tbuckley/cabot-search huggingface dataset:
Abstract 543: Dinutuximab binds specifically to disialoganglioside-2
Authors: Shahriar Yaghoubi, Travis Harrison, Gerald Messerschmidt, Suzana Corritori
Journal: Cancer Research (2019)

Abstract Dinutuximab is a human/murine chimeric monoclonal antibody, approved for maintenance treatment of pediatric patients with high-risk neuroblastoma (NB) in the US, and currently under investigation in a phase III trial (NCT03098030) for 2nd line treatment of relapsed/refractory small cell lung cancer (SCLC). Despite four decades of development, the specificity of dinutuximab binding to its intended target, disialoganglioside-2 (GD2), has not been fully elucidated. Although GD2 is a relatively cancer cell specific antigen, other cell surface gangliosides are ubiquitously expressed on the outer membrane of healthy human cells. Therefore, the main goal of this study was to confirm binding specificity of dinutuximab to GD2. We also compared relative affinity of dinutuximab to GD2 with 14G2a, which is the original murine anti-GD2 antibody from which dinutuximab was derived. To measure dinutuximab and 14G2a binding kinetics to various relevant gangliosides (GD1a, GD1b, GM3, GD3, GM4, GM2 and GD2), an in vitro assay was developed and optimized using the Biacore surface plasmon resonance platform. The results showed that GD2 was the only ganglioside that binds to dinutuximab (relative KD=0.000337M). The relative affinity of GD2 to dinutuximab and 14G2a antibody were comparable and within 2-fold of each other (Table). In conclusion, dinutuximab specifically binds to GD2. The absence of binding to GM3, GD3, GD1a, or GD1b suggests that an exposed N-acetylgalactosamine (GalNAc) moiety is necessary for antibody recognition. The absence of binding to GM2 or GT2 (sugar moiety), which differ from GD2 by the number of sialic residues attached to the basal galactose moiety, suggests that the number of sialic acid residues is also critical for antibody recognition. GD2 binding kinetics of Dinutuximab and 14G2aLigandKD (M)ka (1/Ms)kd (1/s)Chi2 (RU2)Dinutuximab3.37E-042.48E+028.34E-020.78614G2a2.00E-047.11E+021.42E-010.0273 Citation Format: Shahriar Yaghoubi, Travis Harrison, Gerald Messerschmidt, Suzana Corritori. Dinutuximab binds specifically to disialoganglioside-2 [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 543.
Antimicrobial peptides, disease severity and exacerbations in bronchiectasis
Authors: Oriol Sibila, Lídia Perea, Elisabet Cantó, Amelia Shoemark, Diane Cassidy, Alexandria Holly Smith, Guillermo Suarez-Cuartin, Ana Rodrigo-Troyano, Holly R Keir, Martina Oriano, Samantha Ong, Silvia Vidal, Francesco Blasi, Stefano Aliberti, James D Chalmers
Journal: Thorax (2019)

Recently a frequent exacerbator phenotype has been described in bronchiectasis, but the underlying biological mechanisms are unknown. Antimicrobial peptides (AMPs) are important in host defence against microbes but can be proinflammatory in chronic lung disease.To determine pulmonary and systemic levels of AMP and their relationship with disease severity and future risk of exacerbations in bronchiectasis.A total of 135 adults with bronchiectasis were prospectively enrolled at three European centres. Levels of cathelicidin LL-37, lactoferrin, lysozyme and secretory leucocyte protease inhibitor (SLPI) in serum and sputum were determined at baseline by ELISA. Patients were followed up for 12 months. We examined the ability of sputum AMP to predict future exacerbation risk.AMP levels were higher in sputum than in serum, suggesting local AMP release. Patients with more severe disease at baseline had dysregulation of airway AMP. Higher LL-37 and lower SLPI levels were associated with Bronchiectasis Severity Index, lower FEV1 (forced expiratory volume in 1 s) and Pseudomonas aeruginosa infection. Low SLPI levels were also associated with the exacerbation frequency at baseline. During follow-up, higher LL-37 and lower SLPI levels were associated with a shorter time to the next exacerbation, whereas LL-37 alone predicted exacerbation frequency over the next 12 months.Patients with bronchiectasis showed dysregulated sputum AMP levels, characterised by elevated LL-37 and reduced SLPI levels in the frequent exacerbator phenotype. Elevated LL-37 and reduced SLPI levels are associated with Pseudomonas aeruginosa infection and can predict future risk of exacerbations in bronchiectasis.
Abstract 1457: Sustained persistence of IL-2 signaling enhances the antitumor effect of peptide vaccines
Authors: Takumi Kumai, Hussein Sultan, Yasuaki Harabuchi, Esteban Celis
Journal: Cancer Research (2019)

