tbuckley/cabot-search huggingface dataset:
Abstract 1634: BRCA-like phenotype constitutes hallmark of osteosarcoma
Authors: Michal Kovac, Sebastian Ribi, Claudia Blattmann, Michaela Nathrath, Daniel Baumhoer
Journal: Cancer Research (2018)

Abstract Background: Osteosarcomas are aggressive bone tumours with a high degree of genetic heterogeneity, which limits treatment options in patients who do not respond to standard chemotherapy. Methods: We sequenced 104 exomes and low-coverage genomes from 14 time-series consisting of chemotherapy-naïve biopsies, resection specimens, locally recurring tumours and/or distant metastases. We then identified cancer driver mutations, signatures of mutation processes and reconciled clonal structures of tumours with phylogenetic trees, thus building and evolutionary history of each tumour. Where possible, we searched for the evidence of selection acting on the tumours and molecular hallmarks that could be therapeutically exploited. Results: Interrogating genomic data from time series, we identified pathogenic mutations in at least 10 cancer genes, but there was no universal cancer driver event present in the majority of tumours at any given time point. However, &amp;gt;80% of osteosarcomas exhibited specific combination of single-base substitutions, LOH and large-scale genome instability characteristic of BRCA1/2-deficient tumours. In osteosarcoma, "BRCAness" developed recurrently through independent BRCA1/2 mutations and mutations in their binding partners such as PALB2 or CHEK2. We therefore investigated the sensitivity of a panel of osteosarcoma cell lines to the poly(ADP)-ribose polymerase inhibitor talazoparib. In combination with temozolomide, talazoparib led to the to good response of osteosarcoma cell lines, activation of BAX and BAK, loss of mitochondrial membrane potential, DNA fragmentation and caspase-dependent cell death. Conclusion: The acquisition of a BRCA-like phenotype in osteosarcoma has implications for the development of novel treatment strategies using PARP inhibitors alone, or together with standard chemotherapy. Citation Format: Michal Kovac, Sebastian Ribi, Claudia Blattmann, Michaela Nathrath, Daniel Baumhoer. BRCA-like phenotype constitutes hallmark of osteosarcoma [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 1634.
Abstract 827: Anti-tumor efficacy of BA3011, a novel Conditionally Active Biologic (CAB) anti-AXL-ADC
Authors: Leslie L. Sharp, Cathy Chang, Gerhard Frey, Jing Wang, Haizhen Liu, Charles Xing, Safak Yalcin, Marlena Walls, Yong Ben, William J. Boyle, Jay M. Short
Journal: Cancer Research (2018)

