tbuckley/cabot-search huggingface dataset:
Abstract LB-222: Optimization and preclinical characterization of highly potent and stable anti-CD70 ADCs for the potential treatment of CD70 positive cancers
Authors: Lillian Skidmore, Kari Cox, Jessica Kirtley, Tiep Le, Juhi Firdos, Anthony Manibusan, Shiao-Yan Fang, Andy Beck, Shiva Bhowmik, Nick Knudsen, Jianing Wang, Ying Sun, Armando Ayala, Alyssa Powell, Alan Wahl, Feng Tian, Robin Humphreys
Journal: Cancer Research (2016)

Abstract Antibody drug conjugates (ADCs) require coordinated optimization of antibody, linker, and payload to generate potent, specific, and stable cancer therapeutics. CD70 is an attractive ADC tumor target due to its limited expression in normal tissues and over-expression in many solid tumors and hematologic malignancies. Utilizing Ambrx's site-specific EuCODE technology, we have generated and evaluated multiple ADCs with different combinations of linkers and payloads for treatment of CD70 positive cancers. In vitro activity identified specific CD70 ADCs with picomolar potency/activity against CD70 positive cancer cell lines. Conjugation of drug-linkers at different sites in the antibody and modification of linker design improved in vitro activity and in vivo stability of lead CD70 ADCs. Optimized anti-CD70 ADCs were evaluated for pharmacokinetic profile and demonstrated to be efficacious in reducing tumor burden and significantly prolonging survival in an in vivo orthotopic xenograft model of multiple myeloma. In summary, we have generated encouraging preclinical in vitro and in vivo data with stable, site-specific, DAR = 2 anti-CD70 ADCs for the potential treatment of CD70 positive cancers such as multiple myeloma. Citation Format: Lillian Skidmore, Kari Cox, Jessica Kirtley, Tiep Le, Juhi Firdos, Anthony Manibusan, Shiao-Yan Fang, Andy Beck, Shiva Bhowmik, Nick Knudsen, Jianing Wang, Ying Sun, Armando Ayala, Alyssa Powell, Alan Wahl, Feng Tian, Robin Humphreys. Optimization and preclinical characterization of highly potent and stable anti-CD70 ADCs for the potential treatment of CD70 positive cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-222.
Transplantation of Ex Vivo Expanded Cord Blood Progenitor Cells: First Experience in Two Children Affected by Hemoglobinopathies.
Authors: Lorenza Lazzari, Rosaria Giordano, Giovanna Giorgiani, Tiziana Montemurro, Alessandra Giorgetti, Daniela Lisini, Rita Maccario, Paolo Rebulla, Franco Locatelli
Journal: Blood (2005)
PRACTICE POINTER Diagnosing and investigating adverse reactions in metal on metal hip implants
Authors: C Fary, G E Rhys, A Taylor, D Beard, A Carr, S Glyn-Jones
Journal: BMJ (2011)

bmj.com O Feature: Europeans are left to their own devices (BMJ 2011;342:d2748) O Feature: Out of joint: the story of the ASR ( BMJ 2011;342:d2905) ONews: Medical devices regulation needs to be overhauled, says cardiologist (BMJ 2011;343:d6671) Use of metal bearings in hip replacements and resurfacing operations has led to dverse reactio s to metal debris in many patients. This article examines how to assess and manage any patient with a metal on metal total hip replacement who presents with potential joint failure
Experience With the Wearable Cardioverter-Defibrillator in Patients at High Risk for Sudden Cardiac Death
Authors: Nadine K. Wäßnig, Michael Günther, Silvio Quick, Christian Pfluecke, Fabian Rottstädt, Steven J. Szymkiewicz, Steven Ringquist, Ruth H. Strasser, Uwe Speiser
Journal: Circulation (2016)

