tbuckley/cabot-search huggingface dataset:
Abstract 888: A novel assay for the evaluation of ADCC in 3D-culture
Authors: Macarena Irigoyen, Andrea Alms, Yoko Ejiri, Satoru Ayano, Gonzalo Castillo
Journal: Cancer Research (2018)

Abstract In the last few years, one of the most innovative areas of cancer research has been immuno-oncology where significant advancements have been seen, particularly, in the use of monoclonal antibodies to treat cancers. The regulation of immune-mediated killing by monoclonal antibodies is an important mechanism of action, like in the case of trastuzumab, a humanized monoclonal antibody used in the treatment of HER-2 positive breast cancers. Binding of the humanized antibody to the receptor induces antibody-dependent cellular cytotoxicity (ADCC). Assays that monitor this activity are historically difficult to execute suffering from low sensitivity and reproducibility. Furthermore, experiments are typically done in suspension of cells grown as monolayers; often, showing limited clinical translatability when studying solid tumor models. Unencumbered by the limitations of 2D assays, the tumor microenvironment of 3D-cultures includes cell-cell interactions and formations of metabolic gradients, which are vital to understanding drug efficacy and resistance. To study the ADCC triggered by trastuzumab in 3D-cellular models, we developed a novel method to evaluate cellular toxicity in spheroids. In this study, we demonstrated the quantification, with specificity and precision, of the ADCC activity elicited by trastuzumab in 3D-culture. The high HER2-expressing BT474 cell line (target cells) was pre-labeled and formed into spheroids utilizing Kuraray's 384-well Elplasia's microplates. PBMCs (effector cells) isolated from healthy donors were added in the presence or absence of the antibody, trastuzumab, and incubated overnight. Cytotoxicity of the tumor-derived cells was evaluated by counting stained dead cells using a cell imager. In parallel, a 2D-platform for ADCC assay was run and the pharmacology of trastuzumab was characterized. BT474 cells grown as spheroids show an IC50 of 0.09 µg/mL, when the study was done in 2D-culture an IC50 of 0.028 µg/mL was obtained. The ability to evaluate ADCC in both 2D- and 3D- may help the development of more translatable models in the clinic. Citation Format: Macarena Irigoyen, Andrea Alms, Yoko Ejiri, Satoru Ayano, Gonzalo Castillo. A novel assay for the evaluation of ADCC in 3D-culture [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 888.
Abstract 15925: Newt Exosomes are Bioactive on Mammalian Heart, Enhancing Proliferation of Rat Cardiomyocytes and Improving Recovery After Myocardial Infarction
Authors: Eleni Tseliou, Liu Weixin, Jackelyn Valle, Baiming Sun, Maria Mirotsou, Eduardo Marbán
Journal: Circulation (2015)

Introduction: Adult newts can regenerate amputated cardiac tissue (and whole limbs) without fibrosis, unlike adult mammals which lack such regenerative capacity. Exosomes are nanoparticles which mediate intercellular communication and play a critical role in therapeutic regeneration. Hypothesis: We isolated exosomes from a newt mesodermal cell line, and evaluated their bioactivity in rat models. Methods: A1 cells, derived from the amputated limb buds of Notopthalmus viridescense (Brockes JP, 1988), were expanded in culture. Exosomes were isolated by polyethylene glycol precipitation of A1-conditioned serum-free media (or media conditioned by human dermal fibroblasts [DF] as a control) followed by centrifugation. Bioactivity was tested in vitro on neonatal rat ventricular myocytes (NRVM), and in vivo on acute myocardial infarction in Wistar-Kyoto rats (250μg or 500μg of A1-exosomes or vehicle [placebo] injected intramyocardially). Functional and histological analyses were performed 3 weeks after therapy. Results: A1-conditioned media yielded ~2.8±1Billion particles/ml of 129±1.1 nm diameter. In vitro, A1-exosomes increased the proliferative capacity of NRVM compared to DF-exosomes (4.98±0.89% vs 0.77±0.33%, p=0.035). Priming of DFs with A1-exosomes increased SDF-1 secretion compared to DF-exosomes (755±117pg/ml vs.368±21pg/ml, p=0.03). In vivo, both A1-exosome doses increased cardiac function compared to placebo (EF= 46±1% in 250μg, 49±4% in 500μg vs 36±1% in placebo, p=0.045 by ANOVA). Scar size was markedly decreased (11±1% in 250μg, 9±2% in 500μg vs 18±2% in placebo, p=0.006 by ANOVA), and infarct wall thickness was increased after A1-exosome treatment (1.7±0.11mm in 250μg, 1.85±0.16mm in 500μg vs 1.17±0.11mm in Placebo, p=0.01 by ANOVA). Donor-specific antibodies were present at barely detectable levels in the serum of animals that had been injected with A1-exosomes. Conclusions: Newt exosomes stimulate rat cardiomyocyte proliferation and improve functional and structural outcomes in rats with myocardial infarction. Characterization of the RNA and protein content of newt exosomes, now in progress, may provide clues regarding conserved (or newt-unique) molecular mediators of therapeutic benefit.
Midface toddler excoriation syndrome (MiTES) can be caused by autosomal recessive biallelic mutations in a gene for congenital insensitivity to pain, <i>PRDM12</i>
Authors: C. Moss, S.M. Srinivas, N. Sarveswaran, M. Nahorski, V.K. Gowda, F.M. Browne, G. Woods
Journal: British Journal of Dermatology (2018)

