tbuckley/cabot-search huggingface dataset:
Abstract 1255: Delta-tocopherol induced endoplasmic reticulum stress causes autophagic degradation of ER and cell death in bladder cancer models
Authors: Christopher A. Blair, Hanze Hu, Tim Huynh, Maggie Wu, Chung S. Yang, Xiaolin Zi
Journal: Cancer Research (2018)

Abstract Vitamin E has been the subject of numerous basic and clinical studies, which have demonstrated a range of results that necessitate the further analysis of its individual components. We demonstrate that of the major tocopherol components of Vitamin E, Delta tocopherol (δ-T) is significantly more effective than the more common Alpha- and Gamma- tocopherols at inducing bladder cancer cell death in vitro and reduces tumor growth and burden in vivo. As a major site of protein synthesis and folding the endoplasmic reticulum (ER) is highly sensitive to stress induced by increased unfolded protein load, which induces both pro-survival and ultimately pro-apoptotic responses via the different branches of the unfolded protein response (UPR). δ-T induces the UPR in human bladder cancer cells and ultimately results in cell death, inducing both apoptosis and autophagic cell death. Analysis of bladder cancer cells treated with δ-T revealed strong evidence of UPR activation in the form of upregulation and activation of ER stress sensors PERK and IRE1α, and the upregulation of folding chaperone GRP78 and transcription factors ATF4 and CHOP. These changes in turn induced downstream effects including Death Receptor 5 (DR5)-mediated apoptosis and visible induction of autophagy. In addition to the observation of autophagosome formation, induction of autophagy was further confirmed by upregulation of protein expression of components of the autophagic machinery LC3B and Atg family members. Electron Microscope imaging of treated cells revealed the presence of ER-whorls within the large autophagosomes which were themselves visible under conventional light microscopy, which has to our knowledge not been previously observed in cancer models. This observation is supported by the ER stress-based mechanism of action exhibited by δ-T on bladder cancer cells, which recapitulates the observations of the few previous reports of “ER-phagy” described in yeast models. ER stress induced expansion of the ER is believed to aid in the improvement of stressed cells' protein folding capacity, and selective degradation of the ER-whorls formed in this manner by a previously undescribed mechanism of autophagy was first described in yeast and remains unexplored in human cancer models. These findings may provide new insights into δ-T's mechanism of action and inform new approaches to the development of tocopherols as novel chemopreventive agents. Citation Format: Christopher A. Blair, Hanze Hu, Tim Huynh, Maggie Wu, Chung S. Yang, Xiaolin Zi. Delta-tocopherol induced endoplasmic reticulum stress causes autophagic degradation of ER and cell death in bladder cancer models [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 1255.
Abstract 5340: The methylation burden is determined by the duration of exposure to carcinogenic factors
Authors: Harumi Yamada, Hideyuki Takeshima, Tohru Niwa, Takeshi Toyoda, Satoshi Yamashita, Toshikazu Ushijima
Journal: Cancer Research (2018)

Abstract Aberrant DNA methylation accumulated in normal tissues, namely methylation burden, is closely associated with risk of carcinogenesis, especially in cancers related to chronic inflammation. Methylation burden is known to be influenced by multiple factors, such as genetic factors and strengths of carcinogens. However, the impact of the duration of exposure to a carcinogen is still unclear. Here, using a Mongolian gerbil model of Helicobacter pylori (H. pylori)-induced chronic gastritis, we aimed to clarify the impact of the duration of exposure on the methylation burden in normal gastric tissues (gastric mucosae). Following infection with H. pylori, DNA methylation levels at four CpG islands, HE6, SA9, SB5, and SD2, increased, depending upon the exposure duration. After eradication of H. pylori, DNA methylation levels decreased, but tended to be higher in gastric mucosae with a longer infection period. DNA molecules with dense DNA methylation, but not those with sparse DNA methylation, increased depending upon the infection period. DNA methylation levels at one of the four CpG islands, SA9, tended to be higher in the gastric mucosae of gerbils infected with H. pylori than in those of non-infected gerbils, even 50 weeks after eradication. These results showed, for the first time, that the methylation burden in normal tissues is influenced by the duration of exposure to a carcinogenic factor. Citation Format: Harumi Yamada, Hideyuki Takeshima, Tohru Niwa, Takeshi Toyoda, Satoshi Yamashita, Toshikazu Ushijima. The methylation burden is determined by the duration of exposure to carcinogenic factors [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 5340.
Abstract 4495: A CD10+GPR77+ subset of cancer-associated fibroblasts promotes cancer formation and chemoresistance by sustaining cancer stem cells
Authors: Erwei Song
Journal: Cancer Research (2018)