Abstract AXL is a TAM family receptor tyrosine kinase that has been implicated in the pathogenesis of many cancer types. The high level of expression on the cancer cell surface and increased expression in various settings such as PD-1 resistant tumors makes AXL a particularly attractive target for antibody therapeutics. However, AXL is expressed on many normal tissues and has been implicated in wide ranging requisite biological processes including response of endothelial cells to vascular injury, hematopoiesis, and regulation of immune responses. This normal tissue expression combined with the presence of soluble AXL may limit AXL as a target for antibody-drug-conjugates (ADC). The Conditionally Active Biologics (CAB) technology is a patented, proprietary platform that generates antibodies that reversibly bind to target antigen in the context of diseased tissues, but not normal tissues, by taking advantage of the unique cancer microenvironment that is produced largely as a result of the Warburg effect. Using our CAB technology, we have identified anti-AXL CAB Abs that reversibly bind to recombinant AXL and AXL expressing cells under conditions that are present in the tumor microenvironment, but not in normal tissues. BA3011 is a CAB-AXL-ADC. The pharmacological properties of BA3011 were characterized in a number of in vitro and in vivo pharmacology studies. BA3011 binds selectively to human and cyno AXL in conditions reflective of the tumor microenvironment, but has reduced binding under normal tissue conditions. BA3011 demonstrated the ability to induce cytotoxicity of human tumor cell lines expressing AXL in vitro and inhibit tumor growth in LCLC-103H (lung), DU145 (prostate), and MIAPaCa-2 (pancreatic) human tumor xenografts and in selected gemcitabine resistant pancreatic cancer patient derived xenograft models in vivo. In conclusion, our data is consistent with our work on CAB-EGFR-ADC, CAB-ROR2-ADC, CAB-PD-1, and other CAB programs, and suggests that ADCs generated using the CAB technology provide biologics with increased therapeutic index. Specifically, the CAB-AXL-ADC is an excellent candidate for evaluation as a treatment for human cancers that are AXL positive. Citation Format: Leslie L. Sharp, Cathy Chang, Gerhard Frey, Jing Wang, Haizhen Liu, Charles Xing, Safak Yalcin, Marlena Walls, Yong Ben, William J. Boyle, Jay M. Short. Anti-tumor efficacy of BA3011, a novel Conditionally Active Biologic (CAB) anti-AXL-ADC [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 827.
Determinants and Outcomes of Satisfaction With Healthcare Provider Communication Among Cancer Survivors
Authors: Ashish Rai, Xuesong Han, Zhiyuan Zheng, K. Robin Yabroff, Ahmedin Jemal
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: Despite the surge of interest in improving provider communication, empirical research is sparse on the determinants and outcomes of cancer survivors' satisfaction with healthcare provider communication. Methods: Longitudinal Medical Expenditure Panel Survey data spanning 2008 through 2014 was used to identify 4,588 respondents who were ever diagnosed with cancer. A composite score was generated by combining 5 measures of satisfaction. We used multivariate logistic regressions and 2-part models to examine the associations between satisfaction ratings and outcomes, including general, mental, and physical health; office visits; and total healthcare, drug, and out-of-pocket expenditures. Results: The study sample comprised 2,257 nonelderly (age 18-64 years) and 2,331 elderly (age ≥65 years) respondents. Among both age groups, higher satisfaction was associated with fewer comorbidities, fewer year 1 office visits, and absence of year 1 emergency department visits. Membership of higher satisfaction tertile in year 1 was associated with better year 2 mental health (tertile 1 [T1]: predictive margin [PM], 27.1%; tertile 2 [T2]: PM, 35.5%; P=.013; tertile 3 [T3]: PM, 37.0%; P=.005) and general health (T1 [ref]: PM, 30.3%; T3: PM, 38.9%; P=.007) among the elderly. Greater satisfaction was associated with fewer year 2 office visits (T1 [ref]: PM, 7.42 visits; T3: PM, 6.26 visits; P=.038) among the nonelderly; and lower year 2 healthcare expenditures (T1 [ref]: PM, $34,071; T3: PM, $26,995; P=.049) among the elderly. Conclusions: We identified potential differences in cancer survivors' needs and expectations of provider communication based on comorbidities and baseline service use. These results emphasize the need for individualized communication strategies for patients with cancer and survivors shaped by their distinct requirements. Our findings of better health, lower service use, and lower expenditures among more satisfied cancer survivors suggest that interventions to improve provider communication could lead to a more efficient use of healthcare resources.
Abstract 4890: Understanding the crosstalk between glycosylation and drug resistance
Authors: Padmamalini Thulasiraman, Kelbie Kerr
Journal: Cancer Research (2018)

Abstract Although great progress has been made in the treatment of breast cancer, resistance to chemotherapeutic drugs is a problem facing current cancer research, promoting the need to understand the molecular mechanisms involved in breast cancer and identify future targeted therapy. One of the mechanisms by which chemoresistance is attained in cancer cells is mediated through the expression of MDR-related glycoproteins (MRPs). These transmembrane proteins efflux drugs across the plasma membrane, conferring resistance of cancer cells to anticancer drugs. Elevated expression of Multidrug Resistance Protein 1 (MRP1) has been associated with poor prognosis and survival rate among breast cancer patients. Acquiring drug resistance has been correlated to the emergence of metastasis, accounting for the progression of the disease. Altered cell-surface glycosylation is a common feature of cancer initiation and progression. During glycosylation, the MRP1 undergoes N-linked glycosylation but it is unclear how glycosylation impacts the drug transport activity. To examine the crosstalk between MRP1 and Neuraminidase 1 (Neu1), the enzyme that catalyzes the removal of sialic acid residues from glycoproteins, we initiated our studies using plant derived natural product honokiol to examine the effect of honokiol on Neu1. In this study, we demonstrated that honokiol suppressed Neu1 in two breast cancer cell lines using Western Blot Analysis. To determine whether there is a link between Neu1 and MRP1 in improving the efficacy of doxorubicin-facilitated growth suppression, we treated the breast cancer cells with Neu1 inhibitor, Oseltamivir Phosphate (OP) and demonstrated that at 600 ug/ml and 800 ug/ml, OP suppressed breast cancer cell growth. OP in combination with doxorubicin reduced growth of breast cancer cells and enhanced the efficacy of doxorubicin-mediated growth inhibition. Future studies are underway to examine the effect of OP and honokiol on the glycosylation of MRP1. We propose that these studies will lead to the understanding on how glycosylation of MRP1 contributes to the transport of chemotherapeutic agents and eventually to the spread of the disease. Citation Format: Padmamalini Thulasiraman, Kelbie Kerr. Understanding the crosstalk between glycosylation and drug resistance [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 4890.
Why a randomized melanoma screening trial may be a good idea
Authors: A.E. Cust, J.F. Aitken, P.D. Baade, D.C. Whiteman, H.P. Soyer, M. Janda
Journal: British Journal of Dermatology (2018)

