tbuckley/cabot-search huggingface dataset:
Abstract 625: Association between obesity and prostate cancer disease risk and mortality among African American men
Authors: Margaret Saira Pichardo, Tsion Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs
Journal: Cancer Research (2019)

Abstract Prostate cancer (PCa) is a major cause of cancer death in U.S. men. Age-adjusted mortality rates for men of African ancestry (40.8 per 100,000) are more than twice that of men of European ancestry (18.2 per 100,000). Men of African ancestry are more likely to have advanced stage cancer at diagnosis and lower prostate cancer survival rates relative to men of European ancestry of similar age and stage at diagnosis. Risk factors that may explain this survival disparity remain poorly understood. Obesity, a major risk factor for cancer development, aggressiveness and progression, disproportionately affects US men of African ancestry. Age-adjusted prevalence of obesity are higher among men of African ancestry (38.0%) compared to men of European ancestry (34.7%). While it has been previously suggested that obesity may worsen disease-related outcomes among prostate cancer patients, the relationship of obesity and prostate cancer mortality remains unclear, with studies showing mixed or null results in men of African ancestry. Less is known about the underlying biological mechanisms that may contribute to the racial differences observed in the link between obesity and prostate cancer. We previously reported an obesity paradox among African-American men in the NCI-Maryland Prostate Cancer-Case Control Study, with overweight and obese men having a lower risk of being diagnosed with the disease. Here, using Cox proportional hazard regression modeling, we estimated the risk of a PCa mortality for the 976 cases in the study. Our primary analysis suggests an obesity paradox, where obesity may protect against disease mortality among the African-American men. In subsequent analyses, we will examine the role of immune and inflammation markers in mediating or moderating the observed relationship of obesity with PCa in these men. Citation Format: Margaret Saira Pichardo, Tsion Minas, Wei Tang, Tiffany H. Dorsey, Stefan Ambs. Association between obesity and prostate cancer disease risk and mortality among African American men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 625.
Strategies to Improve Test Ordering in Primary Care
Authors: Arthur M Bohnen
Journal: JAMA (2003)

To the Editor: Dr Verstappen and colleagues found that a practice-based, multifaceted strategy using guidelines, feedback, and social interaction resulted in modest improvements in the quality of test ordering by Dutch primary care physicians. In the intervention, physicians received 3 personal feedback reports on 3 different clinical problems, discussed these in small group meetings, related them to evidence-based guidelines, and made plans for change. Such multifaceted interventions are time consuming, and therefore difficult to implement for the large spectrum of clinical problems that primary care physicians face. Furthermore, many studies have found that the effects of information and feedback are limited, and the effects may disappear soon after the end of intervention. In their literature review, for instance, Wensing et al concluded that some, but not all, multifaceted interventions are effective, but that information linked to performance generally was not effective. Largescale interventions, related to sustained change in all possible test-ordering situations, are likely to be ineffective. Thus, I wonder if this is the way to proceed in improving test-ordering behavior. Verstappen et al also concluded that multifaceted interventions are superior to single interventions. However, they made no comparison to any single intervention. Some of these interventions may in fact be quite effective. In a study of Dutch primary care physicians, my colleagues and I found that computer-guided decision support during the actual process of ordering the tests led to much larger effects than those reported by Verstappen et al. Such computer-based interventions are not time consuming, affect behavior at the moment the test is ordered, can be extended to all tests ordered, and can be sustained indefinitely. I suggest that it is time to move forward to more powerful single and simple interventions rather than to more timeconsuming and complex combinations of interventions with limited effectiveness.
Abstract 4350: <i>MAPK1</i> <i>E322K</i> somatic mutation promotes cell proliferation via positive feedback regulation of EGFR/RAF signaling
Authors: Jianqing Zhang, Dewey J. Brooke, Jessica P. Blair, Jaques Riby, Akinyemi I. Ojesina
Journal: Cancer Research (2019)