Abstract Carcinoma-associated fibroblasts (CAFs) are an abundant and heterogeneous population of stromal cells in the tumor microenvironment critically involved in cancer progression. However, the lack of effective tools to isolate CAF subsets has prevented a comprehensive functional characterization of CAFs as well as their therapeutic potentials. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a new CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for the cancer stem cells (CSCs). Mechanistically the functions of the CAF subset are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs are crucial for the successful engraftment of patient-derived xenografts (PDXs) in vivo and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. This discovery represents the first time a functional CAF subset is identified using specific surface markers, which will greatly facilitate future investigations of the tumor microenvironment and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSCs-driven solid tumors. Citation Format: Erwei Song. A CD10+GPR77+ subset of cancer-associated fibroblasts promotes cancer formation and chemoresistance by sustaining cancer stem 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 4495.
Abstract 296: Loss of Romo1 enhances TRAIL-induced apoptosis through Bax upregulation in colon cancer
Authors: Minjee Jo, Jung Lim Kim, So Yeon Jeong, Bo Ram Kim, Yoo Jin Na, Seong Hye Park, Yoon A Jeong, Dae-Hee Lee, Sang Cheul Oh
Journal: Cancer Research (2018)

Abstract Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a protein which is induces cell apoptosis in various cancer. To identify novel sensitizer of TRAIL, we knocked down Reactive Oxygen Species modulator 1 (Romo1). Romo1 is a mitochondrial membrane protein that is in charge of increasing ROS. Romo1 was highly upregulated in various cancers including colorectal cancer. Inhibition of Romo1 significantly increased TRAIL-induced apoptosis in colorectal cancer cells, not colon normal cells. Silencing of Romo1 has resulted in upregulation of Bax protein expression. It has been reported that Bax degraded by ubiquitination. We identify interaction between Bax and Parkin decreased in knockdown of Romo1 condition. Also, suppression of Romo1 lead to mitochondrial dysfunction. Our study suggests that inhibition of Romo1 enhanced TRAIL-mediated apoptosis by regulating Bax ubiquitination. Citation Format: Minjee Jo, Jung Lim Kim, So Yeon Jeong, Bo Ram Kim, Yoo Jin Na, Seong Hye Park, Yoon A Jeong, Dae-Hee Lee, Sang Cheul Oh. Loss of Romo1 enhances TRAIL-induced apoptosis through Bax upregulation in colon 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 296.
PDGF Restores the Defective Phenotype of Adipose-Derived Mesenchymal Stromal Cells from Diabetic Patients
Authors: Vivian Capilla-González, Javier López-Beas, Natalia Escacena, Yolanda Aguilera, Antonio de la Cuesta, Rafael Ruiz-Salmerón, Franz Martín, Abdelkrim Hmadcha, Bernat Soria
Journal: Molecular Therapy (2018)