Linked Article: Halvorsen et al. Br J Dermatol 2018; 179:532–33.
Abstract 4500: BET proteins regulate hyaluronan synthases in pancreatic ductal adenocarcinoma
Authors: Krishan Kumar, Kazumi Ebine, Thao Pham, Meng Shang, Hidayatullah G. Munshi
Journal: Cancer Research (2018)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with an extensive desmoplasia which is composed of multiple extracellular matrix components, including collagen, fibronectin, laminin, and hyaluronan (HA). Inhibitors targeting bromodomain and extra-terminal (BETi) proteins have emerged as potential therapeutic agents and are in clinical trials for a range of malignancies. We have previously shown that BETi attenuate fibrosis in vivo by decreasing collagen expression; however, the effect of BETi on HA has not been previously evaluated. Increased HA, which is synthesized by HA synthases (HAS), is associated with poor outcome in PDAC. Targeting HA has been postulated to provide a potential therapeutic opportunity to overcome PDAC chemo-resistance. Preclinical data have demonstrated that enzymatic degradation of HA with PEGPH20 remodels the tumor microenvironment, decreases the interstitial pressure and enhance the drug entry in tumors. Several ongoing clinical trials are evaluating PEGPH20 in combination with chemotherapies. We now report that BET inhibitors markedly decrease expression of HAS2 and HAS3, which are overexpressed in PDAC. Purpose: The aim of this study is to investigate the role of BET proteins in HA synthesis. Methods: mRNA expression levels HAS2 and HAS3 were determined in a panel of 7 PDAC cell lines by quantitative real-time RT-PCR. Protein expression was determined by western blotting. Results: We found that treatment with BET inhibitors decrease the expression of HAS2 and HAS3 in all cell lines. Furthermore, siRNA mediated knockdown of individual BET proteins demonstrated that HAS2 is primarily regulated by BRD2, while HAS3 is primarily regulated by BRD4. Conclusion: Our results demonstrate that BET proteins play a role in HA synthesis by regulating expression of HAS2 and HAS3 enzymes. Citation Format: Krishan Kumar, Kazumi Ebine, Thao Pham, Meng Shang, Hidayatullah G. Munshi. BET proteins regulate hyaluronan synthases in pancreatic ductal adenocarcinoma [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 4500.
Mitochondrial dysfunction in pathophysiology of heart failure
Authors: Bo Zhou, Rong Tian
Journal: Journal of Clinical Investigation (2018)

Mitochondrial dysfunction has been implicated in the development of heart failure. Oxidative metabolism in mitochondria is the main energy source of the heart, and the inability to generate and transfer energy has long been considered the primary mechanism linking mitochondrial dysfunction and contractile failure. However, the role of mitochondria in heart failure is now increasingly recognized to be beyond that of a failed power plant. In this Review, we summarize recent evidence demonstrating vicious cycles of pathophysiological mechanisms during the pathological remodeling of the heart that drive mitochondrial contributions from being compensatory to being a suicide mission. These mechanisms include bottlenecks of metabolic flux, redox imbalance, protein modification, ROS-induced ROS generation, impaired mitochondrial Ca2+ homeostasis, and inflammation. The interpretation of these findings will lead us to novel avenues for disease mechanisms and therapy.
Idiopathic Portal Hypertension
Authors: Virginia Hernández‐Gea, Anna Baiges, Fanny Turon, Juan Carlos Garcia‐Pagán
Journal: Hepatology (2018)

