tbuckley/cabot-search huggingface dataset:
Abstract CT063: BAT1706 demonstrates high similarity to Bevacizumab in comparative analysis with originator and phase I clinical trials in New Zealand and China
Authors: Jin-Chen Yu
Journal: Cancer Research (2018)

Abstract Bevacizumab, a humanized monoclonal antibody against VEGF, has been approved by FDA to treat colon, lung, renal cancers and glioblastoma. We have developed BAT1706 as a biosimilar to Bevacizumab. Their evaluation was performed using several analytical assays and stress degradation studies. Both products BAT1706 shows similar binding affinity and biological function as Bevacizumab. In additionAdditionally, , several analytical assays and stress degradation studies have been conducted to compare multiple lots of BAT1706 and Bevacizumab. Tthe data indicate that BAT1706 is at least as pure as Bevacizumab and that the following attributes are consistent highly similar between both products: isoelectric point, peptide mapping profile, amino acid sequence, disulfide bond numbers and location, molecular weight and size, binding affinity towards the antigen and relevant immunologic receptors, isoform ratios, levels of impurities, glycosylation parameters, and secondary and tertiary structures. The degradation pathways and rates were evaluated using two different conditions (high temperature and strong light exposure) by means of several stability indicating methods. All Both products showed similar reactions during the incubating conditions and similar degradation rates. These data demonstrated that BAT1706 is highly similar to Bevacizumab, in structure, function, process impurities, and stability attributes. We have also completed two phase I studies with BAT1706 in New Zealand and China. Data revealed that a single IV infusion of BAT1706 (1 mg/kg) is safe and well tolerated in healthy subjects. No death was reported during either study and there was only 1 SAE of fibula fracture, which was not considered as related to BAT1706 by the investigator. The key PK parameters of both Phase I studies also revealed that BAT1706 is a bioequivalent to Bevacizumab. No positive results of anti-drug antibodiesy werewas reported for any subject in either study. Currently, a global randomized, double blind phase III study is on-going, to compare the efficacy, and to evaluate the safety and immunogenicity of BAT1706 to EU Bevacizumab in patients with previously untreated advanced non-squamous NSCLC. Citation Format: Jin-Chen Yu. BAT1706 demonstrates high similarity to Bevacizumab in comparative analysis with originator and phase I clinical trials in New Zealand and China [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 CT063.
Abstract 2642: CBLC is a potential biomarker for the susceptibility to paclitaxel in lung adenocarcinoma
Authors: Yi-Ping Lin, Shiao-Ya Hong, Yu-Rung Kao, Cheng-Wen Wu
Journal: Cancer Research (2018)

Abstract CBL family proteins have been reported as E3 ubiquitin ligases of receptor tyrosine kinases. CBLC is the most divergent member of CBL family in human due to lack of the distal part of C terminus found in other two proteins, CBL and CBLB. By data mining from TCGA database, CBLC expression was frequently upregulated in lung adenocarcinoma. However, very little is known about the tumorigenic functions of CBLC compared to other CBL family proteins. Although patients with lung adenocarcinoma harboring EGFR mutations can be treated with tyrosine kinase inhibitors (TKIs), there is no good target therapy for treating lung adenocarcinoma patients with EGFR wild-type or TKIs resistance. Here, this study is to investigate if CBLC can be a good target for treatment to benefit these patients. In lung adenocarcinoma cells, CBLC knockdown significantly decreased cell viability, while CBLC overexpression increased the ability to form colonies in soft agar. Flow cytometry analyses revealed that CBLC depletion decreased the cell population of G2/M phase and increased cell apoptosis. Our study also showed that CBLC knockdown in EGFR wild-type cells increased the drug resistance to paclitaxel, which is widely used as a first-line chemotherapy drug in lung adenocarcinoma patients with EGFR wild-type or TKI resistance. Taken together, these findings indicate that CBLC might play a role in promoting cell mitosis and could be a potential biomarker of paclitaxel susceptibility for patients with EGFR wild-type lung adenocarcinoma. Citation Format: Yi-Ping Lin, Shiao-Ya Hong, Yu-Rung Kao, Cheng-Wen Wu. CBLC is a potential biomarker for the susceptibility to paclitaxel in lung 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 2642.
Reflexes from the Aortic Baroreceptor Fibers in the Cervical Vagus of the Cat and the Dog
Authors: CYRIL S. ITO, ALLEN M. SCHER
Journal: Circulation Research (1974)