Midface toddler excoriation syndrome (MiTES) is a condition recently reported in three unrelated children. Habitual scratching from the first year of life inflicted deep, chronic, scarring wounds around the nose and eyes. One child had a mild neurological deficit but there was no other evidence of insensitivity to pain. Bilateral distribution and localization to the midface distinguish MiTES from other causes of self-inflicted skin damage such as trigeminal trophic syndrome. An earlier study of five siblings from a consanguineous Irish family, with lesions corresponding to MiTES plus other sensory deficits, showed homozygous mutations in a gene for hereditary sensory and autonomic neuropathy type VIII (HSAN8), PRDM12.To study further cases of MiTES, including analysis of PRDM12.We describe five further children, from four families, with facial lesions typical of MiTES, in whom mutation analysis of PRDM12 was carried out.Homozygous or compound heterozygous pathogenic expansions of the PRDM12 polyalanine tract were found in four of five affected individuals, in three families.Our finding of autosomal recessive mutations in PRDM12 in four of five patients with MiTES extends the phenotypic spectrum of PRDM12 mutations, which usually cause HSAN8, characterized by mutilating self-inflicted wounds of the extremities, lips and tongue. By contrast, MiTES shows severe midfacial lesions with little if any evidence of generalized pain insensitivity. The condition is probably genetically heterogeneous, and other congenital insensitivity to pain and HSAN genes such as SCN11A may be implicated. This new understanding of the nature of MiTES, which can masquerade as factitious disease, will facilitate appropriate management.
Abstract 82: Epigenetic reader ZMYND8 bridges BRD4 and hypoxia-inducible factors to mediate breast cancer progression and metastasis
Authors: Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Jennifer Wang, Chenliang Wang, Xuan Zou, Yingfei Wang, Weibo Luo
Journal: Cancer Research (2018)

Abstract Metastatic breast cancer has high rates of relapse and mortality. The absence of definitive prognostic biomarker and effective therapeutic target is the major obstacle to end this aggressive disease. Epigenetic dysregulation plays a crucial role in breast cancer metastasis. However, the mechanism by which epigenetic dysregulation stimulates the hypoxia-mediated breast cancer progression and metastasis remains unknown. Based on luciferase reporter assays and analysis of expression changes of 720 epigenetic genes in three microarray datasets, we identified epigenetic reader ZMYND8 as a novel hypoxia-inducible factor (HIF) target gene. Human breast cancer tissue microarray data indicated that ZMYND8 is highly expressed in invasive breast tumors and this overexpression is significantly correlated with poor clinical outcomes in patients with breast cancer. ZMYND8 depletion dramatically attenuates the tumorigenic potential of breast cancer cells in colony formation, migration and invasion in vitro, and suppresses breast tumor growth and metastasis in mice. To elucidate the underlying mechanism, we performed co-immunoprecipitation, chromatin immunoprecipitation and quantitative PCR assays and found that ZMYND8 interacts with HIF complex and acetyl lysine 16 of histone H3 at the hypoxia inducible elements (HREs) to provoke the expression of HIF target genes LOX, AGR2, AQP1 and VEGFA. ZMYND8 controls breast cancer growth and metastasis through HIF in mice. We further found that p300 binds and acetylates ZMYND8 in breast cancer cells. Acetylated ZMYND8 interacts with and recruits BRD4 to the HREs to stimulate RNA polymerase II phosphorylation, thereby promoting transcriptional elongation of HIF target genes. ZMYND8 acetylation is necessary and sufficient for breast tumor growth and metastasis in vitro and in mice. Together, p300-ZMYND8-BRD4-HIF axis is critical for breast cancer progression and metastasis. In summary, ZMYND8 represents a positive feedback mechanism that amplifies HIF-mediated breast cancer progression and metastasis, and provides a potential epigenetic target for the prognosis and treatment of breast cancer. Citation Format: Yan Chen, Bo Zhang, Lei Bao, Lai Jin, Mingming Yang, Yan Peng, Jennifer Wang, Chenliang Wang, Xuan Zou, Yingfei Wang, Weibo Luo. Epigenetic reader ZMYND8 bridges BRD4 and hypoxia-inducible factors to mediate breast cancer progression and metastasis [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 82.
Obstructive sleep apnoea and exercise functional capacity: time to move?
Authors: Núria Farré, Geraldo Lorenzi-Filho
Journal: European Respiratory Journal (2018)