Idiopathic portal hypertension (IPH) is a rare disorder characterized by clinical portal hypertension in the absence of a recognizable cause such as cirrhosis. Laboratory tests often reveal a preserved liver function with anemia, leukopenia, and thrombocytopenia due to splenomegaly. Imaging studies reveal signs of portal hypertension, whereas liver stiffness and portal pressure values are usually normal or slightly elevated. Liver biopsy is considered mandatory in order to rule out other causes of portal hypertension, mainly cirrhosis. Liver histology may only show subtle or mild changes, and the definite diagnosis of IPH often requires an expert pathologist and a high-quality specimen. The most frequent clinical presentation is variceal bleeding. Ascites is rarely observed initially, although it may occasionally appear during follow-up. Typical histological findings associated with IPH have been described in patients without portal hypertension, probably representing early stages of the disease. Although the pathophysiology of this entity remains largely unknown, it is frequently associated with underlying immunological disorders, bacterial infections, trace metal poisoning, medications, liver circulatory disturbances, and thrombotic events. The long-term prognosis of patients with IPH, where ascites and the underlying condition are important prognostic factors, is better than in patients with cirrhosis. Treatments that modify the natural history of the disease remain an unmet need, and management of IPH is frequently restricted to control of portal hypertension-related complications.
Abstract 388: p16/MTAP status as a model for investigating gene-environment interactions in metabolism
Authors: Sydney M. Sanderson, Peter Mikhael, Ziwei Dai, Jason W. Locasale
Journal: Cancer Research (2018)

Abstract While the consequences of tumor suppressor gene deletions have been extensively characterized, little is known about how concurrent deletions of neighboring genes can influence the interaction of cancer cells with the environment. Using a panel of tissue-matched cancer cell lines exhibiting either wild-type or homozygous deletions of the p16 locus, metabolomics analysis showed that concurrent deletion of the proximal gene encoding the methionine salvage enzyme methylthioadenosine phosphorylase (MTAP) is associated with a subtle but reproducible global shift in metabolite levels. However, MTAP status does not appear to be predictive of metabolic responsiveness to restriction of key nutrients that feed into and out of the methionine cycle. Of particular interest is the finding that cell lines exhibit remarkable heterogeneity in responsiveness to nutrient availability, seemingly independent of MTAP status or tissue of origin. Similarly, MTAP-deleted cell lines exhibit variable global metabolic reprogramming in response to acute ectopic expression of MTAP, and maintain their heterogeneous responsiveness to nutrient restriction. These findings illustrate the exceptional metabolic diversity across cancer cell lines despite similar culture conditions, demonstrating the usefulness of examining a variety of cell lines in studies of cancer cell metabolism. Citation Format: Sydney M. Sanderson, Peter Mikhael, Ziwei Dai, Jason W. Locasale. p16/MTAP status as a model for investigating gene-environment interactions in metabolism [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 388.
Genetically engineered cell factories produce glycoengineered vaccines that target antigen-presenting cells and reduce antigen-specific T-cell reactivity
Authors: Caroline B.K. Mathiesen, Michael C. Carlsson, Stephanie Brand, Svenning Rune Möller, Manja Idorn, Per thor Straten, Anders E. Pedersen, Sally Dabelsteen, Adnan Halim, Peter Adler Würtzen, Jens Brimnes, Henrik Ipsen, Bent L. Petersen, Hans H. Wandall
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 16134: Semaphorin 4D Supports Communication Between Platelets in the Early Stages of Thrombus Formation
Authors: Kenneth M Wannemacher, Li Zhu, Hong Jiang, Le Wang, Lawrence F Brass
Journal: Circulation (2011)

Platelets normally circulate as single cells, but form stable contacts with each other in response to vascular injury or disease. This process is dependent on cell adhesion molecules and enables pl...
Gangrene of the Extremities of Venous Origin
Authors: Henryhaimovici
Journal: Circulation (1950)

