT, which in 1973-76 randomized 12,866 high risk but CVD free men ages 35-57 to risk factor intervention vs. usual care. Serum samples were collected at baseline and stored for future use. The trial concluded in 1982 but long-term mortality follow-up was ascertained through 2005 using the National Death Index. From MRFIT participants with stored serum from baseline, we sampled 100 men who died of CHD (mean age 47.3 at baseline and 73.9 at death), and 100 men who survived to 2005 (mean age =48.4 at baseline and 80.1 in 2005.) KIM-1 was assayed from stored serum samples using high sensitivity single-molecule counting technology (Erenna ® Immunoassay System, Singulex), with limit of detection (LoD)=0.5 pg/ml, and lower limit of quantification (LLoQ)=2.0 pg/ml. Results were compared between cases and controls using Wilcoxon rank tests and logistic regression. Results: Inter-assay %CVs were 8%. Median KIM-1 was higher for smokers vs. non-smokers and for men with vs. without hypertension, but was not associated with high cholesterol. KIM-1 was significantly higher in cases (183 pg/ml (IQR: 137-239) versus controls, (161 pg/ml (IQR:109-212), p=0.03; OR (95%CI)for Q4 versus Q1 was 2.26 (1.02 - 5.02) Adjusted for age and smoking the OR(95%CI) of fatal CHD for Q4 vs. Q1 was 2.34 (1.02- 5.37), and further adjusted for diastolic BP and serum cholesterol at baseline, was 2.0 (95% CI: 0.8-4.7). Conclusions: Higher serum KIM-1 levels at midlife were associated with a ∼2-fold increased risk of fatal CHD vs. survival over ∼30 years of follow-up. This is the first report of a longitudinal association of circulating KIM-1 levels with fatal CHD in long-term follow-up.
Production of Hyperlipemia and Early Atherosclerosis in Rabbits by a High Vegetable Fat Diet
Authors: Alfredsteiner, Seymourdayton
Journal: Circulation Research (1956)

Feeding of a high vegetable fat diet made up of ground peanuts and purina chow to rabbits resulted in an increase in the serum cholesterol, as well as other serum lipids, including β-lipoprotein fraction. Microscopic lipid deposits in the intima and underlying media of the ascending and thoracic aorta were present in 10 of 33 rabbits at the end of 5 to 12 months. Small areas of gross atherosclerosis of the aorta were found in two rabbits.
Abstract 5240: Functional and therapeutic significance of <i>ESR1</i> gene fusions in breast cancer
Authors: Jonathan T. Lei, Jieya Shao, Jin Zhang, Michael Iglesia, Doug W. Chan, Jin Cao, Meenakshi Anurag, Purba Singh, Xiaping He, Yoshimasa Kosaka, Ryoichi Matsunuma, Robert Crowder, Jeremy Hoog, Chanpheng Phommaly, Rodrigo Goncalves, Susana Romalho, Raquel M. Peres, Nindo Punturi, Cheryl Schmidt, Alex Bartram, Eric Jou, W V. Lai, Oliver Hampton, Anna Rogers, Ethan Tobias, Poojan Parikh, Sherri R. Davies, Shunqiang Li, Cynthia X. Ma, Vera Suman, Kelly K. Hunt, Mark A. Watson, Katherine A. Hoadley, E A. Thompson, Xi Chen, Shyam M. Kavuri, Chad J. Creighton, Christopher A. Maher, Charles M. Perou, Svasti Haricharan, Matthew J. Ellis
Journal: Cancer Research (2018)