Background: This study evaluated the wearable cardioverter-defibrillator (WCD) for use and effectiveness in preventing sudden death caused by ventricular tachyarrhythmia or fibrillation. Methods: From April 2010 through October 2013, 6043 German WCD patients (median age, 57 years; male, 78.5%) were recruited from 404 German centers. Deidentified German patient data were used for a retrospective, nonrandomized analysis. Results: Ninety-four patients (1.6%) were treated by the WCD in response to ventricular tachyarrhythmia/fibrillation. The incidence rate was 8.4 (95% confidence interval, 6.8–10.2) per 100 patient-years. Patients with implantable cardioverter-defibrillator explantation had an incidence rate of 19.3 (95% confidence interval, 12.2–29.0) per 100 patient-years. In contrast, an incidence rate of 8.2 (95% confidence interval, 6.4–10.3) was observed in the remaining cardiac diagnosis groups, including dilated cardiomyopathy, myocarditis, and ischemic and nonischemic cardiomyopathies. Among 120 shocked patients, 112 (93%) survived 24 hours after treatment, whereas asystole was observed in 2 patients (0.03%) with 1 resulting death. ConclusionS: This large cohort represents the first nationwide evaluation of WCD use in patients outside the US healthcare system and confirms the overall value of the WCD in German treatment pathways.
Abstract 4116: Anti-tumor and anti-metastasis efficacy of a novel Notch inhibitor (PF-03084014) in hepatocellular carcinoma
Authors: Wu Chuanxing, Wang Xiaoqi
Journal: Cancer Research (2016)

Abstract Hepatocellular Carcinoma (HCC) is well-known for its aggressive growth and highly metastatic potential. Efficacy of current therapy is limited by fast tumor growth and rapid metastasis. Cancer stem cells (CSCs) represent a distinct population that can be prospectively isolated from tumor tissues and have long-term clonal repopulation and self-renewal capacity. They are highly tumorigenic, metastatic, and resistance to conventional radiation and chemotherapy. Therefore, it is essential to identify effective therapy to target CSCs. In our prior study, Notch deregulation was correlated with poor outcome in HCC. In this study, we investigated anti-tumor and anti-metastatic efficacy of a novel Notch inhibitor (PF-03084014) in liver cancer spherical cells in vitro and sphere cell-derived orthotropic model in vivo. PF-03084014 significantly suppressed liver CSCs spheroid formation (derived from 97H HCC cells), with survival rate less than 20% by higher dose of PF-03084014. In accordance, CD90+, EpCAM+ and Oct4+ liver CSC populations significantly decreased, so as down-regulation the stem cell genes expression such as Sox2 and Nanog. These results suggest a suppressive effect of PF-03084014 on liver CSC self-renewal ability. Low dose PF-03084014 induced cancer spheroid cell differentiation leading to chemosensitization. Moreover, Notch inhibitor (PF-03084014) altered liver CSCs stemness properties and blocked spherogenesis of CSCs in vitro, leading to decrease tumorigenicity in vivo. In HCC spherical cell- and non-spherical cell-derived orthotropic model, PF-03084014 effectively inhibited tumor growth, with tumor size was 2570±690 mm3 in vehicle group vs. 800±500 mm3 in Notch inhibitor group (p &amp;lt; 0.001). More importantly, under PF-03084014 treatment, HCC tumor metastasis to lung was significantly reduced (87.5% metastasis rate in vehicle group vs. 18.75% in PF-03084014 group). To explore the potential mechanism, we found PF-03084014 was able to suppress phosphorylation of STAT3 and AKT, the kinases involving in self-renewal of stem cells. PF-03084014 also reversed endothelial mesenchymal transition (EMT) shown by down-regulation of Snail-1 and up-regulation of E-cadherin. Together, PF-03084014 shows a strong anti-cancer and anti-metastasis effect on HCC spherical cell derived in vitro and in vivo model, which provides a preclinical rational of the PF-03084014 to serve as a new novel drug in liver cancer therapy. Citation Format: Wu Chuanxing, Wang Xiaoqi. Anti-tumor and anti-metastasis efficacy of a novel Notch inhibitor (PF-03084014) in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4116.
Ibrutinib Therapy in Rituximab-Refractory Patients with Waldenström's Macroglobulinemia: Initial Results from an International, Multicenter, Open-Label Phase 3 Substudy (iNNOVATETM)
Authors: Meletios A. Dimopoulos, Judith Trotman, Alessandra Tedeschi, Jeffrey V. Matous, David Macdonald, Constantine Tam, Oliver Tournilhac, Shuo Ma, Albert Oriol, Leonard T. Heffner, Chaim Shustik, Ramón García-Sanz, Robert F. Cornell, Carlos Fernández de Larrea, Jorge J. Castillo, Miquel Granell, Marie-Christine Kyrtsonis, Veronique Leblond, Argiris Symeonidis, Priyanka Singh, Jianling Li, Thorsten Graef, Elizabeth Bilotti, Steven Treon, Christian Buske
Journal: Blood (2015)
Abstract 1301: Anti-invasive and antimetastatic effects of ω3-polyunsaturated fatty acids through inhibition of NF-kB/matrix metalloproteinases in ovarian cancer cells
Authors: Soyeon Jeong, Kaipeng Jing, Soyeon Shin, Soyeon Kim, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim
Journal: Cancer Research (2016)