Abstract The RAS-MAPK signaling cascade serves as the central node in the transduction of signals starting from the binding of the epidermal growth factor (EGF) ligand to the membrane receptors (EGFR) through to the nucleus. Recent studies suggested that different defined thresholds of RAS-MAPK activity are required for maintaining homeostasis as opposed to facilitating malignant transformation, and that Ras-oncogenic toxicity is quantitatively dictated by MAPK function. We and others have demonstrated that somatic MAPK1(E322K) mutations in MAPK1 occur in 8% of cervical squamous cell carcinoma (CSCC) and 3% of head and neck squamous cell carcinoma (HNSCC), suggesting that mutant MAPK1 may play an important part in tumorigenesis. To investigate the molecular mechanism involved in the effects of the mutated MAPK1, we transduced MAPK1 wild type and MAPK1(E322K) mutant as lentiviral constructs into the untransformed human embryonic kidney cell line HA1E. We found that cells expressing MAPK1(E322K) exhibited higher rates of proliferation and cellular mobility compared to the cells transduced with wild type MAPK1. However, the cells expressing wild type MAPK1 presented poor cell proliferation compared to the cells transduced with the empty lentiviral vector. Western blot analyses showed approximately two-fold increase phosphorylation of ERK (T202/Y204) following EGF treatment in the cells harboring the mutation compared to the cells expressing the wild type MAPK1. A similar pattern was observed with phospho-EGFR (T669, Y1148, Y1068, Y1148) phospho-cRaf (S259, S338, S289/296/301), phosphor-RSK1, phospho-AKT (S473, T389), phosphor-GSK3β (S9/21) and phospho-STAT5 (Y694), suggesting that MAPK1(E322K) mutation might reinforce the positive/negative feedback loop on EGFR and cRaf. Our data contributes to the understanding of the roles of MAPK1 in the RAS/RAF-MEK-MAPK1 signaling pathway and might help identifying possible therapeutic targets for HNSCC and CSCC patients with tumors harboring somatic MAPK1(E322K) mutations. Citation Format: Jianqing Zhang, Dewey J. Brooke, Jessica P. Blair, Jaques Riby, Akinyemi I. Ojesina. MAPK1E322K somatic mutation promotes cell proliferation via positive feedback regulation of EGFR/RAF signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4350.
Abstract 367: The connection of vitamin D3 induced cytotoxicity with the vitamin D3 receptor
Authors: Takaya Hoshi, Yuta Abe, Ikumi Sugiyama, Yasuyuki Sadzuka
Journal: Cancer Research (2019)

Abstract [Purpose] This study aims to evaluate the possible antitumor effect of vitamin D. Vitamin D is a group of lipophilic compounds comprising of vitamin D2 and vitamin D3. Vitamin D3 has been shown to play an important role in humans. It has been previously reported that the onset risk of malignant melanoma and leukemia can be decreased by maintaining high vitamin D3 levels in the body. In addition, the cytotoxic effect of vitamin D on breast cancer cells has also been shown. In this study, the relationship between the cytotoxicity of vitamin D3 and vitamin D3 receptor (VDR) expression on melanoma and leukemia cells was examined. [Method] B16F10 melanoma (B16F10) and P388 leukemia (P388) cells were used in this study. Western blot analysis was performed to determine VDR expression in each cell type. To evaluate cytotoxicity, B16F10 or P388 cells were seeded at 1×105 cells/mL, and calcitriol as vitamin D3 (range 9 ng/mL-90 μg/mL) was added at once. After two days, cytotoxicity was evaluated by colorimetric analysis using Cell Counting Kit-8. Additionally, the cytotoxicity of P388 cells was determined following the combined treatment of vitamin D3 and retinoic acid. [Results and Discussion] Western blot analysis revealed that both B16F10 and P388 cell types, expressed VDR with a higher expression in P388 cells. In P388 cells, there was a significant reduction in cell viability following vitamin D3 treatment, which decreased to 10% at 90 μg/mL. In contrast, the viability of B16F10 cells following vitamin D3 treatment only slightly decreased. Interestingly, these results suggest that the cytotoxicity of vitamin D3 correlates with VDR expression. VDR reportedly forms a heterodimer with the retinoid X receptor. However, the presence of retinoic acid did not alter vitamin D3 cytotoxicity. Therefore, it was considered that cytotoxicity induced by vitamin D3 was not connected with the formation of the VDR-retinoid X receptor heterodimer. In conclusion, there was a higher expression of VDR in P388 cells compared with B16F10 cells. This higher expression correlated with a higher level of vitamin D3 cytotoxicity, suggests an antitumor effect of vitamin D3. This study proposes the possibility of using vitamin D3 as a novel treatment for leukemia and other cancers. Citation Format: Takaya Hoshi, Yuta Abe, Ikumi Sugiyama, Yasuyuki Sadzuka. The connection of vitamin D3 induced cytotoxicity with the vitamin D3 receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 367.
3-weekly daratumumab-IMiD-dexamethasone is highly efficacious and cost-effective in relapsed/refractory multiple myeloma.
Authors: James Chim, Vincent Wong, Elaine AU, Yok-Lam Kwong
Journal: Journal of Clinical Oncology (2019)