Abstract RNA sequencing detects estrogen receptor alpha gene (ESR1) fusion transcripts in estrogen receptor positive (ER+) breast cancer but their role in disease pathogenesis remains unclear. Herein we examined multiple in-frame and out-of-frame ESR1 fusions and found only two, both identified in advanced endocrine treatment resistant disease, encoded stable and functional in-frame fusion proteins. In both examples, ESR1-e6&amp;gt;YAP1 and ESR1-e6&amp;gt;PCDH11X, the N-terminal, DNA binding and dimerization motifs encoded by exons 2-6 were fused to C-terminal sequences from the partner gene. Functional properties included estrogen-independent growth, constitutive expression of ER target genes, anti-estrogen resistance, induction of cellular motility in vitro and the development of lung metastasis in vivo. Chromatin immunoprecipitation and RNA sequencing experiments showed both fusions uniquely activated a metastasis-associated transcriptional program. ESR1-e6&amp;gt;YAP1 and ESR1-e6&amp;gt;PCDH11X-induced growth remained sensitive to a CDK4/6 inhibitor, palbociclib, and a patient-derived xenograft (PDX) expressing the ESR1-e6&amp;gt;YAP1 fusion was also responsive. Transcriptionally active ESR1 fusions therefore trigger both endocrine therapy resistance and metastatic progression explaining the association with fatal disease progression, although CDK4/6 inhibitor treatment is predicted to be effective. Citation Format: Jonathan T. Lei, Jieya Shao, Jin Zhang, Michael Iglesia, Doug W. Chan, Jin Cao, Meenakshi Anurag, Purba Singh, Xiaping He, Yoshimasa Kosaka, Ryoichi Matsunuma, Robert Crowder, Jeremy Hoog, Chanpheng Phommaly, Rodrigo Goncalves, Susana Romalho, Raquel M. Peres, Nindo Punturi, Cheryl Schmidt, Alex Bartram, Eric Jou, W V. Lai, Oliver Hampton, Anna Rogers, Ethan Tobias, Poojan Parikh, Sherri R. Davies, Shunqiang Li, Cynthia X. Ma, Vera Suman, Kelly K. Hunt, Mark A. Watson, Katherine A. Hoadley, E A. Thompson, Xi Chen, Shyam M. Kavuri, Chad J. Creighton, Christopher A. Maher, Charles M. Perou, Svasti Haricharan, Matthew J. Ellis. Functional and therapeutic significance of ESR1 gene fusions in breast cancer [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 5240.
Abstract 3554: The role of P2RY14 in acute leukemia
Authors: Kinjal Shah, Julhash Kazi
Journal: Cancer Research (2018)

Abstract Leukemia is a group of blood cancers that originate in the bone marrow and involves uncontrolled proliferation of different types of blood cells. The PI3K/mTOR pathway is the second most frequently deregulated pathway in a majority of cancers such as breast cancer, lung cancer and melanomas as well as leukemia. There are several promising drugs targeting this pathway for use in the clinic. However, acquired resistance to the drugs remains a major challenge to overcome. Mutations in the genes coding for receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs) are quite common in all forms of acute leukemia. This can be a major cause of deregulation of the PI3K-mTOR pathway. To understand how cells display resistance to the dual PI3K/mTOR inhibitor, we used a panel of acute leukemic cell lines. We observed that while a number of cell lines displayed sensitivity to the dual PI3K/mTOR pathway inhibitor PKI-587, many cells displayed substantial resistance. Cells sensitive to PKI-587 also showed aberrant activation of the PI3K/mTOR pathway and also displayed sensitivity to a panel of various other PI3K/mTOR inhibitors. Using RNA sequencing data from the COSMIC database, we compared gene expression between the cell lines that are either resistant or sensitive to PKI-587. We found that the expression of P2RY14 was around 9-fold upregulated in cells showing resistance to PKI-587. Thus, we identified Purinergic receptor 14, P2RY14, as the target gene. P2RY14 is a G protein-coupled receptor that has not been much studied in hematologic malignancies. However, this receptor seems to have a role in the localization of Hematopoietic Stem Cells (HSCs) and in promoting regenerative capabilities following injury. Acute lymphoblastic leukemia patients with higher expression of P2RY14 mRNA displayed relatively poor survival compared to patients carrying the lower expression of P2RY14. To understand the role of this receptor in leukemia, we stably transfected the murine pro B cell line Ba/F3 with P2RY14. Activation of P2RY14 by its ligand, UDP glucose, resulted in selective induction of ERK1/2 phosphorylation. Taken together, our data suggest that the GPCR P2RY14 couples to ERK signaling which probably has a significant role in acute leukemia. Nevertheless, further in vitro testing of the receptor functionality with various biochemical and molecular biology techniques is required before this receptor, P2RY14, can be utilized as a therapeutic target in the future treatment of acute leukemia. Citation Format: Kinjal Shah, Julhash Kazi. The role of P2RY14 in acute leukemia [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 3554.
Surveillance for melanoma (MEL): Results of a database study of stage I-III MEL.
Authors: Corey Rearick, Fei Ding, Yan Lin, Amy Rose, Cindy Sander, Michael Davis, Panayiotis V Benos, Hussein Abdul-Hassan Tawbi, Ahmad A. Tarhini, John M. Kirkwood, Diwakar Davar
Journal: Journal of Clinical Oncology (2018)