Abstract Peptide vaccines can be a successful and cost-effective way of generating T-cell responses against defined tumor antigens, especially when combined with immune adjuvants such as poly-IC. However, strong immune adjuvants can induce a collateral increase in numbers of irrelevant, nonspecific T cells, which limits the effectiveness of the peptide vaccines. Here, we report that providing prolonged IL2 signaling in the form of either IL2/ anti-IL2 complexes or pegylated IL2 overcomes the competitive suppressive effect of irrelevant T cells, allowing the preferential expansion of antigen-specific T cells, and increasing the therapeutic effectiveness of the vaccines against established tumors. This vaccination strategy using peptides and sustained IL2 could be taken into the clinic for the treatment of cancer. Citation Format: Takumi Kumai, Hussein Sultan, Yasuaki Harabuchi, Esteban Celis. Sustained persistence of IL-2 signaling enhances the antitumor effect of peptide vaccines [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 1457.
Abstract 351: A targeted nanocomplex of the IKBKE siRNA inhibits invasiveness and growth of triple negative breast cancer cells
Authors: Zhen Zhao, Yuanke Li, Kun Cheng
Journal: Cancer Research (2019)

Abstract IκB kinase ϵ (IKBKE, or known as IKKϵ), an important mediator in the activation of NF-κB pathway, was recently identified as an oncogene in breast cancer and overexpressed in approximately 30% of breast carcinomas. It is also highly expressed in TNBC cells, which is correlated with angiogenesis process, high metastasis in NF-κB pathway of TNBC. We found that silencing IKBKE in TNBC cells using siRNA significantly inhibits the proliferation, migration and invasion of TNBC cells by specific silenced 71% of IKBKE in vitro. In vivo study indicated that IKBKE siRNA can inhibit TNBC tumor growth after peritumoral injection at a IKBKE siRNA dose of 0.3 mg/kg. We next developed a CD44-targeting, cholesterol-peptide based nanocomplex to co-deliver the IKBKE siRNA and cabazitaxel to TNBC cells. The nanocomplex showed the synergistic effect of the IKBKE siRNA and cabazitaxel on inhibiting the growth of TNBC tumors in vivo. Modification of the nanocomplex with CD44 further improved tumor uptake and anti-tumor efficacy of the nanocomplex. Our results suggest that IKBKE siRNA is a promising anti-tumor agent for TNBC therapy, and co-delivery of IKBKE siRNA and cabazitaxel using a CD44-targeting nanocomplex is a potential strategy for TNBC treatment. Moreover, this multifunctional delivery system provides a platform for other combination therapy including an siRNA and a chemotherapy drug. Citation Format: Zhen Zhao, Yuanke Li, Kun Cheng. A targeted nanocomplex of the IKBKE siRNA inhibits invasiveness and growth of triple negative breast cancer cells [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 351.
Retrospective analysis of renal toxicity in breast cancer patients following zoledronic acid or pamidronate treatment
Authors: L. Chen, T. L. Nikolas, G. Markowitz, J. Green, N. Wintfeld, M. Neary, M. Duh
Journal: Journal of Clinical Oncology (2006)