The baroreceptor fibers which arise from the aortic arch course centrally within the vagus nerve in the dog, and they usually follow this path in the cat. Near the origin of the superior laryngeal nerve, a separate branch of the cervical vagus (the cervical aortic nerve) arises. Previously, it was thought that this nerve contained all the important baroreceptor afferents. Aortic baroreceptor fibers that are not within the cervical aortic nerve were studied in the anesthetized cat and dog after cervical aortic and carotid sinus nerves had been sectioned. Some experiments were acute, but most were conducted 13-60 days after nerve section (to allow transected nerves to degenerate). After degeneration, baroreceptor activity was found in the peripheral aortic nerves in most animals. The sensory terminals of the surviving baroreceptor fibers were on the aortic arch on the left side and at the root of the right subclavian artery on the right side. In one of four chronic cats, four of eight chronic dogs after degeneration, and one of three animals in acute experiments a depressor response (8-70 mm Hg in chronic and 10 mm Hg in acute experiments) followed stimulation of the peripheral aortic nerve. The surviving aortic baroreceptor fibers coursed centrally in the cervical vagus.
New Noninvasive Method for Coronary Flow Reserve Assessment
Authors: CarloCaiati, CristianaMontaldo, NormaZedda, AlessandroBina, SabinoIliceto
Journal: Circulation (1999)

Background—We tested the hypothesis that blood flow velocity could be recorded in the left anterior descending coronary artery (LAD) during transthoracic echocardiography by use of second harmonic echo Doppler modality along with contrast enhancement (intravenous Levovist) at rest and after pharmacologically induced maximal vasodilation to assess coronary flow reserve (CFR) with a totally noninvasive approach. Methods and Results—Fifty-six consecutive patients undergoing coronary angiography underwent transthoracic contrast-enhanced pulsed-wave Doppler recording of blood flow velocity in the LAD by use of harmonic color Doppler as a guide at rest and after maximal vasodilation by dipyridamole infusion. Contrast enhancement with the harmonic mode greatly improved the success rate of recording adequate pulsed-wave Doppler signal in the LAD. CFR was (mean±SD) 1.54±0.7 in patients with (group 1) and 2.79±0.9 in patients without (group 2) significant LAD stenosis (lumen narrowing >70%) (P<0.001); sensitivity a...
Abstract 5685: Nanocage-therapeutics prevailing phagocytosis and immunogenic cell death awakens immunity against cancer
Authors: Gihoon Nam, Gi Beom Kim, In-San Kim
Journal: Cancer Research (2018)

Abstract A growing appreciation of the relationship between the immune system and tumorigenesis has led to the development of strategies aimed at ‘re-editing' the immune system to kill tumors. Here, we report a novel tactic for overcoming the activation-energy threshold of the immunosuppressive tumor microenvironment and mediating the delivery and presentation of tumor neoantigens to the host's immune system. This nature-derived nanocage not only efficiently presents ligands that enhance cancer cell phagocytosis, it also delivers drugs that induce immunogenic cancer cell death. The designed nanocage-therapeutics induces the release of neoantigens and danger signals in dying tumor cells, and leads to enhancement of tumor cell phagocytosis and cross-priming of tumor specific T cells by neoantigen peptide-loaded antigen-presenting cells. We observed potent inhibition of tumor growth and complete eradication of tumor through systemic tumor-specific T-cell responses in tumor draining lymph node and spleen and further, infiltration of CD8+ T cells into the tumor site. Remarkably, after removal of the primary tumor, all mice treated with this nanocage-therapeutics are protected against subsequent challenge with the same tumor cells, suggesting development of lasting, tumor-specific responses. This designed nanocage-therapeutics ‘awakens' the host's immune system and provokes a durable systemic immune response against cancer. Citation Format: Gihoon Nam, Gi Beom Kim, In-San Kim. Nanocage-therapeutics prevailing phagocytosis and immunogenic cell death awakens immunity against 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 5685.
Genetically Induced Moderate Inhibition of the Proteasome in Cardiomyocytes Exacerbates Myocardial Ischemia-Reperfusion Injury in Mice
Authors: ZongwenTian, HanqiaoZheng, JieLi, YifanLi, HuaboSu, XuejunWang
Journal: Circulation Research (2012)