Diabetes is a chronic metabolic disorder that affects 415 million people worldwide. This pathology is often associated with long-term complications, such as critical limb ischemia (CLI), which increases the risk of limb loss and mortality. Mesenchymal stromal cells (MSCs) represent a promising option for the treatment of diabetes complications. Although MSCs are widely used in autologous cell-based therapy, their effects may be influenced by the constant crosstalk between the graft and the host, which could affect the MSC fate potential. In this context, we previously reported that MSCs derived from diabetic patients with CLI have a defective phenotype that manifests as reduced fibrinolytic activity, thereby enhancing the thrombotic risk and compromising patient safety. Here, we found that MSCs derived from diabetic patients with CLI not only exhibit a prothrombotic profile but also have altered multi-differentiation potential, reduced proliferation, and inhibited migration and homing to sites of inflammation. We further demonstrated that this aberrant cell phenotype is reversed by the platelet-derived growth factor (PDGF) BB, indicating that PDGF signaling is a key regulator of MSC functionality. These findings provide an attractive approach to improve the therapeutic efficacy of MSCs in autologous therapy for diabetic patients. Diabetes is a chronic metabolic disorder that affects 415 million people worldwide. This pathology is often associated with long-term complications, such as critical limb ischemia (CLI), which increases the risk of limb loss and mortality. Mesenchymal stromal cells (MSCs) represent a promising option for the treatment of diabetes complications. Although MSCs are widely used in autologous cell-based therapy, their effects may be influenced by the constant crosstalk between the graft and the host, which could affect the MSC fate potential. In this context, we previously reported that MSCs derived from diabetic patients with CLI have a defective phenotype that manifests as reduced fibrinolytic activity, thereby enhancing the thrombotic risk and compromising patient safety. Here, we found that MSCs derived from diabetic patients with CLI not only exhibit a prothrombotic profile but also have altered multi-differentiation potential, reduced proliferation, and inhibited migration and homing to sites of inflammation. We further demonstrated that this aberrant cell phenotype is reversed by the platelet-derived growth factor (PDGF) BB, indicating that PDGF signaling is a key regulator of MSC functionality. These findings provide an attractive approach to improve the therapeutic efficacy of MSCs in autologous therapy for diabetic patients.
Abstract 1373: Circular RNAs generated from the <i>BRCA1</i> pseudogene regulates the DNA damage response through SERBP1 RNA-binding protein
Authors: Yoo J. Han, Jing Zhang, Jennifer M. Mason, Toshio F. Yoshimatsu, Xinxin Du, Ian Hurley, Danny E. Kim, Aparna Anantharaman, Laia P. Brunet, Aleix Prat, John Kwon, Kannanganattu V. Prasanth, Olufunmilayo I. Olopade
Journal: Cancer Research (2018)

Abstract The genomic region encompassing the BRCA1 gene includes the BRCA1P1 pseudogene (BRCA1P1) within ~170kb at chromosome 17q21. The homology and proximity of BRCA1 and BRCA1P1 create a hot spot for recombination, resulting in a large genomic rearrangement found in some families with breast and ovarian cancers. While the significant role of BRCA1 in regulating the DNA damage response (DDR) is well defined, little is known about the biological properties of the BRCA1P1 pseudogene. To functionally annotate BRCA1P1, we conducted a CRISPR-Cas 9 knockout of the pseudogene, as well as knockdown of the expression using antisense oligonucleotides. Both knockout and knockdown of the pseudogene result in increases in apoptosis and sensitivity to DNA damaging drugs. Depletion of BRCA1P1 accumulates spontaneous DNA damage foci and leads to replication fork stalling. Mechanical studies reveal that the BRCA1P1 generates circular RNAs, which are retained in nuclei. Mass spectrometry followed by chromatin isolation by RNA purification (ChIRP) identifies a specific association of the circular RNAs with SERBP1 RNA-binding protein, which was confirmed by ChIRP-Western. Consequently, BRCA1P1 knockout decreased SERBP1 protein expression in the nuclei. Based on the previous report that SERBP1 binds to mRNAs of DDR proteins and controls their translation, we propose a mechanism of BRCA1P1-driven regulation of DDR protein expression through SERBP1. Our data indicate that the BRCA1P1 pseudogene plays a role in regulating replication fork progression and genomic instability in breast cancer cells through an interaction with SERBP1 RNA-binding protein. Citation Format: Yoo J. Han, Jing Zhang, Jennifer M. Mason, Toshio F. Yoshimatsu, Xinxin Du, Ian Hurley, Danny E. Kim, Aparna Anantharaman, Laia P. Brunet, Aleix Prat, John Kwon, Kannanganattu V. Prasanth, Olufunmilayo I. Olopade. Circular RNAs generated from the BRCA1 pseudogene regulates the DNA damage response through SERBP1 RNA-binding protein [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 1373.
Thromboxane A2-Induced Inhibition of Voltage-Gated K+ Channels and Pulmonary Vasoconstriction
Authors: AngelCogolludo, LauraMoreno, LisardoBosca, JuanTamargo, FranciscoPerez-Vizcaino
Journal: Circulation Research (2003)