Abstract Ovarian cancer is leading cause of gene cological cancer death in the United States. It is reported that about 14,000 patients will die to ovarian cancer in United States, 2015. ω3- and ω6-PUFAs are considered as essential fatty acids because they cannot be synthesized in mammals. The ω3-desaturase (fat-1) converts ω6-PUFAs to ω3-PUFAs. Cancer cells and transgenic mice stably expressing fat-1 geneare useful models to study the anti-cancer effects of ω3-PUFAs. Here, we show anti-invasive and anti-metastatic action of ω3-PUFA in ovarian cancer.DHA significantly inhibited cell invasion and wound healing activity of human ovarian PA-1 cells. DHA also abolishedthe induction of matrix-metalloproteinases (MMPs) and cyclooxygenase (COX2) as well as the transactivity of NF-κB in PA-1 cells. When ID8 cells were subcutaneously implanted into fat-1 transgenic mice, the tumor size and volume were smallin comparison to wild-type mice. The growth inhibition of tumor was also confirmed with the increase in the level of TUNEL-positive cells. Additionally, when ID8 cells were injected via tail vein of fat1 mice, the lung metastasis was remarkably inhibited in fat-1 transgenic mice. Furthermore, the proliferation of fat-1-stably expressing PA-1 (f-PA-1) cells was more attenuated than that of cells expressing control vectors. The invasion and NF-κB/MMPs promoter activities were also decreased in f-PA-1 cells. These results suggest that ω3-PUFAs inhibit invasion and metastasis of ovarian cancer cells through inhibition of NF-κB/MMPs. Therefore, ω3-PUFAs may contribute an effective and safe therapeutic approach for the chemoprevention and treatment of human ovarian cancer. [This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (2007-0054932)] Citation Format: Soyeon Jeong, Kaipeng Jing, Soyeon Shin, Soyeon Kim, Young-Joo Jeon, Jun-Young Heo, Gi-Ryang Kweon, Seung-Kiel Park, Jong-Il Park, Kyu Lim. Anti-invasive and antimetastatic effects of ω3-polyunsaturated fatty acids through inhibition of NF-kB/matrix metalloproteinases in ovarian cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1301.
Case 17-1975
Authors: Bernard R. Aserkoff, James J. Galdabini
Journal: New England Journal of Medicine (1975)

Presentation of Case First admission. A 61-year-old man was admitted to the hospital because of pain in the right flank.He was well until 25 years previously, when a clinical diagnosis of alcoholic fatty liver was made. For the next 22 years he abstained from alcohol, and the results of liver-function tests returned to normal. Three years before entry he resumed the consumption of alcohol, 175 to 235 ml daily. Five months before admission, after a viral infection, fatigue and anorexia developed, accompanied by an aching pain in the right flank that persisted.He had undergone appendectomy in childhood. . . .
Abstract 4866: Development and characterization of novel CD40 antibody agonists for cancer immunotherapy
Authors: Laura A. Vitale, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, James Storey, Lawrence Thomas, Joel Goldstein, Henry C. Marsh, Tibor Keler
Journal: Cancer Research (2016)