564 Background: In breast cancer (BC) patients (pts), reports suggest that some i.v. bisphosphonates (BPs) are associated with an incremental renal toxicity risk. Few studies have investigated this risk in clinical practice. We retrospectively analyzed rates of renal toxicity in BC pts treated with zoledronic acid (ZO), pamidronate (PA), or no BP treatment (NT). Methods: Pts were identified through medical and pharmacy claims and laboratory data from &gt;35 managed care plans between 01/2000 and 12/2004. Inclusion criteria: female pts with ≥2 claims for BC, no gap in health plan coverage, and serum creatinine measurements available from before and after first ZO or PA infusion. BC pts receiving NT provided a separate reference group. Observations were analyzed from first infusion to health plan disenrollment (BP monotherapy) or before BP switch. Renal impairment was defined as a ≥25% decrease in glomerular filtration rate (GFR,abbreviated MDRD formula) from baseline. Andersen-Gill model, adjusted for demographics and baseline comorbidities, was used to analyzer multiple events in a given pt, as physician practice patterns indicate that administration of both BPs continues even after the development of a first nephrotoxic event. Results: 312 ZO pts, 166 PA pts, and 2,862 NT pts were included. ZA and PA groups had comparable baseline characteristics, renal-related comorbidities, and baseline GFR. Both BP groups were more frequently exposed to chemotherapies and nephrotoxic drugs than the NT group (p&lt;0.0001). ZO and PA groups had similar renal impairment rates that were significantly higher than the NT group and increased with treatment duration (ZO 15.8%, PA 15.6%, NT 7.3% in pts treated for &lt;6 months, increasing to ZO 42.0%, PA 40.0%, NT 16.9% in pts treated for ≥18 months). Mean renal impairment events per person-year were significantly higher for ZO than PA (0.93 vs 0.81, p=0.019). Multiple-event analysis showed a significantly higher renal impairment risk for ZO than PA (hazards ratio=1.4, p&lt;0.0001). Conclusions: In this study on BC pts, renal impairment was more commonly seen in ZO and PA pts than in NT pts. ZO and PA pts have similar renal impairment risk, but ZO pts are more likely to experience multiple impairment events after repeated administrations. [Table: see text]
Generation of antibodies that target and kill MUC1 expressing cancer cells via a novel cell-tethered MUC1 α/β junction epitope
Authors: M. Karmely, D. B. Rubinstein, D. H. Wreschner
Journal: Journal of Clinical Oncology (2007)

3034 Background: MUC1 protein has generated considerable interest as a target for tumor killing. However, a serious shortcoming of anti-MUC1 antibodies generated to date is that they recognize epitopes within the strongly immunogenic tandem-repeat-array of the MUC1 a- chain which is released from the cell into the circulation. Soluble shed MUC1 a-chain sequesters anti-tandem-repeat-array antibodies, severely limiting their ability to reach MUC1-expressing malignant cells. Rather than target freely circulating MUC1 a-chain, we identified the junction of the MUC1 a-subunit to cell-membrane-bound MUC1 β-subunit as a preferable cell-tethered MUC1 epitope; since the site is not shed, antibodies recognizing it are more effective in targeting MUC1 expressing cells. Methods: To circumvent the immunogenicity of the a-chain tandem repeat array we formulated a novel antibody generating protocol utilizing immunization with both MUC1 cDNA and with the alternatively-spliced MUC1/X protein isoform from which the tandem repeat array is deleted. After immunization and hybridoma formation, anti- MUC1 a/β junction antibodies were selected. Results: DMC209 monoclonal antibodies uniquely specific for the MUC1 a/β junction were generated. The antibodies specifically bind the MUC1 a/β junction on full-length MUC1 expressed by breast and ovarian cancer cells, and on MUC1-positive malignant plasma cells of multiple myeloma. To demonstrate that anti-MUC1 a/β junction antibodies kill malignant cells, immunotoxin conjugates were formed with anti-MUC1 a/β junction polyclonal antibodies generated in our cDNA/protein immunization protocol and PE38, a powerful pseudomonas exotoxin. The antibody-exotoxin conjugates were potently cytocidal to MUC1-expressing malignant cells. Significantly, cell killing was abrogated by addition of soluble MUC1/X protein, highlighting that the cell-killing immunotoxin gains cell entry via the MUC1 a/β junction. Conclusions: The MUC1 a/β junction has been identified as an important cell-tethered MUC1 epitope against which highly specific antibodies can be generated capable of killing MUC1-expressing cells. These studies point to effective anti-MUC1-based immuno-therapeutic strategies. No significant financial relationships to disclose.
Pendelluft Detection Using Electrical Impedance Tomography in an Infant. Keep Those Images in Mind
Authors: Felipe S. Rossi, Eduardo L. V. Costa, Daniela D. M. Iope, Pedro H. D. Pacce, Camila Cestaro, Luisa Z. Braz, Albert Bousso, Marcelo B. P. Amato
Journal: American Journal of Respiratory and Critical Care Medicine (2019)
Using the Coronary Calcium Score to Guide Statin Therapy: A Cost-Effectiveness Analysis
Authors: Mark J Pletcher, Stephanie R Earnshaw, Reto Auer, Kathryn A Phillips, Philip Greenland, Michael Pignone
Journal: Circulation (2012)