Voltage-gated K+ channels (KV) and thromboxane A2 (TXA2) play critical roles in controlling pulmonary arterial tone under physiological and pathological conditions. We hypothesized that TXA2 might inhibit KV channels, thereby establishing a link between these two major pathogenic pathways in pulmonary hypertension. The TXA2 analogue U46619 inhibited IK(V) (Emax=56.1±3.9%, EC50=0.054±0.019 μmol/L) and depolarized pulmonary artery smooth muscle cells via activation of TP receptors. In isolated pulmonary arteries, U46619 simultaneously increased intracellular Ca2+ concentration and contractile force, and these effects were inhibited by nifedipine or KCl (60 mmol/L). U46619-induced contractions were not altered by the inhibitors of tyrosine kinase genistein or Rho kinase Y-27632 but were prevented by the nonselective protein kinase C (PKC) inhibitors staurosporine and calphostin C. Furthermore, these responses were sensitive to Go-6983 but insensitive to bisindolylmaleimide I and Go-6976. Based on the speci...
DNA Repair Gene Alterations and PARP Inhibitor Response in Patients With Metastatic Castration-Resistant Prostate Cancer
Authors: Eric Lu, George V. Thomas, Yiyi Chen, Alexander W. Wyatt, Paul Lloyd, Jack Youngren, David Quigley, Raymond Bergan, Shawna Bailey, Tomasz M. Beer, Felix Y. Feng, Eric J. Small, Joshi J. Alumkal
Journal: Journal of the National Comprehensive Cancer Network (2018)

Background: PARP inhibition is a promising therapeutic strategy for the treatment of men with metastatic castration-resistant prostate cancer whose tumors harbor homologous recombination DNA repair gene alterations. However, questions remain for many practicing clinicians about which patients are ideally suited for PARP inhibitor treatment. This report details our institutional experience using PARP inhibitor therapy in patients whose tumors harbored specific DNA repair gene alterations. Patients and Methods: We performed a retrospective chart review to identify patients at Oregon Health & Science University who were treated with PARP inhibition. We identified 8 patients and determined the impact of the specific DNA repair gene alterations on tumor response and time on treatment with PARP inhibition. Results: A number of DNA repair gene alterations were identified. Three patients had pathogenic BRCA2 mutations and one had a BRCA2 mutation of uncertain significance. Conversely, the 4 other patients' tumors harbored alterations in other DNA repair genes, none of which were clearly pathogenic. A statistically significant difference in benefit was seen between patients whose tumors harbored BRCA2 gene alterations and those whose tumors did not, as measured by >50% decline in prostate-specific antigen levels (100% vs 0%; P=.03) and duration on therapy (31.4 vs 6.4 weeks; P=.03). Conclusions: Our results demonstrate that not all DNA repair alterations are equally predictive of PARP inhibitor response. Importantly, all responding patients had tumors harboring BRCA2 DNA repair alterations, including one without a known pathogenic mutation. Conversely, among the 4 nonresponders, several DNA repair alterations in genes other than BRCA2 were identified that were not clearly pathogenic. This demonstrates the need to carefully examine the functional relevance of the DNA repair alterations identified, especially in genes other than BRCA2, when considering patients for PARP inhibitor treatment.
Prevalence of C-Reactive Protein Elevation and Time Course of Normalization in Acute Pericarditis
Authors: MassimoImazio, AntonioBrucato, SilviaMaestroni, DavideCumetti, AntonioDominelli, GiuseppeNatale, RitaTrinchero
Journal: Circulation (2011)

Background—The role of inflammatory markers is not well defined for either diagnosis or treatment of pericarditis. The aim of this study is to prospectively evaluate the frequency of high-sensitivity C-reactive protein (hs-CRP) elevation in patients with acute pericarditis, its time course of normalization, and the possible importance for diagnosis, therapy, and prognosis. Methods and Results—Two hundred consecutive patients with viral or idiopathic acute pericarditis (mean age, 53±15.5 years; 103 men) were studied from August 2005 to August 2007 in 2 Italian referral centers. Hs-CRP was determined at presentation and then every week until normalization. Hs-CRP elevation was recorded in 156 of 200 cases (78%) at presentation. Recognized causes of a negative hs-CRP at presentation were early assessment in 15 of 44 cases (34%) and previous anti-inflammatory therapies in 22 of 44 cases (50%). Hs-CRP normalization was achieved with the following time course: 120 of 200 (60%) at week 1, 170 of 200 (85%) at wee...
Abstract DDT02-01: FAP-4-1BBL: A next generation, targeted costimulatory agonist for cancer immunotherapy
Authors: Pablo Umana
Journal: Cancer Research (2018)