Obstructive sleep apnoea (OSA) is defined by repetitive episodes of obstructive respiratory events, characterised by marked reduction (hypopnoea) or cessation of respiration (apnoea) due to upper airway obstruction during sleep. Each respiratory event leads to episodes of asphyxia and progressive but futile generation of excessive negative intrathoracic pressure. The patient is typically self-rescued by an arousal from sleep that leads to opening of the airway and resumption of breathing [1]. OSA is common in the general population across the whole human life span from infants to the elderly [2]. There is good evidence built over the past 30 years that OSA may trigger a cascade of mechanisms that are harmful to the cardiovascular and metabolic system, including sympathetic over activity, oxidative stress, endothelial dysfunction and insulin resistance. OSA is also associated with hypertension, arrhythmias, progression of atherosclerosis and increased cardiovascular mortality due to acute myocardial infarction and stroke [3–6]. Despite all these evidence, the impact of OSA on cardiorespiratory fitness (CRF) is controversial. This is an important question because low levels of CRF have been associated with a high risk of cardiovascular disease and all-cause mortality [7–9]. CRF is a potentially stronger predictor of mortality than established cardiovascular risk factors [9, 10]. Although CRF can be quantified by different means, including metabolic equivalents (METS) or peak oxygen consumption ( V ′O2peak), the evidence available so far shows that, irrespective of the method used, low CRF is associated with worse prognosis [9]. Patients with sleep apnoea have reduced exercise capacity. Should exercise programmes be included in their routine clinical management? <http://ow.ly/TukR30ksqjG>
Abstract 1765: A humanized anti-CD47 monoclonal antibody that directly kills human tumor cells and has additional unique functional characteristics
Authors: Robyn Puro, Katherine Liu, Benjamin Capoccia, Michael Donio, Ronald Hiebsch, Myriam Bouchlaka, Alun Carter, Pamela Manning, Kathleen Crowley, Robert Karr
Journal: Cancer Research (2018)

Abstract CD47 is a cell surface glycoprotein that interacts with signal regulatory protein alpha (SIRPα) on macrophages and dendritic cells triggering a “don't eat me” signal that inhibits phagocytosis. Many tumors evade immune surveillance by overexpressing CD47, thereby preventing their recognition by phagocytes. Blocking the interaction of SIRPα/CD47 promotes phagocytosis and tumor cell destruction leading to a reduction in tumor burden. We have developed a humanized anti-CD47 antibody, AO-176, that blocks the interaction between CD47 and SIRPα and exhibits several additional novel functional characteristics. These characteristics include the induction of cell death in multiple human tumor cell lines in a cell autonomous manner (not ADCC), assessed by an increase in phosphatidylserine/7AAD positive staining. A second novel characteristic is enhanced binding to tumor cells at acidic pH. AO-176 binds to human tumor cell lines in the high pM to low nM range at physiologic pH, however, binding is enhanced up to 20-fold at an acidic pH of 6.5. The acidic pH of the tumor microenvironment which ranges from 6.4-7.2 is characteristic of solid tumors and correlates with tumor progression and metastasis. As a result of this enhanced binding at acidic pH, AO-176 has the potential added advantage of tumor-specific targeting. A third novel characteristic exhibited by AO-176 is its selective binding to tumor cells while exhibiting reduced binding to normal cells including red blood cells (cynomolgus monkey and human), endothelial, epithelial and skeletal muscle cells. In addition to these novel characteristics, AO-176 also exhibits dose-dependent efficacy in multiple mouse tumor models. Taken together, the unique combination of functional characteristics of AO-176, including induction of cell-autonomous killing, enhanced binding to tumor cells at acidic pH, significantly reduced binding to normal cells and potent in vivo efficacy provides the preclinical rationale for further development. Citation Format: Robyn Puro, Katherine Liu, Benjamin Capoccia, Michael Donio, Ronald Hiebsch, Myriam Bouchlaka, Alun Carter, Pamela Manning, Kathleen Crowley, Robert Karr. A humanized anti-CD47 monoclonal antibody that directly kills human tumor cells and has additional unique functional characteristics [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 1765.
Patent Foramen Ovale and Risk of Perioperative Stroke—Reply
Authors: Pauline Yeung Ng, Timothy T. Houle, Matthias Eikermann
Journal: JAMA (2018)