e19521 Background: Daratumumab (dara) with immunomodulatory agents (IMiD) and dexamethasone (dex) is highly effective in relapsed multiple myeloma (MM). The recommended schedule of dara is weekly for 8 doses, followed by 2-weekly for 8 doses, and then every 4-weekly thereafter. Given the high cost and the long half-life as an antibody, a 3-weekly dosing of dara was used together with IMiD/dexamethasone. Methods: Dara at 16mg/kg was used every 3-weekly with lenalidomide or pomalidomide. Patient achieving best response received single agent IMiD maintenance until disease progression. Results: Fourteen relapsed MM patients were enrolled. One had received weekly dara from a private oncologist, hence was excluded from analysis. Thirteen patients at a median age of 63 years (range: 50-84 years) were studied. The median number of previous therapies was 2 (range: 1-5), with nine patients (69.2%) having undergone autologous stem cell transplantation. Three patients (23.1%) were refractory to bortezomib, seven patients (53.8%) to lenalidomide, and eight patients (61.5%) to last treatment. At relapse, two (15.4%) had high LDH, eight (61.5%) impaired renal function, and three (23.1%) extramedullary disease. Treatment was dara-lenalidomide-dex in six (46.2%), and dara-pomalidomide-dex in seven (53.8%). Responses after four cycles included CR in 5 patients (38.5%), VGPR in five patients (38.5%), and PR in three patients (23.1%). After a median of four dara infusions (range: 3-10), the best responses included CR in seven patients (53.8%), nCR in two patients (15.4%), VGPR in two patients (15.4%), and PR in two patients (15.4%). Median time to VGPR was one month. At 10 months, the OS was 90%, and PFS 54.7%. Three patients progressed, one of whom died of ruptured hepatic plasmacytoma. The most frequent toxicity was haematological especially neutropenia (all grades: 92.3%, Grade ¾: 76.9%), infusion reaction (38.5%, all grade ½), neuropathy (38.5%, all grade ½), gastrointestinal (all grades: 38.5%, grade ¾: 7.7%), and sepsis (all grades: 30.8%; grade ¾: 23.1%). Neutropenia was effectively prevented with prophylactic G-CSF. Conclusions: In conclusion , a 3-weekly dara-IMiD-dex regimen is highly efficacious, inducing deep and rapid responses, hence cost-effective for less affluent countries. In view of prevalent grade 3/4 neutropenia despite less frequent dara, 3-weekly dara might be more suitable for Asian patients.
Abstract CT064: Intranasal brain delivery using NEO100 for recurrent glioblastoma
Authors: Thomas C. Chen, Naveed Wagle, David Peereboom, Lynne Taylor
Journal: Cancer Research (2019)