Author(s): Pletcher, Mark J; Earnshaw, Stephanie R; Auer, Reto; Phillips, Kathryn A; Greenland, Philip; Pignone, Michael
Enhanced Efficacy of the SYK Inhibitor Entospletinib and Chemotherapy in Infant Acute Lymphoblastic Leukemia
Authors: Joseph Patrick Loftus, Anella Yahiaoui, Feng Shen, David Lopez, Igor Mikaelian, Patrick A Brown, Stacey Tannheimer, Ann Forslund, Sarah K Tasian
Journal: Blood (2017)
Abstract 13084: Left Atrial Deformation is Impaired After Epirubicin-based Chemotherapy In Patients With Breast Cancer
Authors: Maria Florescu, Lucia Stefania Magda, Dan Jinga, Oana Aurelia Enescu, Diana Mihalcea, Berenice Maria Suran, Mircea Cinteza, Dragos Vinereanu
Journal: Circulation (2011)

Subclinical impairment of LV deformation in patients with breast cancer, treated with epirubicin, was demonstrated previously, but data on left atrial (LA) function are lacking. Therefore, we inves...
Abstract 492: Spatial overlap analysis of myeloid and T cell compartments identifies distinct subgroups in the cohort of selected colorectal primary tumors
Authors: Natalie Zwing, Marta Canamero, Fabien Gaire, Konstanty Korski
Journal: Cancer Research (2019)

Abstract The immune contexture of colorectal cancer (CRC) tumors classifies clinically relevant immune subtypes that are extensively studied. Recent developments in digital computational pathology supporting spatial characterization of tumor immune infiltrate allow more comprehensive analysis of relevant cell to cell interactions. Leveraging that methodology in the current study, we tried to address the question how the distribution of myeloid cells in the tumor microenvironment (TME) of CRC affects the effector functions and distribution of cytotoxic T cells. We applied multicolored immunohistochemistry to identify monocytic (CD11b/CD14) and granulocytic (CD11b/CD15) myeloid cell populations together with proliferating and non-proliferating cytotoxic T cells (Ki67/CD8). Through automated object detection and image registration using HALO software (IndicaLab), we measured the extent of overlap between the areas occupied by myeloid and T cells. Subsequently, we correlated it with other parameters such as CD8 T cell proliferation ratio, amount of necrosis, MMR status, tumor mutational burden and CMS classes. With this approach, we identified distinct categories of CRC based on the myeloid - T cell overlap irrespective of the MMR status. These categories reflect certain functional areas in the TME and correlate with specific gene signatures that mainly include T effector and memory together with myeloid inflammatory and immunosuppressive signatures. Our results emphasize the importance of analyzing spatial organization of immune infiltrate in TME and shed a new light on myeloid and T cell interactions in CRC. The approach we used has a potential to be applied in immunotherapy related biomarker studies. Citation Format: Natalie Zwing, Marta Canamero, Fabien Gaire, Konstanty Korski. Spatial overlap analysis of myeloid and T cell compartments identifies distinct subgroups in the cohort of selected colorectal primary tumors [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 492.
Abstract 650: Gut microbiota population may be used to predict chemotherapeutic responsiveness in triple negative breast cancer
Authors: Alaa Bawaneh, Adam S. Wilson, Kenysha YJ Clear, Akiko Chiba, Katherine L. Cook
Journal: Cancer Research (2019)