Rationale:Both cardiomyocyte-restricted proteasome functional enhancement and pharmacological proteasome inhibition (PSMI) were shown to attenuate myocardial ischemia/reperfusion (I/R) injury. The role of cardiac proteasome dysfunction during I/R and the perspective to diminish I/R injury by manipulating proteasome function remain unclear. Objectives:We sought to determine proteasome adequacy in I/R hearts, create a mouse model of cardiomyocyte-restricted PSMI (CR-PSMI), and test CR-PSMI impact on I/R injury. Methods and Results:Myocardial I/R were modeled by ligation (30 minutes) and subsequent release of the left anterior descending artery in mice overexpressing GFPdgn, a validated surrogate proteasome substrate. At 24 hours of reperfusion, myocardial proteasome activities were significantly lower whereas total ubiquitin conjugates and GFPdgn protein levels were markedly higher in all regions of the I/R hearts than the sham controls, indicative of proteasome functional insufficiency. CR-PSMI in intact m...
Abstract 2513: FGFRL1 deficiency reduces motility and tumor growth of cells derived from esophageal squamous cell carcinoma
Authors: Yoshinori Takei, Takafumi Matsumura, Kazuaki Watanabe, Hirokazu Nakamine, Tetsuo Sudo, Kazuharu Shimizu, Yutaka Shimada
Journal: Cancer Research (2018)

Abstract Fibroblast growth factor receptor-like 1 (FGFRL1) belongs to the FGFR protein family. We previously reported that FGFRL1 is highly expressed in esophageal squamous cell carcinoma (ESCC) patients with lymph node metastasis and with the depth of ESCCs. Furthermore, transient inhibition of FGFRL1 expression induces cell cycle arrest and apoptosis of ESCC cells. However, the intracellular domain of FGFRL1 lacks the tyrosine kinase domain. Thus the mechanisms of which FGFRL1 contributes to the development of ESCC are unclear. Two cell lines (Clone 15 and 21) deficient for FGFRL1 expression were established from an ESCC cell line (KYSE520) using the CRISPR-Cas9 method. We evaluated the characteristics of these two cell lines in vitro and in vivo. In these FGFRL1-deficient KYSE520 cells, actin filaments around the nucleus were observed sparsely, whereas the filaments along the plasma membranes were observed as strong as those in the parent KYSE520 cells. Depleting FGFRL1 reduced cell motility in vitro and, decelerated tumor growth in a mouse xenograft model. Microarray analysis of mRNA expression revealed that FGFRL1-depletion resulted in reduced expression of MMP-1 and FGFBP1. In conclusions, FGFRL1-deficiency reduced both cell motility and tumor growth of KYSE520 cells. This is consistent with that high expression of FGFRL1 coincident with lymph node metastasis and poor prognosis. These results demonstrate that FGFRL1 expressed in ESCC cells has a role in aggressiveness of ESCCs. Citation Format: Yoshinori Takei, Takafumi Matsumura, Kazuaki Watanabe, Hirokazu Nakamine, Tetsuo Sudo, Kazuharu Shimizu, Yutaka Shimada. FGFRL1 deficiency reduces motility and tumor growth of cells derived from esophageal squamous cell carcinoma [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 2513.
Association Between Smoking Behavior and Cognitive Functioning in Patients With Psychosis, Siblings, and Healthy Control Subjects: Results From a Prospective 6-Year Follow-Up Study
Authors: Jentien M. Vermeulen, Frederike Schirmbeck, Matthijs Blankers, Mirjam van Tricht, Richard Bruggeman, Wim van den Brink, Lieuwe de Haan, Therese van Amelsvoort, Behrooz Z. Alizadeh, Agna A. Bartels-Velthuis, Nico J. van Beveren, Richard Bruggeman, Wiepke Cahn, Lieuwe de Haan, Philippe Delespaul, Carin J. Meijer, Inez Myin-Germeys, Rene S. Kahn, Frederike Schirmbeck, Claudia J.P. Simons, Neeltje E. van Haren, Jim van Os, Ruud van Winkel
Journal: American Journal of Psychiatry (2018)