Abstract NO CHANGES TO ORIGINAL ABSTRACT NEO100 is a GMP quality, purified perillyl alcohol (POH) which has been undergoing clinical trials under IND approval (144,595) entitled "Open label, Phase I/IIa dose escalation study of safety and efficacy of NEO100 in recurrent grade IV glioma." It was granted orphan drug and fast track status by the FDA. Inclusion criteria include temozolomide failure, bevacizumab naïve, tumor less than 3x3 cm, and Karnofsky score greater than or equal to 60. Patients were enrolled from University of Southern California (USC), Cleveland Clinic, and University of Washington. Total number of patients to be enrolled for Phase I is 12 with four dose escalating cohorts of 3 patients per cohort. The remaining 31 patients would be enrolled after maximal tolerated dosage (MTD) for Phase IIa. The delivery is intranasal via a nasal nebulizer using the concept of nasal brain delivery via the olfactory and trigeminal nerves for delivery to the brain and tumor. To date, 8 patients have been enrolled. Cohort 1 received 96 mg/dose qid, Cohort 2 received 144 mg/dose qid, cohort 3 received 192 mg/dose qid, and cohort 4 will receive 288mg/dose qid. No toxicities were detected. Inhalation was very well tolerated. The duration of the trial is for 6 months. To date, 3 patients have not shown evidence of progression for greater than 6 months (one patient 1 year (cohort 2), one patient 7 months (cohort 3), one patient 6 months) (cohort 3). This is the first FDA approved trial for intranasal delivery to malignant gliomas. Although preliminary, we are encouraged by the progression free survival of 3/8 patients in this dose escalation trial. Citation Format: Thomas C. Chen, Naveed Wagle, David Peereboom, Lynne Taylor. Intranasal brain delivery using NEO100 for recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT064.
Baseline computed-tomography (CT)-evaluated sarcopenia predicts toxicity from first-line chemotherapy in metastatic gastric cancer (mGC) patients
Authors: S. Catanese, G. Aringhieri, C. Cappelli, C. Vivaldi, S. Vitali, I. Pecora, F. Salani, G. Pasquini, F. Balducci, R. Piercarlo, M. Lencioni, E. Vasile, V. Massa, A. Falcone, D. Caramella, L. Fornaro
Journal: Annals of Oncology (2019)
Abstract 18622: Prevention of Complex and Hybrid N Glycosylation Causes Dilated Cardiomyopathy
Authors: Andrew R Ednie, Wei Deng, Kay Pong Yip, Eric S Bennett
Journal: Circulation (2017)

Protein glycosylation is an essential post-translational modification that affects a myriad of physiological processes. Humans with genetic defects in glycosylation often present with multi-system ...
Abstract 4102: DNA methylation and repressive histones in the promoters of immune checkpoints in tumor tissues and peripheral blood of breast and colorectal cancer patients
Authors: Eyad Elkord, Varun Sasidharan Nair, Salman M. Toor
Journal: Cancer Research (2019)

Abstract Higher expression of immune checkpoints in tumor microenvironment plays significant roles in inhibiting anti-tumor immunity, which is associated with poor prognosis and progression of cancer patients. Major epigenetic modifications in both DNA and histone could be involved in upregulation of immune checkpoints (ICs) in cancer. We investigated transcriptomic expression of different ICs and some ligands including PD-L1 and galectin-9 in the tumor microenvironment (TME) and in circulation of primary breast cancer (PBC) and colorectal cancer (CRC) patients. We found that transcriptomic expressions of PD-1, CTLA-4, TIM-3 and LAG-3 in PBC and PD-1, CTLA-4, TIM-3, TIGIT, PD-L1 and galectin-9 in CRC were significantly upregulated in tumor tissues (TT), compared with normal tissues (NT). Additionally, expressions of TIM-3, TIGIT, and PD-L1 were significantly upregulated, while LAG-3 was downregulated in peripheral blood of both PBC and CRC patients. We then investigated the epigenetic modifications beyond this upregulation of immune checkpoint genes. Interestingly, we found that CpG islands in the promoters of PD-1, CTLA-4 and TIM-3 in PBC, and CTLA-4 and TIGIT in CRC patients were significantly hypomethylated in tumor compared with normal tissues. Notably, CpGs in PD-L1 promoter were completely hypomethylated in PBC and CRC in both TT and NT. In addition, PD-L1 was hypomethylated in in peripheral blood of both PBC and CRC patients, while TIGIT was hypomethylated only in circulation of CRC patients, compared with healthy donors. Next, we checked the abundance of repressive histones (H3K9me3 and H3K27me3) in the promoter regions of ICs/ligands. We found that in PBC TT, distribution of both H3K9me3 and H3K27me3 was lower in the promoters of PD-1, CTLA-4 and LAG-3, while distribution of only H3K27me3 was lower in TIM-3 promoter, compared with NT. Furthermore, in CRC TT, the distribution of H3K9me3 was lower in PD-1 and TIGIT promoters, and H3K27me3 was lower in CTLA-4 promoter, while both H3K9me3 and H3K27me3 were lower in TIM-3 promoter, compared with NT. Our data demonstrate that both DNA methylation and repressive histones are involved in upregulation of ICs and their ligands in the tumor microenvironment and peripheral blood of breast and colorectal cancer patients. These epigenetic modifications could be useful as diagnostic/prognostic biomarkers and/or therapeutic targets in breast and colorectal cancers. Citation Format: Eyad Elkord, Varun Sasidharan Nair, Salman M. Toor. DNA methylation and repressive histones in the promoters of immune checkpoints in tumor tissues and peripheral blood of breast and colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4102.
Abstract 30: The development of a 3D cell-culture model of drug-induced oral mucositis
Authors: Maria P. Lambros, QinQin Fei, Jonathan Moreno
Journal: Cancer Research (2019)