Gangrene of the extremities of venous origin is reviewed; it is a rare but distinct clinicopathologic entity hitherto not widely known. A classification of the cases of thrombophlebitis complicated with gangrene is presented, based on the presence of the peripheral pulses: (1) cases with palpable arteries; (2) cases with nonpalpable but patent arteries. Patency of the entire arterial system of the involved extremity, as verified by anatomic findings, is necessary for correct diagnosis. Complete blockage of the venous system appears to be the initiating and main cause, angiospasm playing a secondary role. The gangrene usually remains superficial and limited. Hence, a conservative surgical attitude is emphasized.
Possible Inhibition of Focal Cerebral Ischemia by Angiotensin II Type 2 Receptor Stimulation
Authors: MasaruIwai, Hong-WeiLiu, RuiChen, AyumiIde, ShokoOkamoto, RyujiHata, MasahiroSakanaka, TetsuyaShiuchi, MasatsuguHoriuchi
Journal: Circulation (2004)

Background— The role of angiotensin II receptor subtypes was investigated in focal brain ischemia induced by middle cerebral artery (MCA) occlusion. Methods and Results— In Agtr2+ (wild-type) mice, MCA occlusion induced focal ischemia of ≈20% to 30% of the total area in coronal section of the brain. The ischemic area was significantly larger in angiotensin II type 2 receptor–deficient (Agtr2−) mice than in Agtr2+ mice. The neurological deficit after MCA occlusion was also greater in Agtr2− mice than in Agtr2+ mice. The decrease in surface cerebral blood flow after MCA occlusion was significantly exaggerated in the peripheral region of the MCA territory in Agtr2− mice. Superoxide production and NADPH oxidase activity were enhanced in the ischemic area of the brain in Agtr2− mice. An AT1 receptor blocker, valsartan, at a nonhypotensive dose significantly inhibited the ischemic area, neurological deficit, and reduction of cerebral blood flow as well as superoxide production and NADPH oxidase activity in Agtr...
Abstract 4493: p190B RhoGAP modifies growth factor signaling in breast cancer in a non-cell autonomous manner
Authors: Eduardo Castro, Aaron Preston, Mykal Quinlan, Peter McHenry
Journal: Cancer Research (2018)

Abstract Estrogen mediates the growth and differentiation of breast epithelial cells and plays an important role in breast cancer progression. The upregulation of estrogen receptors has been linked to p190B RhoGAP in vivo. p190B regulates the activity of several Rho GTPases in vitro. To better understand the molecular mechanism of p190B's role in tumor progression, we sought to develop a cell culture model that would recapitulate the effects of p190B on various growth factor signaling pathways. Protein expression of p190B was knocked down using siRNA in MCF-7 breast cancer cells cultured in the absence of steroid hormones. Upon stimulation with estrogen, cell proliferation did not significantly differ between MCF-7 cells expressing reduced p190B and those expressing normal levels of p190B, suggesting that the effects of p190B on estrogen receptor expression are not cell autonomous and that additional components of the tumor microenvironment are required to recapitulate the in vivo findings. Citation Format: Eduardo Castro, Aaron Preston, Mykal Quinlan, Peter McHenry. p190B RhoGAP modifies growth factor signaling in breast cancer in a non-cell autonomous manner [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 4493.
α1-Adrenergic Activation Inhibits β-Adrenergic–Stimulated Unitary Ca2+ Currents in Cardiac Ventricular Myocytes
Authors: LongChen, NabilEl-Sherif, MohamedBoutjdir
Journal: Circulation Research (1996)

We have previously shown that whole-cell L-type Ca2+ current that was stimulated through β-adrenergic receptors was negatively modulated by α1-adrenergic activation. In the present study, we investigated the kinetic basis of this modulation at the single-channel level in adult rat ventricular myocytes using Ba2+ as the charge carrier. Unitary current sweeps were evoked by 300-ms depolarizing pulses to 0 mV, from a holding potential of −50 mV at 0.5 Hz. During control conditions, the ensemble-averaged current amplitude was 0.18±0.01 pA (n=7). To achieve β-adrenergic stimulation (β effect), cells were superfused with norepinephrine (10 μmol/L) in the presence of prazosin (10 μmol/L), an α1-adrenergic blocker. β-Adrenergic stimulation enhanced ensemble-averaged current (from 0.18±0.01 to 0.75±0.04 pA, P<.05, n=7), increased the open-time constants, and decreased the closed-time constants. To activate α1-receptors while maintaining the β-adrenergic stimulation, cells were superfused with norepinephrine alone ...