The high prevalence of smoking and cognitive deficits in schizophrenia patients is well known, but findings regarding the association between the two are contradictory, and longitudinal studies are lacking. The authors sought to examine the multi-cross-sectional association between smoking behavior and performance in specific cognitive domains and the longitudinal association between change in smoking behavior and change in cognitive functioning in a large prospective study.The authors conducted a cohort study of patients with nonaffective psychosis (N=1,094), their siblings (N=1,047), and healthy control subjects (N=579). At baseline and at 3- and 6-year follow-ups, smoking behavior was assessed with the Composite International Diagnostic Interview and cognitive functioning with a test battery. Multivariate linear mixed-effects regression analyses were conducted to assess associations between smoking and cognitive domains while adjusting for variation in demographic factors, psychopathology, medication, and substance use. Bonferroni correction for multiple testing was applied.At baseline, 66.6% of the patients smoked, compared with 38.3% of the siblings and 25.2% of the control subjects. Significant multi-cross-sectional associations were found between smoking and lower processing speed in the patient and control groups compared with the nonsmoking patient group (estimate=-2.38, SE=0.84) and the nonsmoking control group (estimate=-3.13, SE=1.06). In siblings, smoking was significantly associated with lower performance in working memory and reasoning and problem solving compared with nonsmoking. Also, the number of cigarettes smoked per day was negatively associated with these domains. Patients, but not siblings and control subjects, who quit smoking showed a significant improvement in processing speed (estimate=4.90, SE=1.73).The study findings indicate that smoking is associated with poorer cognitive performance in patients, their siblings, and healthy control subjects compared with nonsmoking. Smoking cessation may improve processing speed in patients.
Human Papillomavirus Status and Esophageal Adenocarcinoma
Authors: Sukhbinder Dhesy-Thind
Journal: JAMA Network Open (2018)

Shanmugarajah Rajendra, MSc, MD, FRACP; Wei Xuan, PhD; Neil Merrett, FRACS; Preeti Sharma, BSc; Prateek Sharma, MD; Darren Pavey, FRACP; Tao Yang, PhD, FRCPA; Leonardo D. Santos, FRCPA; Omar Sharaiha, FRACP; Girish Pande, PhD, FRACS; Peter Cosman, PhD, FRACS; Xiaojuan Wu, MBBS, MSc; Bin Wang, MBBS, MMed, PhD
Abstract IA01: SWI/SNF (BAF) complex mutations in cancer: Mechanisms and vulnerabilities
Authors: Charles W. M. Roberts
Journal: Clinical Cancer Research (2018)

Abstract Data emerging over the last several years implicate SWI/SNF (BAF) chromatin remodeling complexes as a major tumor suppressor as frequent inactivating mutations in at least nine different SWI/SNF subunits, collectively identified in 20% of all cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers and neuroblastoma; of the BRG1 (SMARCA4) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; and of the BRD7 subunit in breast cancers. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when SNF5 (SMARCB1/INI1/BAF47) became the first SWI/SNF subunit linked to tumor suppression over fifteen years ago when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT, we have shown that these cancers are diploid and have remarkably simple genomes. We now study the complex using mouse models, cell lines, and primary human tumor samples. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented, including our recent efforts that identify a central role for SWI/SNF complexes in enhancer regulation. Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) complex mutations in cancer: Mechanisms and vulnerabilities [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA01.
Abstract 1369: Analysis of association between homologous recombination deficiency and tumor mutational burden in solid tumors
Authors: Hua Li, Liqun Wu, Tao Shou, Bo Jiang, Li Zhuang, Kunsong Li, Xiang Tan, Chao Guo, Weidong Guo, Yan Guan, Zheng Chen, Xiao Ding, Jun Guo, Zhenfang Du, Qiang Cui, Yue Che, Ming Yao
Journal: Cancer Research (2018)