In Reply Dr Rigatelli and Mr Zuin suggest the need to further characterize PFO to identify subgroups of the population with PFO who are at increased risk of perioperative stroke and hence, targets for preoperative optimization.
Nimotuzumab plus paclitaxel and cisplatin as 1st line treatment for unresectable esophageal squamous cell carcinoma: Long term follow-up of survival in a phase II study.
Authors: Xiaodong Zhang, Jun Jia, Ming Lu, Xicheng Wang, Jifang Gong, Jie Li, Jian Li, Yan Li, Xiaotian Zhang, Zhihao Lu, Jing Yu, Zhiwei Sun, Ying Yang, Lin Shen
Journal: Journal of Clinical Oncology (2017)

e15573 Background: The role of anti-epidermal growth factor receptor (EGFR) targeting treatment in esophageal squamous cell carcinoma (ESCC) is still uncertain. We conducted a prospective phase 2 study of paclitaxel, cisplatin, and nimotuzumab (TPN) as first-line treatment in unresectable or metastatic ESCC (NCT01336049). The objective response rate was 51.8%. Here we reported long-term follow-up results of that initial trial. Methods: 59 patients were enrolled from Mar 2011 to Apr 2013 and treated with the TPN regimen (nimotuzumab 200mg weekly, paclitaxel 175mg/m 2 on day1, and cisplatin 30mg/m 2 on day1 and 2, repeat every 3 weeks for total six cycles). Patients were allowed to receive sequential radiotherapy in case of local-regional disease or controlling symptom. Results: 56 of 59 patients were eligible for evaluation. After a median follow-up of 32.2months, the median progression-free survival (PFS) and overall survival (OS) were 18.1±4.2 months (95% Confidence: 9.8-26.4) and 26.2±10.0 months (95% Confidence: 6.6-45.8) in 29 patients with unresectable local-regional disease, while those were 6.6±0.4 months (95% Confidence: 5.8-7.5) and 11.5±3.7 months (95% Confidence: 4.2-18.8) respectively in 27 patients with metastatic disease. Patients of male, with multiple lymph node station metastasis, visceral metastasis, no response to TPN treatment, and without radiotherapy had worse OS. Even in some patients with multiple stations lymph node metastasis or recurrent disease of local-regional lymph node metastasis, TPN with sequential radiation seemed could bring longer survival time. But multivariate cox-regression analysis only confirmed that the TPN treatment was associations with OS. Compared with those of complete and partial response, patients of stable disease and progression had poor OS (HR = 2.32, 95% CI: 1.03-5.05, p = 0.03). Conclusions: the combination of nimotuzumab, paclitaxel, and cisplatin is effective as first-line treatment for patients with unresectable and metastatic ESCC, especially those with sequential radiotherapy. Clinical trial information: NCT01336049.
Re: Valeria Panebianco, Yoshifumi Narumi, Ersan Altun, et al. Multiparametric Magnetic Resonance Imaging for Bladder Cancer: Development of VI-RADS (Vesical Imaging-Reporting And Data System). Eur Urol 2018;74:294–306
Authors: Andrea Necchi, Antonella Messina, Alberto Briganti
Journal: European Urology (2018)
Overexpression of RANK and M-CSFR in Monocytes of G551D-Bearing Patients with Cystic Fibrosis
Authors: Frédéric Velard, Marie Laure Jourdain, Dina Abdallah, Jacky Jacquot, Nicola Ronan, Yvonne McCarthy, Evelyn Flanagan, Barry Plant
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Response to: ’Protective effects of antimalarials in Chinese patients with systemic lupus erythematosus' by Wang <i>et al</i>
Authors: Nadine Müller-Calleja, Karl J Lackner
Journal: Annals of the Rheumatic Diseases (2018)

In their letter, Wang et al 1 present further data showing impressively the beneficial effects of antimalarials and in particular hydroxychloroquine (HCQ) in patients with systemic lupus erythematosus. They refer to our article on the interference of HCQ with proinflammatory signalling pathways.2 We showed that HCQ prevents activation of endosomal NADPH-oxidase (NOX) by cell surface receptors, for example, the receptors for tumour …
Abstract 4519: Preliminary data of a stool test for lung cancer from a prospective study
Authors: Martin Tobi, Yosef Y. Tobi, Fadi Antaki, MaryAnn Rambus, Michael Lawson
Journal: Cancer Research (2018)