Abstract CD40 is a key molecule in the regulation of immune responses and its activity can be modulated using antibodies. In particular, agonist CD40 antibodies are highly effective in preclinical tumor models either through direct interaction with CD40-expressing lymphomas, or indirectly through the activation of an adaptive anti-tumor immune response. To date, limited clinical data have been reported with strong CD40 agonist antibodies; nonetheless it seems likely that targeting this pathway will require a balance between the benefits of immune stimulation to drive anti-tumor responses, and the damage that can result from non-specific immune cell activation. We set out to develop novel human anti-CD40 antibodies with different levels of agonist activity to identify a lead candidate for systemic application. Anti-CD40 monoclonal antibodies (mAbs) were generated by immunization of human Ig transgenic mice with recombinant and cell surface expressed human CD40. Hybridomas developed from these mice were screened using CD40 binding assays and activity on a reporter cell line engineered to express CD40 and NFêB-responsive luciferase. The variable regions of lead antibodies that displayed differential activity were cloned into vectors containing human IgG1 or IgG2 constant domains and expressed in CHO cells. These human CD40 mAbs were further characterized by analysis of binding affinity, CD40L blocking activity, B cell and dendritic cell activation, and anti-tumor activity in xenograft tumor models. We found a wide range of activities among the CD40 mAbs that is linked to epitope specificity as well as the isotype. In general, the IgG2 isotype mAbs had greater signaling activity than their IgG1 counterparts. The lead candidate mAbs are undergoing additional testing related to functional and toxicity parameters before a final candidate is nominated for clinical development. Citation Format: Laura A. Vitale, Thomas O’Neill, Jenifer Widger, Andrea Crocker, Li-Zhen He, Jeffrey Weidlick, Karuna Sundarapandiyan, James Storey, Lawrence Thomas, Joel Goldstein, Henry C. Marsh, Tibor Keler. Development and characterization of novel CD40 antibody agonists for cancer immunotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4866.
Inhibition of Bromodomain and Extraterminal Domain Family Proteins Ameliorates Experimental Renal Damage
Authors: Beatriz Suarez-Alvarez, José Luis Morgado-Pascual, Sandra Rayego-Mateos, Ramon M. Rodriguez, Raul Rodrigues-Diez, Pablo Cannata-Ortiz, Ana B. Sanz, Jesus Egido, Pierre-Louis Tharaux, Alberto Ortiz, Carlos Lopez-Larrea, Marta Ruiz-Ortega
Journal: Journal of the American Society of Nephrology (2016)

Renal inflammation has a key role in the onset and progression of immune- and nonimmune-mediated renal diseases. Therefore, the search for novel anti-inflammatory pharmacologic targets is of great interest in renal pathology. JQ1, a small molecule inhibitor of bromodomain and extraterminal (BET) proteins, was previously found to preserve renal function in experimental polycystic kidney disease. We report here that JQ1-induced BET inhibition modulated the in vitro expression of genes involved in several biologic processes, including inflammation and immune responses. Gene silencing of BRD4, an important BET protein, and chromatin immunoprecipitation assays showed that JQ1 alters the direct association of BRD4 with acetylated histone-packaged promoters and reduces the transcription of proinflammatory genes (IL-6, CCL-2, and CCL-5). In vivo, JQ1 abrogated experimental renal inflammation in murine models of unilateral ureteral obstruction, antimembrane basal GN, and infusion of Angiotensin II. Notably, JQ1 downregulated the expression of several genes controlled by the NF-κB pathway, a key inflammatory signaling pathway. The RelA NF-κB subunit is activated by acetylation of lysine 310. In damaged kidneys and cytokine-stimulated renal cells, JQ1 reduced the nuclear levels of RelA NF-κB. Additionally, JQ1 dampened the activation of the Th17 immune response in experimental renal damage. Our results show that inhibition of BET proteins reduces renal inflammation by several mechanisms: chromatin remodeling in promoter regions of specific genes, blockade of NF-κB pathway activation, and modulation of the Th17 immune response. These results suggest that inhibitors of BET proteins could have important therapeutic applications in inflammatory renal diseases.
Maleimide-functionalized closo-dodecaborate albumin conjugates (MID-AC): Unique ligation at cysteine and lysine residues enables efficient boron delivery to tumor for neutron capture therapy
Authors: Shunsuke Kikuchi, Daisuke Kanoh, Shinichi Sato, Yoshinori Sakurai, Minoru Suzuki, Hiroyuki Nakamura
Journal: Journal of Controlled Release (2016)
Abstract 1853: Single-cell multiplexed profiling of protein-level changes induced by EGFR inhibitor gefitinib
Authors: Ilona Holcomb, Gajalakshmi Dakshinamoorthy, Benjamin Liu, Marc Unger, Ramesh Ramakrishnan, Haibiao Gong
Journal: Cancer Research (2016)