Abstract Background: Multiple types of tumors exhibit DNA repair dysfunction via homologous recombination deficiency (HRD) due to genetic and epigenetic alterations of HR pathway genes, including BRCA1/2, PALB2, ATM, ATR, CHK1/2, BARD1, BIRP1, MRE11A, RAD51 family and FANC family. Some studies showed that tumors with homologous recombination deficiency might result in more mutations than tumors with non-deficient HR. Accumulating evidence suggests that tumor mutational burden (TMB) evaluated by comprehensive genomic profiling was associated with the responses of immune checkpoint inhibitors in solid tumors. Methods: FFPE tumor samples of 777 Chinese patients were collected for next-generation sequencing (NGS)-based targeted panel assay across multiple types of tumors, including lung, breast, soft tissue, gastrointestinal and gynecology cancers. There were 471 males (60.6%) and 306 females (39.4%) with a median age of 58 years old. Genomic alterations of HR-related genes and TMB values were assessed by next-generation sequencing assay, including single base substitution, short and long insertions/deletions, copy number variations, gene fusions and rearrangements. Results: In total, 25% of the 777 solid tumor patients had at least one genomic alteration of the HR genes (N=197, HRD group). The top mutant HR genes included BRCA1/2 (28.8%), FANC family (27.6%), ATM (27.4%), ATR (11.2%), RAD51 family (8%), BARD1 (7.6%), PALB2 (7.1%), BIRP1 (5.6%), CHK1/2 (5.0%) and MRE11A (4.6%). TMB was 10.4 muts/Mb in the HRD group compared to 6.4 muts/Mb in the rest of the patients (p&amp;lt;0.01). In addition, 43.2% of the patients in the HRD group had TMB-high values, which was higher than in the non-HRD group at 22.8% (P&amp;lt;0.01). High TMB values were more commonly detected in the colorectal cancer patients. Conclusions: Our study revealed that the solid tumors harboring HR gene mutation were more likely to have higher TMB values. BRCA1/2, FANC family and ATM were the most common mutant genes. CRC was the dominant cancer type showing high TMB values associated with HRD. Further analysis is warranted to investigate the association. Citation Format: Hua Li, Liqun Wu, Tao Shou, Bo Jiang, Li Zhuang, Kunsong Li, Xiang Tan, Chao Guo, Weidong Guo, Yan Guan, Zheng Chen, Xiao Ding, Jun Guo, Zhenfang Du, Qiang Cui, Yue Che, Ming Yao. Analysis of association between homologous recombination deficiency and tumor mutational burden in solid tumors [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 1369.
Abstract SY29-03: The impact of aerobic exercise on breast cancer progression
Authors: Erik R. Nelson
Journal: Cancer Research (2018)

Abstract In 1924, Otto Warburg first postulated that cancer was caused by altered metabolism, specifically the reliance of cancer cells on glycolysis. Since then, this altered metabolism has been recognized as a "hallmark of cancer," with numerous studies supporting this. It is now clear that pathologies resulting in perturbed homeostasis at the level of the organism, such as obesity, diabetes, and hypercholesterolemia, are also associated with tumor progression. Since aerobic exercise is known to alter systemic homeostasis, we reasoned that it may also impact tumor progression. In this regard, emerging epidemiologic evidence indicates an inverse correlation between exercise and the onset of many forms of cancer, including breast cancer. Intriguingly, several studies have found that self-reported physical activity is associated with decreased recurrence. We have now directly tested the impact of exercise on the progression of breast cancer, using several murine models of mammary cancer, finding that exercise significantly reduces tumor growth and metastasis. Subsequent work has been focused on delineating the molecular mechanisms by which exercise hinders the progression of breast cancer. We will discuss these results and present our current understanding of how exercise influences tumor pathophysiology. Collectively, our work suggests that aerobic exercise may offer an effective complementary adjunct therapy with current standard of care. Citation Format: Erik R. Nelson. The impact of aerobic exercise on breast cancer progression [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 SY29-03.