Abstract This talk will describe a new drug candidate for cancer immunotherapy, FAP-4-1BBL, a next generation, tissue-targeted agonist of the 4-1BB costimulatory receptor. Agonizing 4-1BB to enhance the activity of antitumor T cells has been successfully exploited by 2nd and 3rd generation CAR T-cell therapies for hematological malignancies. However, the clinical development of first-generation, 4-1BB agonistic antibodies for systemic administration has been hampered by significant hepatic toxicity. Here we describe a next generation, fibroblast activated protein (FAP)-targeted 4-1BB agonist whose activity is independent of Fc-gamma-receptor (FcγR)-binding, is safe in preclinical models (including non-human primates using doses of up to 50 mg/kg) and is significantly more potent and efficacious than first generation, standard 4-1BB agonistic antibodies when compared side-by-side in preclinical models. In preclinical models, combination of FAP-4-1BBL with T-cell bispecific antibodies leads to significant increases in T cell infiltration into the tumor, CD8/Treg ratio and anti-tumoral efficacy. We conclude that the tumor-targeted cross-linking of 4-1BB provides a safe and effective way for co-stimulation of T cells for cancer immunotherapy and its combination with T-cell bispecific antibodies may provide a convenient “off-the-shelf,” systemic cancer immunotherapy approach for many tumor types. Citation Format: Pablo Umana. FAP-4-1BBL: A next generation, targeted costimulatory agonist 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 DDT02-01.
Systemic Arterial Blood Pressure during Exercise in Patients with Atherosclerosis Obliterans of the Lower Limbs
Authors: Einarlorentsen
Journal: Circulation (1972)

Systemic intraarterial blood pressure and heart rate have been measured during exercise on a foot ergometer in 13 patients suffering from unilateral intermittent claudication. Each limb was exercised separately for 5 min. Both systolic and diastolic blood pressure increased to significantly higher levels during exercise with the diseased limbs than during exercise with the nondiseased limbs. No significant difference was found in heart rate. After cessation of exercise the blood pressure and heart rate dropped abruptly. For the first 2 min of recovery the systolic blood pressure in the diseased limbs stayed higher than the pressure measured at rest immediately before exercise. Ten patients were also exercised for 2 or 3 min with arrested circulation. During this period no significant differences between the diseased and nondiseased limbs were found in relation to blood pressure or heart rate.
Henry Teuton Burrowes Beers
Authors: David Jones, Peter McNamee
Journal: BMJ (2018)

Harry Teuton Burrowes Beers was born in east Belfast and was educated at Nettlefield Primary School and the Royal Belfast Academical Institution. After qualifying he endured a gruelling houseman’s year in the Waveney Hospital, where he was on a rota of one in one …
Dynamics of Carotid Sinus Elasticity During Pressor Reaction
Authors: JánGero, MáriaGerová
Journal: Circulation Research (1962)

The volume-elasticity coefficient of the sinocarotid region, in vivo and in situ, in experiments on anesthetized dogs, was studied in the course of an induced pressor reaction in order to elucidate some controversial questions concerning the role of the distensibility of the sinus wall in the mechanisms of excitation of the sinocarotid receptors. The coefficient of volume-elasticity, calculated as pulse pressure/pulse volume ratio, was evaluated in relation to mean B.P., recorded simultaneously. Changes in the coefficient of elasticity of the sinocarotid region were found to precede compensation of the pressor reaction, viz., in the period of compensation the coefficient of elasticity of the sinocarotid wall--under otherwise equal physical conditions--was lower than in the period of rising pressure. The above-mentioned relations can be ascertained also after resection of the Hering nerve, i.e., after deafferentation and serious injury to the efferent innervation of the sinocarotid region. These changes ar...