Abstract Purpose: Mucositis is a debilitating disease affecting cancer patients. Mucositis is an adverse effect of radiation or chemotherapy. In the past, our lab has developed a model of radiation-caused mucositis using a validated human tissue substitute of oral mucosa and studied the post radiation cellular and molecular stresses and their prevention. In this project, we wished to develop an in-vitro model of chemical-, or drug-induced oral mucositis. For this purpose, we used a three dimensional (3-D) cell culture model of oral mucosa and as the drug to induce mucositis we used everolimus. Everolimus belongs to rapalogs which represent important therapies against cancer but one of its adverse-effects is mucositis. Mucositis caused by everolimus develops early in therapy and progresses quickly to grade 3 making patients to postpone life-saving therapies. Thus, it is very important to understand and prevent the development of everolimus-caused mucositis. Methods: The 3-D cell cultures of primary human oral keratinocytes grown on top of primary human oral fibroblasts were purchased from MatTek Corporation. These 3-D cell cultures (tissues) are similar to human oral mucosal tissue and have been validated as its substitutes. Different 3-D tissues were treated for 24, 40 and 60 hours with 8, 16, 32, and 64 ng/ml of everolimus. Tissues which received no treatment were used as controls. We then evaluated the tissue histology using H and E staining, and gene expression using RNA-sequencing. Results: Tissues which were treated with everolimus show signs of distress based on the concentration of everolimus and the duration of the treatment. Low and medium concentration of everolimus (8ng/ml) and (16 or 32 ng/ml), respectively, show no, or minimal tissue distress after 24 hours of treatment duration. Tissues which received a high concentration of everolimus (64 ng/ml) even at a short duration of treatment, show signs of distress, as evidenced by atypical proliferation at the keratinous epithelium, vacuoles, or shredded keratin layers, as well as, higher apoptosis, and expression of pro-inflammatory cytokine genes. In general, the higher the concentration of everolimus and the longer the duration of the treatment, the more the signs of the stress in tissues. Conclusion: The cell and molecular stress that the 3-D tissue cultures of human oral mucosa experience depends on the drug concentration and the duration of treatment. Acknowledgment We thank Novartis for their support. Citation Format: Maria P. Lambros, QinQin Fei, Jonathan Moreno. The development of a 3D cell-culture model of drug-induced oral mucositis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 30.
Abstract 15433: Lpa Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins Abstract
Authors: Wei-qi Wei, Xiaohui Li, Qiping Feng, Jonathan Mosley, Iftikhar Kullo, Christian Shaffer, Sarah Bland, Peggy Peissig, Nancy Cox, Charles M Stein, Jerome I Rotter, Todd Edwards, Michiaki Kubo, Shiro Maeda, Momoko Horikoshi, David Crosslin, Yukihide Momozawa, Russell Wilke, Eric A Larson, David Cronkite, Elizabeth Karlson, Gail Jarvik, George Hripcsak, Ning Shang, Jennifer Pacheco, Laura Rasmussen-Torvik, Ming Ta Michael Lee, Marylyn Ritchie, Marc Williams, Eric B Larson, Dan M Roden, Ronald Krauss, Joshua Denny
Journal: Circulation (2017)

Introduction: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with HMG-CoA reductase inhibitors (statins) decreases circulating levels of low-density lipoprotein...
The risk of hepatitis B virus (HBV) reactivation in patients with gastrointestinal stromal tumours (GIST) under imatinib mesylate treatment
Authors: K. Soufleris, G. Lazaraki, P. Pavlioglou, E. Stergiou, K. Paraskevaidou, D. Tzilves
Journal: Annals of Oncology (2019)