Abstract Lung cancer is the biggest cancer killer Worldwide with a limited prognosis despite personalized treatment regimens. Low-dose CT scanning as a means to early diagnosis has been disappointing due to the high false positive rate. Other non-invasive means of testing need to be developed that offer both timely diagnosis and predict prognosis. Methods: In the course of stool testing in a large scale testing of patients at increased risk of CRC we were able to ascertain 55 patients documented to have prospectively been diagnosed with lung cancer. Stool and colonic effluents were tested for anti-adenoma antibody (Adnab-9) reactivity by ELISA and Western blot. Survival data were obtained where available. Results: Of 55 cancers 40% were squamous (SSC), 23.7 were adenocarcinoma, 14.6 small, 12.7 large cell and 9% were designated NSCLC. 49.1% of the lung cancer patients had adnab-9 testing. Overall 53.6% (14 of 26) had positive testing compared to 2 of 11 controls (18.2%) which bordered on significance (OR5(CI1-29)). Cancers with higher lethality were more likely to test positive (67% for both small and large cell lung cancers, 50% SCC and adenocarcinoma, 33% NSCLC). In the larger groups overall survival was worse in those testing positive (474 versus 844 days in SCC and 54 versus 749 days in adenocarcinoma patients). Most importantly the time from a positive test to the clinical diagnosis ranged from 2.72 years for small cell, 3.13 for adenocarcinoma, 5.07 for NSCLC, 6.07 for SSC, and 6.24 for large cell cancer). In excluded cases where lung cancer was believed to be metastatic 75% of cancers were positive. Conclusions: At a projected real world sensitivity of 0.53 and specificity of 0.82 and the ability to predate diagnosis by up to 4.7 years overall, this test could help direct lung cancer screening. In addition, the Adnab-9 testing selectively detects worse tumor types (67%) and those with worse prognosis amongst the more common, favorable phenotypes thus making early diagnosis possible in those patients who stand to benefit most from this strategy. Metastatic lung cancer also detected by the test should be identified by the follow-up imaging studies and therefore would not be considered to be a major pitfall. Citation Format: Martin Tobi, Yosef Y. Tobi, Fadi Antaki, MaryAnn Rambus, Michael Lawson. Preliminary data of a stool test for lung cancer from a prospective study [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 4519.
Remnant-Like Particle Cholesterol, Low-Density Lipoprotein Triglycerides, and Incident Cardiovascular Disease
Authors: Anum Saeed, Elena V. Feofanova, Bing Yu, Wensheng Sun, Salim S. Virani, Vijay Nambi, Josef Coresh, Cameron S. Guild, Eric Boerwinkle, Christie M. Ballantyne, Ron C. Hoogeveen
Journal: Journal of the American College of Cardiology (2018)
Abstract 2320: Heme oxygenase-1 mediates ferroptosis
Authors: Shih-Kai Chiang, Shuen-Ei Chen, Ling-Chu Chang
Journal: Cancer Research (2018)

Abstract Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic target for cancer treatment. BAY 11-7085 (BAY), which is a well-known IκBα inhibitor, suppressed viability in cancer cells via induction of ferroptotic death in an NF-κB-independent manner. This study was aimed to characterize the underlying mechanism by BAY and demonstrate its potential chemotherapeutic targets for cancer treatment. Reactive oxygen species scavenging, relief of lipid peroxidation, replenishment of glutathione and thiol-containing agents, as well as iron chelation, rescued BAY-induced cell death in human breast cancer cells (MDA-MB-231 and MDA-MB-468) and glioblastoma cells (DBTRG-05MG). The results from quantitative real-time PCR and western blotting analysis showed that BAY upregulated a variety of nuclear factor-E2-related factor 2 (Nrf2) target genes related to redox regulation, particularly heme oxygenase-1 (HO-1) and solute carrier family 7 membrane 1 (SLC7A11). Studies with pharmacological inhibitors and shRNA interventions suggested that the hierarchy of induction is Nrf2-SLC7A11-HO-1. The ferroptotic process induced by hHO-1 overexpression further indicated that HO-1 is a key mediator of BAY-induced ferroptosis that operates through cellular redox regulation and iron accumulation. Our study discovered that BAY induced ferroptosis via Nrf2-SLC7A11-HO-1 pathway and provided new insights to understand the mechanism of HO-1-induced ferroptosis, suggesting HO-1 as a new chemotherapeutic target for cancer treatment. Citation Format: Shih-Kai Chiang, Shuen-Ei Chen, Ling-Chu Chang. Heme oxygenase-1 mediates ferroptosis [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 2320.