Abstract Single-cell molecular analysis has become increasingly important in biomedical research, especially in the field of cancer research, where cell heterogeneity is a characteristic feature. We developed a multiplexed single-cell protein detection assay for the C1™ system that can isolate and process 96 individual cells in parallel. The assay uses oligonucleotide-conjugated antibodies, which produce a detectable DNA amplicon only when they bind to the target protein. The resulting DNA amplicons are quantified by qPCR on the Biomark™ HD system. Data are analyzed using the Singular™ Analysis Toolset. A total of 50 antibody binders were developed for this assay to target proteins related to apoptosis, cell cycle, cell proliferation, tumor suppressors, biomarkers, stem cells, growth factors and proteins associated with specific cancers, such as breast and prostate cancers. The assay can be performed in a 48-plex format, which yields over 4,600 datapoints in two days. Assay sensitivity and specificity were assessed using recombinant proteins and various cell lysates. To demonstrate the usefulness of this assay, we used it to profile the protein level changes in A431 cells treated with epidermal growth factor receptor (EGFR) inhibitor gefitinib. EGFR is a member of ErbB family of type I tyrosine kinases, whose overexpression and mutations are involved in a variety of cancers. While much effort has been made to investigate the consequences of EGFR activation or inhibition, hardly any information is available regarding how EGFR regulation changes protein expression in single cells. Using a multiplexed protein assay, we discovered some interesting co-expression patterns of proteins in single cells. We also demonstrated that TNFRSF10B was upregulated, while MET, GATA3, BRCA1, CCNB1, Ki-67 and CCNA2 were downregulated by gefitinib treatment. Notably, the reduction of the cell cycle-related proteins CCNB1 and CCNA2 and the cell proliferation marker Ki-67 was consistent with the inhibited cell growth by gefitinib. In addition, we measured mRNA expression to investigate the association between protein and mRNA levels in single cells. Single-cell analysis—determining protein changes and analyzing the correlation between different proteins at the single-cell level—yields valuable information that is not achievable using bulk-cell analysis. Citation Format: Ilona Holcomb, Gajalakshmi Dakshinamoorthy, Benjamin Liu, Marc Unger, Ramesh Ramakrishnan, Haibiao Gong. Single-cell multiplexed profiling of protein-level changes induced by EGFR inhibitor gefitinib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1853.
Abstract 2599: Association of periodontal disease and breast health in women undergoing screening mammography
Authors: Hannah Lui Park, Teofilia Acheampong, Kathleen Nguyen, Cindy Nguyen, Argyrios Ziogas, Richard Kelly, Andrea Alvarez, Kathryn M. Larsen, Deborah Goodman, Hoda Anton-Culver
Journal: Cancer Research (2016)

Abstract It is well established that chronic and persistent inflammation contributes to cancer development. Chronic inflammation is often associated with periodontal disease, or gum disease. Periodontal disease, which can be prevented or ameliorated by following proper oral hygiene, is known to be associated with various systemic disorders including coronary heart disease and some cancers, including head and neck cancer and pancreatic cancer. However, little is known about its potential association with breast cancer, with only one report in which periodontal disease was a positive predictor for breast cancer in a Swedish cohort. To examine if a potential link exists between periodontal disease and breast cancer in a separate cohort, mammography patients from the UC Irvine Athena Breast Health Network cohort were recruited to participate in a survey that included questions about their periodontal health. Diagnosis of invasive breast cancer, DCIS, and benign breast diseases was determined through data extraction from electronic medical records. There was no association between periodontal disease and DCIS or invasive breast cancer. However, there was a significant difference in the frequency of breast cysts among women with periodontal disease compared to women without periodontal disease (p&amp;lt;0.01). Women with periodontal disease were at least 4-fold more likely to have breast cysts, even after adjusting for potential confounders including age, race/ethnicity, and smoking history (p&amp;lt;0.05). To our knowledge, this is the first report on an association between periodontal disease and breast cysts. Our data suggest that further studies on potential links between periodontal disease and breast health are warranted. Citation Format: Hannah Lui Park, Teofilia Acheampong, Kathleen Nguyen, Cindy Nguyen, Argyrios Ziogas, Richard Kelly, Andrea Alvarez, Kathryn M. Larsen, Deborah Goodman, Hoda Anton-Culver. Association of periodontal disease and breast health in women undergoing screening mammography. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2599.
Reply to Valerian Ciprian Lucan, Salvatore Butticè, Rosa Pappalardo, Carlo Magno's Letter to the Editor re: Mark W. Ball, Nathaniel Readal, Phillip M. Pierorazio, Mohamad E. Allaf. Splitting One Kidney into Two: Robotic Partial Kidney Transplant in a Porcine Model. Eur Urol 2016;69:968–9
Authors: Mark W. Ball, Mohamad E. Allaf
Journal: European Urology (2016)