Abstract Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and predominately affects young and minority women. TNBC is characterized by a high recurrence rate, with about 34% of TNBC patients relapsing around 2.6 years. This type of breast cancer lacks targeted therapy options and is limited to chemotherapy treatment options. The purpose of our study was to determine whether gut microbiota populations correlate with chemotherapeutic responsiveness and may be a predictive biomarker of outcome. Moreover, we want to determine the impact of targeting the microbiome on chemotherapy efficacy. In this study, 8-week old female BALB/c mice were injected with TNBC 4T1-luciferase cells into their L4/5 mammary fat pad. Once tumors developed, mice were either untreated (control group), treated with 1 x weekly 2.5 mg/kg IV doxorubicin (DOX), or treated with doxorubicin + antibiotics (mixture of streptomycin, ampicillin, and colistin in the drinking water to ablate host bacterial populations). Tumors were collected at the end of the study. Fecal samples were collected at time point 0 weeks (T0; before therapy when tumors were approximately 100 mm3) and time point 4 weeks (T4; after treatment). We subdivided the doxorubicin treated group into DOX-responders (tumors stopped growing or shrank) or DOX-nonresponders (tumors continued to grow on treatment). Tumors from the DOX-responders and DOX + antibiotics groups were significantly smaller and mice from these groups displayed reduced lung weight, suggesting decreased lung metastatic burden. 16S-bacterial sequencing analysis was performed on breast tumor tissue and feces. We demonstrate that at T0, elevated fecal Ruminococcus correlates with DOX-nonresponsiveness. Furthermore, at T4, we show increased fecal abundance of Oscillospira and Bacteroidales are associated with better therapeutic outcome. Protein analysis of primary 4T1 breast tumor tissue indicate a significant elevation of apoptosis (cleaved caspase-3 protein levels) in DOX-responders and DOX + antibiotic treated mice. We also stained breast tumor tissue and lung tissue for bacteria to confirm presence of microbiota by immunohistochemistry. Taken together our data demonstrates that chemotherapy efficacy is modulated by the microbiome. Moreover, fecal microbiota populations could be used as a predictive biomarker of chemotherapeutic responsiveness and suggests that modulation of the gut microbiome through dietary or probiotic interventions may affect therapeutic outcomes. Citation Format: Alaa Bawaneh, Adam S. Wilson, Kenysha YJ Clear, Akiko Chiba, Katherine L. Cook. Gut microbiota population may be used to predict chemotherapeutic responsiveness in triple negative breast cancer [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 650.
Healthcare implications of Clodtridium difficile infection after bone marrow transplant: Nationwide Readmission Database review.
Authors: Mohamed Hegazi, Eman Elsabbagh
Journal: Journal of Clinical Oncology (2019)

e18538 Background: Clostridium difficile infection (CDI) is a common complication following hematopoietic stem cell transplant in adults and is associated with substantial morbidity, and mortality. Despite this association, the first 90 days readmission rates and characteristics are poorly characterized. Objective: Utilizing the Nationwide Readmission Database (HCUP-NRD); we intended to analyze rates, predictors and hospitalization cost of CDI readmission after Hematopoietic Stem Cell Transplant (HSCT) in adults. Methods: Adult patients admitted after HSCT with at least 3 months of follow-up were included for analysis using administrative claim codes for CDI in the 2014 Nationwide Readmission Database. According to HSCT type, patients were stratified to either Umbilical Cord Blood Transplant (UCBT) or Bone Marrow Transplant (BMT) (autologous and allogenic). We subsequently evaluated for CDI readmission by day 90. Results: A total of 17,412 adult patients met the inclusion criteria, including 1.3 % that received UCBT, 98.7% that received BMT. All-causes readmission rate was 32.7% (5695/17412) and CDI readmission rate was 7.9% (450/5695). The median age was 60 years, 56.2% were male, median length of stay was 8 days and the median time lapsed after transplant discharge and CDI readmission was 28 days. The most common payer was private insurance at 57.6%. The median cost per CDI admission was $62,125 with net total cost $15.3 million. Conclusions: (1) CDI 90-day readmission rate among adult patients treated with HSCT is a significant morbidity and associated with considerable cost. (2) Further studies are warranted to evaluate factors that can contribute to decreased rate of CDI readmissions following HSCT.
Positive Predictive Values and Potential Success of Suicide Prediction Models—Reply
Authors: Bradley E. Belsher, Derek J. Smolenski, Larry D. Pruitt
Journal: JAMA Psychiatry (2019)

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Carnitine palmitoyl transferase 1A deficiency in an adult with recurrent severe steato hepatitis aggravated by high pathologic or physiologic demands: A roller-coaster for internists
Authors: Prasit Phowthongkum, Kanya Suphapeetiporn, Vorasuk Shotelersuk
Journal: Clinical and Molecular Hepatology (2019)

We would like to present an interesting case