9586 Background: Optimal surveillance for MEL recurrence is elusive. While consensus guidelines agree on surveillance imaging for high-risk MEL, there is no consensus regarding optimal modality for surveillance and routine imaging surveillance is not recommended for stage IA-IIA MEL. We examined the utility of surveillance in stage I-III MEL. Methods: Patients (pts) at the University of Pittsburgh's Melanoma Program 1991-2011 were queried using a clinical database. Eligible pts had stage I-III MEL and underwent routine surveillance with clinical examination, chest x-rays (CXR). Minimum follow-up was 9 months (mos). CXR positivity was determined by primary review of attending radiologist report. Pt documentation was queried for information pertaining to relapse, details of advanced imaging, pathology and treatment. Primary endpoints were the incidence of pulmonary (pulm) and extra-pulm metastases. Results: 324 pts with 2,700 CXRs were identified, of whom 114 (35%) had stage I, 63 (20%) stage II, and 147 (45%) stage III MEL. Median duration of screening was 46 mos. During this period, pulm mets were identified in 11%, 25% and 26% of stage I, II and III MEL respectively. Of these, CXR was initially diagnostic in 85%, 81%, and 92% respectively. Incidence of extra-pulm mets was 8%, 24% and 29% for stage I-III MEL, in whom diagnosis was made on advanced imaging ordered to evaluate examination findings and/or pt symptoms. Conclusions: Incidence of pulm and extra-pulm mets in MEL increases by stage, and CXR reliably detects pulm mets, although a higher incidence of non-pulm mets in stage II-III pts diminishes the value of CXR for relapses overall. Our data suggests that routine CXR surveillance detects few relapses in high-risk stage II-III pts. Melanoma mets by site/stage. Skin/LN (N/%) Pulm (N/%) Extra-pulm (N/%) Any site (N/%) Multiple sites (N/%) Isolated Total Stage I 3 (3%) 2 (2%) 13 (11%) 9 (8%) 16 (14%) 4 (4%) Stage II 7 (11%) 5 (8%) 16 (25%) 15 (24%) 23 (37%) 10 (16%) Stage III 19 (13%) 19 (13%) 38 (26%) 42 (29%) 58 (39%) 25 (17%) All Pts 29 (9%) 26 (8%) 67 (21%) 66 (20%) 97 (30%) 39 (12%)
Transventricular Mitral Valvotomy
Authors: Frankgerbode
Journal: Circulation (1960)

In a consecutive series of 200 operations for relief of mitral stenosis, transventricular valvotomy was performed whenever digital valvotomy was found to be ineffective. The operative mortality was 12.5 per cent. In a series of 17 second operations for mitral stenosis, the transventricular method was similarly used, with 2 operative deaths. A left lateral thoracotomy was employed, with reentry through the left atrium. The results of transventricular valvotomy were more satisfactory than when the usual commissurotomy through the left atrium was employed.